Clinical trial NCT01524679
Conditions: Chronic Hepatitis B
Keywords: chronic hepatitis B
Sponsor: Johannes Gutenberg University Mainz
Start date: 2012-08-01; Completion date: 2017-08-28
Enrollment: 170 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A prospective, randomised, open-label phase IIb clinical trial assessing the effect of pegylated interferon alfa-2a(Pegasys®) 180 μg once weekly for 48 weeks added to an ongoing nucleos(t)ide based treatment in patients with chronic HBeAg-negative hepatitis B

The primary objective of the trial is to investigate whether the add-on of pegylated interferon alfa-2a to a continued treatment with nucleos(t)ide analogues increases the percentage of patients who have significant decrease (≥ 1log10) of HBs antigen after 48 weeks.

170 Patients with chronic hepatitis B, HBe antigen negative, already being treated with an oral antiviral regimen and having a nondetectable viral load for at least 12 months are included.

Detailed description:

Arms: arm 1: pegylated interferon alfa-2a (Pegasys®) 180 μg once weekly for 48 weeks added to an ongoing nucleos(t)ide based treatment in patients with chronic HBeAg-negative hepatitis B arm 2: ongoing nucleos(t)ide based treatment alone
Interventions: intervention 1: Pegylated interferon alfa-2a plus nucleos(t)ide(s)
Intervention descriptions: intervention 1: Pegylated interferon alfa-2a, s.c. 180 μg 1x/wk in addition to nucleos(t)ide(s)

Protocol documents:
Prot_000.pdf: 
PADD-ON 
EudraCT No: 2011-002812-10 
CONFIDENTIAL
1 of 44 
A prospective, randomised, open-label phase IIb clinical trial 
assessing the effect of pegylated Interferon alfa-2a (Pegasys®) 
180 µg once weekly for 48 weeks in addition to an ongoing 
nucleos(t)ide based treatment on quantitative HBsAg levels in 
patients with chronic HBeAg-negative hepatitis B 
PADD-ON 
Peg-interferon ADDed to an Ongoing Nucleos(t)ide based treatment in patients with 
chronic hepatitis B to induce decrease of HBs antigen  
EudraCT No: 2011-002812-10 
Sponsor trial code: PADD-ON 
Roche code: ML 27787 
Final Version 2.0- Date 19.04.2013 
Sponsor
Coordinating/Principal investigator 
University Medical Center of the 
Johannes Gutenberg-University Mainz 
represented by the executive board of the University 
represented by the scientific member of the executive board 
Univ.-Prof. Dr. Dr. R. Urban 
Univ.-Prof. Dr. U. Förstermann 
Department/    
institution 
I. Medizinische Klinik und   
Poliklinik      
Name 
Univ.-Prof. Dr. med. M. Schuchmann 
Univ.-Prof. Dr. med. P. R. Galle 
Address 
 Langenbeckstr. 1, 55131 Mainz 
Phone 
+49 (0)6131 17 7104 7275 
Fax 
+49 (0)6131 17 2728 5595 
e-Mail 
schuchm@uni-mainz.de
peter.galle@unimedizin-mainz.de 
Operating institution of Sponsors
Biometrician
Department/ 
institution 
I. Medizinische Klinik und   
Poliklinik represented by the director 
Name 
Univ.-Prof. Dr. med. P.R. Galle 
Address 
Langenbeckstr. 1, 55131 Mainz 
Phone    
+49 (0)6131 177275 
Fax       
    +49 (0)6131 175595 
e-Mail 
 peter.galle@unimedizin-mainz.de 
Department/    
Institution           Interdisciplinary Centre for Clinical 
trials (IZKS) Mainz        
Name 
 
D. Wachtlin 
Address 
Langenbeckstr. 2, 55131 Mainz 
Phone 
+49 (0)6131 179921 
Fax 
+49 (06131) 179914 
e-Mail 
 
wachtlin@izks-mainz.de 
This protocol is a confidential information and is intended solely for the guidance of the clinical 
trial. This protocol may not be disclosed to third parties not associated with the clinical trial or used 
for any other purpose without the prior written consent of the sponsor. 


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List of abbreviations 
AE 
 
Adverse event 
AFP  
 
alpha-fetoprotein 
ALT  
 
alanine aminotransferase 
AMA 
 
anti-mitochondrial antibody 
AMG 
 
German drug law (Arzneimittelgesetz) 
ANA 
 
anti-nuclear antibody 
ANC  
 
absolute neutrophil count 
ANCA  
Anti-neutrophil cytoplasmic antibody 
APC 
 
antigen presenting cell 
AST  
 
aspartate aminotransferase 
BMD   
bone mineral density 
BUN  
 
blood urea nitrogen 
CHB  
 
chronic hepatitis B 
CPK  
 
creatine phosphokinase 
CK  
 
creatinine Kinase 
CPT  
 
Child-Pugh-Turcotte 
CRF 
 
Case report form 
CV 
 
Curriculum vitae 
CT  
 
Computed Tomography 
dATP   
deoxyadenosine triphosphate 
DF  
 
disoproxil fumarate 
DMSO  
Dimethyl sulfoxide 
DNA  
 
deoxyribonucleic acid 
DSMB  
Data safety monitoring board 
EC/IEC  
Ethics committee/Independent ethics committee 
e-CRF  
Electronic case report form 
ECG  
 
Electrocardiogram 
EEG  
 
electroencephalogram 
EMEA   
European Medicines Evaluation Agency 
ETV  
 
Entecavir 
EU  
 
European Union 
FDA  
 
(U.S.) Food and Drug Administration 
FSI 
 
First subject in 
FTC  
 
Emtricitabine 
g 
 
g-force 
Gamma-GT 
gamma-glutamyl transferase 
GCP 
 
Good clinical practice 
GCP-V  
GCP regulation 
HBeAb  
hepatitis B e antibody 
HBeAg  
hepatitis B e antigen 
HBsAg   
hepatitis B surface antigen 
HBV  
 
hepatitis B virus 
HCC  
 
hepatocellular carcinoma 
HCV  
 
hepatitis C virus 
HDL 
 
high density lipoprotein 
HDV  
 
hepatitis D virus 
HIV  
 
human immunodeficiency virus 
HLA 
 
human leukocyte antigen 
ICH 
 
International conference on harmonization of technical requirements for registration of  
 
 
pharmaceuticals for human use 
IFN 
 
interferon 
IgG 
 
immunglobulin G 
IL-2 
 
interleukin 2 
IMP 
 
Investigational medicinal product 
IRB 
 
Institutional review board 
ISRCTN 
International standard randomised controlled trial number 
INN 
 
International nonproprietary name 
INR  
 
international normalized ratio 


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ISF 
 
Investigator site file 
IUD  
 
intra-uterine device 
IV  
 
Intravenous 
LAM  
 
lamivudine 
LBW  
 
lean body weight 
LDH  
 
lactate dehydrogenase 
LDL 
 
low density lipoprotein 
LFT  
 
liver function test 
LKP 
 
Clinical Trial Director according to AMG (Leiter der Klinischen Prüfung) 
LLN  
 
Lower limit of normal 
LSI 
 
Last subject in 
LSO 
 
Last subject out 
MedDRA 
Medical dictionary for regulatory activities terminology 
MELD   
Model for End Stage Liver Disease 
mITT 
 
Intention to treat 
MRI  
 
magnetic resonance image 
Non-IMP 
Non investigational medicinal product 
NSAID  
Nonsteroidal anti-inflammatory drugs 
Nuc 
 
nucleos(t)ide analogon 
PBMC  
Peripheral blood mononuclear cells 
PCR  
 
polymerase chain reaction 
PE  
 
physical examination 
Peg 
 
pegylated 
Peg-IFN  
Pegylated interferon alfa-2a 
PO  
 
oral administration (per os, by mouth) 
PT  
 
prothrombin time 
QD  
 
once daily 
RNA  
 
ribonucleic acid 
rpm 
 
rounds per minute 
RPMI  
Roswell Park Memorial Institute medium 
RR 
 
Response Rate 
rt  
 
reverse transcriptase 
SAE 
 
Serious adverse event 
SAP 
 
Statistical analysis plan 
SC  
 
subcutaneous 
SDV 
 
Source data verification 
SLA 
 
anti-soluble liver antigen antibody 
SMA 
 
anti-smooth muscle antibody 
SOC 
 
standard of care 
SPC 
 
Summary of product characteristics 
SUSAR 
Suspected unexpected serious adverse reaction 
TDF  
 
tenofovir DF, tenofovir disoproxil fumarate 
TID  
 
three times a day 
TMF 
 
Trial master file 
TNF 
 
tumor necrosis factor 
T-regs  
regulatory T-cells 
ULN  
 
upper limit of the normal range 
US  
 
United States 
 
 
 


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Synopsis 
 
Title 
A prospective, randomised, open-label phase IIb  clinical trial assessing the effect of 
pegylated interferon alfa-2a (Pegasys®) 180 µg once weekly for 48 weeks in addition to 
an ongoing nucelos(t)ide based treatment on quantitative HBsAg levels in patients with 
chronic HBeAg-negative hepatitis B 
Short title 
PADD-ON 
Peg-interferon ADDed to an Ongoing Nucleos(t)ide based treatment in patients with 
chronic hepatitis B to induce decrease of HBs antigen  
EudraCT No 
2011-002812-10 
Sponsor trial code 
PADD-ON 
Roche code 
ML 27787 
Indication 
Chronic viral hepatitis B, HBe-antigen negative 
Phase 
Phase IIb 
Treatments 
Test product: Pegylated interferon alfa-2a, s.c. 180 µg once per week in addition to 
nucleos(t)ide(s) 
Reference therapy: Nucleos(t)ide therapy  
Primary objective 
The primary objective of the trial is to investigate whether the add-on of pegylated 
interferon alfa-2a to a continued treatment with nucleos(t)ide analogues increases the 
percentage of patients who have significant decrease (≥1log10) of HBs antigen after 48 
weeks. 
Secondary objectives 
 
To evaluate safety and tolerability of pegylated interferon alfa-2a when combined 
with tenofovir, entecavir, lamivudine, adefovir, or a combination of lamivudine or 
entecavir with adefovir or tenofovir 
o 
Adverse events 
o 
Vital signs, physical examination 
o 
Laboratory test abnormalities 
o 
Laboratory test value changes over time 
 
To identify biological variables predicting HBs antigen decrease:  
o 
viral genotype 
o 
time course of HBs antigen level  
 
Scientific objectives 
 
To determine the effect of pegylated interferon on frequency and functional 
properties of HBV-specific cytotoxic and regulatory T-cells in responder and 
nonresponder patients  
 
To identify potentially predictive biomarkers 
Trial design 
Prospective, randomised, open-label 
Trial population 
Main inclusion criteria: 
Subjects meeting all of the following criteria will be considered for enrolment to the trial: 
 
Chronic hepatitis B, HBe antigen negative  
 
Treatment with a stable oral antiviral treatment (not containing telbivudine) and a 
fully suppressed viral load for at least 12 months (below limit of detection in 
conventional HBV-PCR assays, e.g. <116 copies / mL or <20 IU/mL) 
 
18-70 yrs 
 
willingness and ability to give informed consent and to follow study procedures 
 
willingness to use adequate contraception 
Main exclusion criteria: 
Subjects presenting one of the following criteria will not be enrolled in the trial: 
 
contraindications against treatment with pegylated interferon, e.g. depression, 
uncontrolled epilepsy, autoimmune diseases, pregnancy, leukocytopenia or 
thrombocytopenia at screening, etc.  
 
active alcohol or drug abuse 
 
preexisting polyneuropathy 
Trial duration and dates 
First subject in: July September 2012 
Last Subject In: July 2013 December 2014 
Last subject out: June 2014 November 2015 (end of follow-up January 2015 May 2016) 
Duration of the trial 30 44 months


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Number of subjects 
It is planned to enrol 170 subjects 
Number of sites 
10-16-25 trial sites are planned to participate. 
Primary endpoint 
The primary endpoint is the objective response after 48 weeks of combination therapy. 
The response is defined as a confirmed reduction of ≥1log10 in HBs antigen compared to 
baseline. 
Secondary endpoints 
 
Decline of quantitative HBs antigen at week 12 and 24 
 
Rate of patients with at least 10% HBs antigen loss at week 24 compared to 
baseline  
 
HBsAg seroconversion defined as percentage of subjects who become HBsAg 
negative and anti-HBs positive during the observation period 
 
Safety and tolerability of pegylated interferon alfa-2a when added to a continuing 
treatment with tenofovir, entecavir, lamivudine, adefovir, or a combination of 
those:  Analysis of adverse events and laboratory data. 
 
HBs antigen levels at all measurement times 
Statistical analysis 
The response rates will be compared between the treatment groups by Fisher’s exact 
test. The primary analysis population is the modified Intention to treat population 
comprising all randomised patients for which the primary endpoint can be assessed. 
Further supportive analyses are planned (Per Protocol Analysis, Logistic Regression with 
relevant covariates). 
 
Secondary endpoints will be analysed using appropriate methods depending on the scale 
of the respective parameter. Analyses of secondary endpoints will be interpreted 
descriptively. 
 
Safety:  
Frequencies of subjects experiencing at least one adverse event (AE) will be displayed 
by body system and preferred term according to MedDRA terminology.  A subject listing 
of AEs will be prepared. 
Listings will be prepared for each laboratory measure and will be structured to permit 
review of the data per subject as they progress on treatment. 
Summary tables will be prepared to examine the changes of laboratory measures over 
time. Additionally, shift tables will be provided to examine the changes of laboratory data 
from normal baseline to values outside the corresponding reference range during/after 
treatment. 
 


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Flow chart – Treatment group (Pegasys® + nucleos(t)ide) 
 
 
Visit 1 
Visit 2 
Visit 
3 
Visit 
4
 
Visit 
5 
Visit 
6
 
Visit 
7
 
Visit 
8 
Visit 
9
 
Visit 
10
 
Visit 
11 
Visit 
12
 
Visit 
13
 
Visit 
14 
Visit 
15 
Screening 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
EoT 
EoFU 
Week  
-4 to 0 
Week 0 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Week 
72 
Informed consent  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 Lead ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virology 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver assessment 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug screening, urinalysis 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy screening 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
Randomisation 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination
1 
C 
T 
T 
T 
T 
T 
T 
T 
T 
T 
T 
T 
T 
C 
C 
AEs
2, concomitant med. 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Routine laboratory tests
3 
III 
I 
I 
I 
II 
I 
I 
II 
I 
I 
I 
I 
I 
II 
II 
HBV-PCR 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
x 
x 
HBs antigen / anti-HBs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Immunology
4 
 
x 
x 
x 
 
 
 
 
 
 
 
 
 
x 
 
Bio-
5  and genetic markers
6 
 
x
5,6 
x
5 
x
5 
x
5 
 
 
x
5 
 
 
x
5 
 
 
x
5 
x
5 


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Flow chart – Control group (nucleos(t)ide only) 
 
Visit 1 
Visit 2 
 
 
Visit 
3 
 
 
Visit 
4 
 
 
Visit  
5 
 
 
Visit  
6 
Visit  
7 
Screening 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
EoT 
EoFU 
Week  
-4 to 0 
Week 0 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Week 
72 
Informed consent  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 Lead ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virology 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver assessment 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug screening, urinalysis 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy screening 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
Randomisation 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination
1 
C 
T 
 
 
T 
 
 
T 
 
 
T 
 
 
C 
C 
AEs
2, concomitant med. 
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
Routine laboratory tests
3 
III 
I 
 
 
II 
 
 
II 
 
 
I 
 
 
II 
II 
HBV-PCR 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
x 
x 
HBs antigen / anti-HBs 
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
Immunology
4 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Bio-
5  and genetic markers
6 
 
x
5,6 
 
 
x
5 
 
 
x
5 
 
 
x
5 
 
 
x
5 
x
5 


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Footnotes: 
1. Virology: HCV, HDV, HIV testing; HBe Ag, anti-HBe, anti-HBc 
2. Physical examination: “C” is a complete physical examination. “T“ is a targeted physical examination including measurements of vital signs, 
and evaluation of organ systems particularly associated with adverse event(s) symptoms. 
3. For patients with early withdrawal from medication, the End of follow-up visit is at 24 weeks after the End of treatment visit.  
I = erythroctes, hemoglobin, hematocrit, platelets, total leukocytes and differential, AST, ALT, total bilirubin, gamma-GT, alkanine 
phostphatase, total bilirubin (and conjugated bilirubin if total bilirubin is >1.5 x ULN), LDH, sodium, potassium, calcium, creatinine (and 
calculated clearance), blood urea nitrogen (BUN), uric acid, glucose, PT, INR 
II = erythroctes, hemoglobin, hematocrit, platelets, total leukocytes and differential, AST, ALT, total bilirubin, gamma-GT, alkanine 
phostphatase, total bilirubin (and conjugated bilirubin if total bilirubin is >1.5 x ULN), LDH, sodium, potassium, calcium, creatinine (and 
calculated clearance), blood urea nitrogen (BUN), uric acid, glucose, PT, INR, albumin, TSH, fT3, fT4 
III = erythroctes, hemoglobin, hematocrit, platelets, total leukocytes and differential, AST, ALT, total bilirubin, gamma-GT, alkanine 
phostphatase, total bilirubin (and conjugated bilirubin if total bilirubin is >1.5 x ULN), LDH, sodium, potassium, calcium, creatinine (and 
calculated clearance), blood urea nitrogen (BUN), uric acid, glucose, PT, INR, albumin, TSH, fT3, fT4, AFP, IgG, ANA, SMA, SLA, LKM, 
AMA, ANCA, ferritin, lipid profile (triglycerides, total cholesterol, HDL, LDL), HLA typing, urinalysis 
4. Immunology/Immune monitoring: Blood samples (50 mL each) for PBMC purification and immune monitoring  
5. Biomarkers: blood samples of 15-20 mL each, serum samples to be stored at -80 °C 
6.  Genetic Markers: 2 vials of 2 mL EDTA blood to be frozen in liquid nitrogen and stored at -80°C. 


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Treatment algorithm 
 


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Table of Contents 
 
1 
INTRODUCTION .................................................................................................................... 12 
1.1 
Scientific background ....................................................................................................... 12 
1.2 
Trial rationale ................................................................................................................... 13 
1.3 
Treatments and rationale for dose selection .................................................................... 13 
1.4 
Summarized risk-benefit assessment .............................................................................. 13 
2 
TRIAL OBJECTIVES .............................................................................................................. 14 
2.1 
Primary objective.............................................................................................................. 14 
2.2 
Secondary objectives ....................................................................................................... 14 
2.3 
Scientific objectives .......................................................................................................... 14 
3 
TRIAL DESIGN ...................................................................................................................... 14 
3.1 
Trial duration and schedule .............................................................................................. 14 
3.2 
Number of subjects .......................................................................................................... 15 
3.3 
Primary endpoint .............................................................................................................. 15 
3.4 
Secondary endpoints ....................................................................................................... 15 
3.5 
Measures taken to minimize/avoid bias ........................................................................... 15 
3.5.1 
Randomisation ....................................................................................................... 15 
3.5.2 
Blinding ................................................................................................................... 16 
3.6 
Selection and withdrawal of subjects ............................................................................... 16 
3.6.1 
Inclusion criteria ..................................................................................................... 16 
3.6.2 
Exclusion criteria .................................................................................................... 16 
3.6.3 
Withdrawal criteria .................................................................................................. 18 
3.6.4 
Premature closure of trial sites ............................................................................... 18 
3.6.5 
Premature closure of the clinical trial ...................................................................... 18 
4 
TRIAL TREATMENTS ............................................................................................................ 19 
4.1 
Investigational treatments ................................................................................................ 19 
4.1.1 
General information about investigational medicinal product (IMP) ....................... 19 
4.1.2 
Therapeutic effects ................................................................................................. 20 
4.1.3 
Special warnings and precautions for use .............................................................. 20 
4.1.4 
Known side effects of pegylated interferon alfa-2a................................................. 20 
4.1.5 
Dosage schedule .................................................................................................... 21 
4.1.6 
Treatment interruptions .......................................................................................... 21 
4.1.7 
Overdose instruction .............................................................................................. 22 
4.1.8 
Dose Adjustment for adverse reactions.................................................................. 22 
4.1.9 
Treatment assignment ............................................................................................ 22 
4.1.10 
Treatment after the end of the trial ......................................................................... 22 
4.1.11 
Packaging and labelling ......................................................................................... 22 
4.1.12 
Drug storage, supplies and accountability .............................................................. 23 
4.1.13 
Procedures for monitoring subject compliance ....................................................... 23 
4.2 
Not permitted medication ................................................................................................. 23 
5 
TRIAL SCHEDULE ................................................................................................................ 23 
6 
TRIAL METHODS .................................................................................................................. 26 
6.1 
Assessment of efficacy .................................................................................................... 27 
6.2 
Assessment of safety ....................................................................................................... 27 
6.2.1 
Adverse events ....................................................................................................... 27 
6.2.1.1 
Definitions .......................................................................................................... 27 
6.2.1.2 
Assessment of AEs by investigator .................................................................... 29 
6.2.1.3 
Period of observation ......................................................................................... 30 
6.2.1.4 
Documentation of AEs and Follow up ................................................................ 30 
6.2.1.5 
Immediate reporting of SAEs by investigator ..................................................... 31 
6.2.1.6 
Immediate Reporting of pregnancy by investigator ............................................ 31 
6.2.1.7 
Safety evaluation and Reporting by sponsor ..................................................... 31 
6.2.1.8 
Emergency procedures ...................................................................................... 32 


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6.2.2 
Other safety data .................................................................................................... 32 
6.3 
Other assessments .......................................................................................................... 32 
6.3.1 
Immune monitoring ................................................................................................. 32 
6.3.2 
Bioinformatic analysis of genetic markers .............................................................. 32 
6.3.3 
Other biomarkers .................................................................................................... 32 
6.3.4 
Prior and concomitant illnesses .............................................................................. 32 
6.3.5 
Prior and concomitant treatments........................................................................... 32 
7 
STATISTICS .......................................................................................................................... 33 
7.1 
Sample size ..................................................................................................................... 33 
7.2 
Analysis populations ........................................................................................................ 33 
7.3 
Efficacy analyses ............................................................................................................. 33 
7.3.1 
Definition and analysis of primary endpoint ............................................................ 34 
7.3.2 
Analysis of secondary endpoints ............................................................................ 34 
7.3.3 
Analysis of Subgroups ............................................................................................ 34 
7.3.4 
Interim analyses ..................................................................................................... 34 
7.4 
Analysis of adverse events .............................................................................................. 34 
7.5 
Analysis of clinical laboratory findings .............................................................................. 35 
8 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................................. 35 
8.1 
Requirements for investigational sites and staff ............................................................... 35 
8.2 
Direct entries .................................................................................................................... 35 
8.3 
Direct access to source data/documents ......................................................................... 35 
8.4 
Investigator site file and archiving .................................................................................... 35 
8.5 
Monitoring ........................................................................................................................ 36 
8.6 
Inspection by authorities and audits ................................................................................. 36 
8.7 
Audits ............................................................................................................................... 36 
9 
DATA MANAGEMENT ........................................................................................................... 36 
9.1 
Responsibilities ................................................................................................................ 36 
9.2 
Data collection ................................................................................................................. 36 
9.3 
Data handling ................................................................................................................... 37 
9.4 
Storage and archiving of data .......................................................................................... 37 
10 
ETHICAL AND LEGAL ASPECTS ......................................................................................... 37 
10.1  Good clinical practice ....................................................................................................... 37 
10.2  Patient information and informed consent ........................................................................ 38 
10.3  Confidentiality .................................................................................................................. 38 
10.4  Responsibilities of investigator ......................................................................................... 38 
10.5  Approval of trial protocol and substantial amendments ................................................... 39 
10.6  Continuous information to independent ethics committee/ institutional review board ...... 39 
10.7  Submission to local regulatory/competent authorities ...................................................... 39 
10.8  Independent data monitoring committee (IDMC) ............................................................. 39 
10.9  Insurance ......................................................................................................................... 39 
10.10 Agreements ...................................................................................................................... 40 
10.10.1 
Financing of the trial ............................................................................................... 40 
10.10.2 
Report ..................................................................................................................... 40 
10.10.3 
Publication policy .................................................................................................... 40 
11 
SIGNATURES ........................................................................................................................ 41 
12 
DECLARATION OF INVESTIGATOR .................................................................................... 42 
13 
REFERENCES ....................................................................................................................... 43 
 
 


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1 INTRODUCTION 
1.1 Scientific background 
Nucleos(t)ides are very successful in avoiding disease progression in patients with chronic 
hepatitis B by suppressing HBV-DNA replication. However, in most patients this requires long-term 
medication of undefined length. HBsAg seroconversion as a marker for endogenous immunological 
control is observed only in a minority of these patients, even under a long-term nucleos(t)ide 
therapy12, and it almost never occurs in HBe-Ag negative hepatitis B2. 
This calls for more effective treatment regimens to achieve immunological control within a defined 
treatment duration. 
An acute hepatitis B is effectively controlled in more than 95% of cases by the immune system. 
The “innate immunity” is the first and decisive mechanism as it activates specific cellular immune 
responses3. However, if this response fails, the immune system switches to a more or less anergic 
state, which allows chronic replication. Several parts of the immune system have been shown to be 
affected in chronic infection: HBV antigen-specific CD4+ T-cells are less active against viral 
antigens4, intrahepatic CD8+ T-cells in general are functionally impaired5, the expression of 
“programmed death-1”(PD-1)-receptors on lymphocytes is increased6, and the number of 
CD4+CD25+Foxp3+ T-cells (T-regs), is higher, leading to suppression of the specific immune 
response7. In addition, it was reported that HBs antigen directly inhibits antigen-presentation of 
professional APCs like macrophages8. 
The peripheral quantitative HBs antigen correlates with the amount of intracellular cccDNA which is 
the latent reservoir of HBV-DNA inside the hepatocytes. Some data show that HBsAg levels can 
be reduced by long-term nucleos(t)ide treatment910, with the newer drugs being more effective11.  
Interestingly, it was shown that treatment with nucleos(t)ide analogues partly restores the number 
of hepatitis B-specific CD4+ T-cells12. Most recent data further support the idea that viral load 
reduction re-increases immunological function of the innate immune system13 and decreases PD-1 
and PD-L1 expression on HBV-specific T-cell populations14. 
Interferon is known to be even more effective in reducing HBsAg15. It acts via induction of several 
proteins, which stimulate innate and adaptive immunity16. Effectivity of interferon seems to be 
higher if pre-treatment levels of IFN Type I response genes and proteins are not already elevated 
in chronic infection.  
The faster the decline of quantitative HBs antigen under interferon treatment, the more often an 
HBsAg seroconversion was observed in the subsequent time17. The assessment of this decline 
may therefore be used to decide at an early time point which patient will profit from interferon 
treatment18.  
The potency of both interferon and modern nucleos(t)ide analogues to reduce HBsAg levels is 
suggestive to combine both substances. Previous trials using this combination were not 
successful, but in these studies, less potent nucleos(t)ides were used, and were always started at 
the same time as interferon19,20, although it is known that it usually takes several months until HBV-
DNA is completely suppressed. A recently published trial combined adefovir or lamivudine with 
peg-interferon but extended treatment duration for up to 96 months, reaching high rates of HBsAg 
seroconversion of 30% with lamivudine and 24% with adefovir21.   
Recently, a combination of peg-interferon and telbivudine showed the rate of HBsAg reduction is 
markedly more rapid with the combination than either drug alone. Unfortunately, the combination 
arm had increased rates of peripheral neuropathy; thus the study was terminated prematurely22. 
Pilot data 
We monitored HBsAg levels of twelve patients who had decided to receive additional peg-
interferon alfa-2a as an individualized therapy. Nine patients were male, mean age was 44 (range 
25-60) years. Three patients were HBeAg positive. Cirrhosis was histologically proven in four 


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patients. Current treatment comprised lamivudine (one patient), lamivudine plus adefovir (two 
patients), entecavir (seven patients), or entecavir plus tenofovir (two patients). When starting 
additional interferon treatment, viral load had already been undetectable for an average of 24.6 
(range 10-57) months. Mean baseline HBsAg was 4,695 (range 16-15,120) IU/ml and was 
negatively correlated with time of complete viral suppression (correlation coefficient: - 0.234). 
In two patients HBsAg continuously declined by -2.6log10 and -3.58log10 to week 28 and 36 as 
compared to baseline. The slope started in week 8 and 16, respectively. The first patient was 
HBeAg negative, was infected with genotype D, had a very low initial HBsAg level, and HBV had 
already been suppressed by entecavir for 27 months. HBsAg dropped down to 0.04 U/l. The 
second patient was HBeAg-positive, infected with genotype A, and HBV was fully suppressed for 
ten months with entecavir plus tenofovir. She had an HBeAg seroconversion at week 24 and even 
developed anti-HBs of 10 U/l at week 32. In all other patients quantitative HBsAg only decreased 
by 0.07 log10 (range 0.01 - 0.25 log10) over 8-24 weeks of combination therapy (mean 16 weeks), 
and therefore, interferon was stopped. Side effects were comparable to interferon monotherapy30.  
1.2 Trial rationale 
In patients with HBeAg negative hepatitis B decrease or loss of HBs antigen occurs only rarely 
during therapy with either nucleos(t)ide analogues or interferon, even if  suppression of viral 
replication (as indicated by an undetectable HBV-DNA) is achieved. As there are no known means 
to induce immune control of HBV yet, these patients often need long-time medication for many 
years.  
The rationale of this trial is to assess whether, in patients with chronic HBeAg-negative hepatitis B, 
the addition of pegylated interferon alfa-2a to an ongoing therapy with nucleos(t)ide analogues 
increases the percentage of patients who have a significant decrease (≥ 1log10) of HBs antigen 
after 48 weeks. This might then predict loss of HBsAg in the future and the option to terminate 
antiviral therapy. 
1.3 Treatments and rationale for dose selection 
Patients in the treatment group and in the control group will continue their oral medication with 
lamivudine, adefovir, entecavir, tenofovir or a combination thereof. In addition, patients in the 
treatment group will receive 180 µg of pegylated interferon alfa-2a once weekly for 48 weeks. The 
dosing and duration of the interferon therapy are the same as recommended for a monotherapy of 
chronic hepatitis B.  
Due to the increased neurotoxicity of pegylated interferon alfa-2a when combined with telbivudine 
in a previous study, use of telbivudine is not allowed. 
Previous studies on monotherapy with pegylated interferon have shown that decrease of HBs 
antigen after 12 to 24 weeks can be predictive of HBs antigen loss or seroconversion and may thus 
be used to determine treatment failure at an early timepoint. However, most of the patients in those 
studies had HBeAg positive hepatitis B. The kinetics of HBs antigen decrease in HBeAg negative 
patients might be different. In addition, the effect of the treatment with nucleos(t)ide analogues, 
especially when started months or years before, is unknown.  
To account for these factors, interferon therapy in this trial should continue for 48 weeks in all 
patients in the treatment group independent of the occurrence of HBs antigen decrease or loss.  
1.4 Summarized risk-benefit assessment 
The effectiveness as well as possible risks and side effects of both pegylated interferon alfa-2a and 
nucleos(t)ide analogues are well described.  
Side effects of interferon can be very disagreeable and, in the case of uncontrolled hematologic 
alterations, even dangerous; nevertheless in most cases these side effects resolve within a few 
months of the termination of interferon treatment. More severe side effects with a lasting impact on 
patients’ health (e.g. contribution to the development of autoimmune disease, lasting depression) 
are rare.  


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Oral antiviral agents, nucleoside and nucleotide analogues that are used in the treatment of 
hepatitis B, are usually well tolerated. However, they must be taken regularly, and, in most cases, 
over a course of many years or even life-long. Risks of this kind of therapy are on the one hand 
side the possible development of resistance mutations, and on the other side effects that might 
develop over many years (e.g. nephropathy or osteoporosis).  
In recent years, interferon-alfa has been used in combination with different nucleos(t)ide analogues 
in the setting of clinical trials, and for the combination with lamivudine or adefovir no significant 
additional toxicity or interactions were noted19-21,23. A study using a combination of peg-interferon 
with telbivudine however had to be terminated because of a higher incidence of polyneuropathy in 
the treatment group22. Therefore, patients on telbivudine treatment will not be included into this 
study, and all patients will be closely monitored for adverse events, especially for the development 
of polyneuropathy.  
In summary, we feel that the prospect that a combination therapy might reduce HBsAg and 
ultimately lead to a loss of HBsAg in some patients, thereby allowing for them to stop all antiviral 
therapy (and the associated long-term side effects), compensates for the possible risks.  
The investigators will be informed about any relevant or new findings related to combined therapy 
of peg-interferon and antiviral agents. 
2 TRIAL OBJECTIVES 
2.1 Primary objective 
The primary objective of the trial is to investigate whether the add-on of pegylated interferon alfa-
2a to a continued treatment with nucleos(t)ide analogues increases the percentage of patients who 
have significant decrease (≥1 log10) of HBs antigen after 48 weeks.  
2.2 Secondary objectives 
The secondary objective(s) of the trial are  
 
To evaluate the safety and tolerability of pegylated interferon alfa-2a when combined with 
tenofovir, entecavir, lamivudine, adefovir, or a combination of those, 
o Adverse Events (classified into mild/moderate/severe) 
o Tolerability, vital signs and physical examination 
o Laboratory test abnormalities 
o Laboratory test value changes over time 
 
To identify biological variables predicting HBs antigen decrease, e.g.: 
o viral genotype 
o time course of HBs antigen level  
2.3 Scientific objectives 
 
To determine the effect of pegylated interferon on the frequency and functional properties of 
HBV-specific cytotoxic and regulatory T-cells in responder and non-responder patients  
 
To identify potentially predictive biomarkers 
3 TRIAL DESIGN 
3.1 Trial duration and schedule 
The overall duration of this trial is expected to be 24 44 months. The subject recruitment is 
proposed to start in January September 2012 and end in June 2012 December 2014.  
There will be an individual screening period of approximately 4 weeks. After randomisation, the 
treatment period will take 48 weeks. Follow-up will continue for another 24 weeks.  


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The actual overall trial duration or subject recruitment period may vary from this time period. 
 
 
3.2 Number of subjects 
It is planned to enrol 170 subjects in the clinical trial, i.e. 114 subjects in the treatment group and 
56 subjects in the control group. Recruitment and treatment of subjects are expected to be 
performed in 10-16-25 trial centers.  
3.3 Primary endpoint  
The primary endpoint is the objective response after 48 weeks of combination therapy. The 
response is defined as a confirmed reduction of ≥1log10 in HBs antigen compared to baseline. 
3.4 Secondary endpoints 
 
Decline of quantitative HBs antigen at week 12 and 24  
 
Rate of patients with at least 10% HBs antigen loss at week 24 compared to baseline 
 
HBsAg seroconversion defined as percentage of subjects who become HBsAg negative 
and anti-HBs positive during the observation period 
 
Safety and tolerability of pegylated interferon alfa-2a when added to a continuing treatment 
with tenofovir, entecavir, lamivudine, adefovir, or a combination of those:  Analysis of 
adverse events and laboratory data. 
 
HBs antigen levels at all measurement times 
3.5 Measures taken to minimize/avoid bias 
3.5.1 Randomisation  
Subjects will be randomised after checking if all inclusion criteria are met and no exclusion criterion 
is met. Randomisation will be done in a 2:1 ratio (Pegylated interferon alfa-2a in addition to 
nucleos(t)ide(s) vs. Nucleos(t)ide therapy) using block randomisation stratified by HBsAg at 
screening (<20.000 IU/mL vs. ≥20.000 IU/mL). Randomisation lists will be generated at IZKS 
Mainz by means of a SAS program. The randomisation list will be kept in safe and confidential 
custody at IZKS Mainz. 
A web based randomisation tool developed by IZKS Mainz will be used within this trial allowing 
investigators to randomise patients via a secure web interface. Role specific access rights and the 
need to confirm all details necessary for stratified randomisation (HBsAg at screening (<20.000 
IU/mL vs. ≥20.000 IU/mL) are incorporated within the tool and will reduce the risk of misuse and 


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unintended randomisations. The randomisation tool will not be released for use within the study 
before all components implemented specifically for the trial have been sufficiently tested. 
3.5.2 Blinding 
This trial is an open controlled trial. Blinding of patients and study personal would be challenging 
because pegylated interferon alfa-2a is administered as subcutaneous injection. The lack of 
blinding is less problematic in this trial, since the primary endpoint is not prone to subjective 
influence.  
3.6 Selection and withdrawal of subjects 
No subject will be allowed to enrol in this trial more than once. 
Enrolled patients who discontinue from the trial before intake of at least one dose of study 
medication will be replaced. 
3.6.1 Inclusion criteria 
Subjects meeting all of the following criteria will be considered for admission to the trial: 
 
Chronic hepatitis B, HBe antigen negative, confirmed by documented positive HBs antigen 
for > 6 months 
 
Treatment with a nucleos(t)ide regimen (lamivudine, adefovir, entecavir, tenofovir or one of 
the following combinations: lamivudine/adefovir, lamivudine/tenofovir, entecavir/adefovir or 
entecavir/tenofovir) and a fully suppressed viral load for at least 12 months (below limit of 
detection in conventional HBV-PCR assays, e.g. <116 copies/mL or <20 IU/mL) 
 
Quantitative HBsAg value available at least 180 days prior to screening 
 
HBsAg ≥1000 100 IU/mL   
 
Normal retinal finding on fundoscopy within 6 months prior to Day 1 (baseline) 
 
18-70 years 
 
Ability of subject to understand character and individual consequences of clinical trial 
 
Signed and dated informed consent of the subject must be available before start of any 
specific trial procedures. 
 
Women of childbearing potential have to be practicing a medically accepted contraception 
during trial and a negative pregnancy test (serum or urine) should be existent before trial. 
3.6.2 Exclusion criteria 
Subjects presenting with any of the following criteria will not be included in the trial: 
 
HBe antigen positive Hepatitis B 
 
Co-infection with HCV, HDV or HIV – as based on positive serology or PCR 
 
Ongoing antiviral treatment with telbivudine 
 
Contraindications against treatment with pegylated interferon, e.g. severe depression, 
epilepsy, autoimmune diseases, pregnancy, leukocytopenia or thrombocytopenia at 
screening, etc.  
 
Preexisting polyneuropathy 
 
Histologically proven liver cirrhosis, Decompensated liver disease, or history of 
decompensated liver disease, as evidenced by ascites, portal hypertension, jaundice or 
hepatic encephalopathy, coagulopathy, varices, history of varicose bleeding, or any other 
clinical evidence of decompensation. (Patients with stable liver cirrhosis are eligible for this 
study, if a history of decompensated liver disease as outlined above has been excluded.) 
 
History of alcohol or drug abuse other than cannabis within the past 12 months. Patients 
with documented drug and alcohol addiction free history of at least 12 months who are, in 
the opinion of the investigator, unlikely to relapse, may be enrolled in the study.  


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 
Body mass index < 18 or > 35 kg/m2 
 
Usage of any investigational drugs within 12 3 months before enrolment; or the planned 
usage of an investigational drug during the course of the current study 
 
Known hypersensitivity to any ingredient of the study drugs 
 
A condition that is defined as one which in the opinion of the investigator may put the 
patient at risk because of participation in the study or may influence the results of the study 
or the patient’s ability to participate in the study. 
 
Active malignancy or history of malignancy within the last 5 years (with the exception of 
appropriately treated basal cell carcinoma of the skin or in situ carcinoma of the uterine 
cervix). Suspected but yet unproven hepatocellular carcinoma. 
 
Alpha fetoprotein value >100 ng/mL at screening; if > 20 ng/mL and ≤ 100 ng/mL, patients 
can be included if there is no evidence of liver cancer in an appropriate imaging study (e.g., 
ultrasound, CT scan, MRI) within past 6 months of Day 1. 
 
Total bilirubin >2 x ULN with ratio of direct/indirect > 1 (Patients with Gilbert’s syndrome are 
not excluded.) 
 
ALT or AST level >3 x ULN 
 
Prothrombin time INR (Institutional Normalised Ratio) prolonged to >1.5 
 
Hemoglobin < 11.5 g/dL for women and < 12.5 g/dL for men 
 
White blood cell count < 2,000 cells/mm3 
 
Absolute neutrophil count < 1,500 cells/mm3 
 
Platelet count < 90,000 cells/mm³ 
 
TSH, fT3 and fT4 outside normal limits and no adequately controlled thyroid function; 
patients with TSH below the lower limit of normal may be enrolled if free T4 is normal and 
there is no clinical evidence of hyperthyroidism or hypothyroidism. 
 
Poorly controlled diabetes mellitus as evidenced by HbA1c > 7.5%  
 
Hemoglobinopathy (e.g., thalassemia major or sickle cell anemia) 
 
History of moderate, severe or uncontrolled psychiatric disease, especially depression, 
including a history of hospitalisation or prior suicidal attempt; patients with a history of mild, 
stable depression may be enrolled provided that a pre-treatment assessment of the 
patient’s psychiatric disease supports that the patient is clinically stable.  
 
Clinical evidence of chronic cardiac disease (e.g., coronary artery disease, congestive heart 
failure, uncontrolled hypertension, significant arrhythmia) 
 
Clinically significant abnormalities on screening ECG 
 
Clinical evidence of chronic pulmonary disease (e.g., chronic obstructive pulmonary 
disease) associated with functional impairment 
 
Active autoimmune disease, including autoimmune hepatitis 
 
Organ transplant history, other than cornea or hair 
 
Active seizure disorder within the past 2 years; patients may be enrolled if on stable 
medication and seizures have not been experienced for more than 2 years before 
enrolment. 
 
Requirement for chronic systemic corticosteroids (nasal or pulmonary steroids will be 
allowed) 
 
Pregnancy and lactation 
 
Medical or psychological condition that would not permit completion of the trial or signing of 
informed consent 


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3.6.3 Withdrawal criteria 
Subjects can withdraw their consent at their own request without given reasons at any time during 
the trial. This should be without any disadvantages for the subject. However the investigator should 
try to perform a final visit to get concluding findings of investigation. 
In addition, subjects may be withdrawn from the trial for the following reasons 
 
At their own request. 
 
If, in the investigator’s opinion, continuation of the trial would be detrimental to the subject’s 
well-being. 
 
For women, if it becomes known that the subject is pregnant. 
 
If development of a toxicity or adverse event warrants drug discontinuation. 
 
If polyneuropathy develops and is confirmed by a neurologist, withdrawal will be discussed 
according to severity of the symptoms  
 
If the Patient has to take any concomitant drug interfering with the study medication 
 
If the Patient needs any excluded concomitant medication (see chapter 4.2) 
 
If Patient is no longer able to participate for other medical reasons (e.g., surgery, adverse 
events, pregnancy or other diseases). 
In all cases, the reason for withdrawal must be recorded in the CRF and in the subject’s medical 
records. In case of withdrawal of a subject at his/her own request, if possible the reason should be 
asked for and documented. The subject must be followed up and if possible, all examinations 
scheduled for the final trial day should be performed and documented.  
For patients with early withdrawal from medication, the End Follow up visit is at 24 weeks after the 
End of Treatment visit. For patients with a detectable VL in the End of Follow-up visit after negative 
VL in the previous visits, an independent confirmatory measurement of viral load is required. 
If a patient is withdrawn from the study prior to Visit 2 (Baseline at week 0), only data with regard to 
demographics, AEs and concomitant medications will be captured and reported. 
Lost to follow-up:  
A patient will be considered lost to follow-up if the investigator is not able to contact him despite 
multiple attempts (at least 2 telephone contacts plus 1 mailing). Any patient who prematurely 
discontinues from the study at any time must have their appropriate visit eCRF pages completed. If 
the patient terminates the trial early, Visit 14 or 6 (end of treatment) and the Trial completion Form 
must be completed (cf. section 5, End of follow-up). If the patient terminates the trial early and 
does not return for Visit 14, the Trial Completion from should be completed explaining the reason.  
3.6.4 Premature closure of trial sites 
Trial sites may be closed at any time during the trial at the discretion of the sponsor. Reasons for 
premature closing of a trial center include: 
 
Major protocol violations 
 
Violations of legal and ethical regulations (GCP) 
 
Poor recruitment 
 
Non-compliance of investigator. 
3.6.5 Premature closure of the clinical trial 
The following reasons the whole trial may be discontinued at the discretion of the sponsor: 
 
New risks for subjects become known. 
 
Inefficacy of the trial medication becomes evident. 
 
Occurrence of AEs unknown to date in respect of their nature, severity, and duration or the 
unexpected increase in the incidence of known AEs. 


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 
Medical or ethical reasons affecting disadvantageous the continued performance of the 
trial. 
 
Difficulties in the recruitment of subjects. 
The ethic committees (EC) and the competent authorities must then be informed. Should the trial 
be closed prematurely, all trial material (completed, partially completed, blank CRF, randomisation 
envelopes, investigational medicinal products, etc.) must be returned to the sponsor or fetched by 
the monitor. 
4 TRIAL TREATMENTS  
4.1 Investigational treatments 
Pegylated interferon alfa-2a (Pegasys®) (IMP): 
The treatment group will receive pegylated interferon alfa-2a (Pegasys®) 180 µg s.c. once weekly 
for 48 weeks.  
The initial dose will be given in the clinic. Subjects will be taught self-administering injections at the 
baseline visit, and will be encouraged to self-administer all subsequent doses. Alternatively, a 
trained caregiver may administer peg-IFN injections per investigator discretion.  
Patients will be instructed to return empty containers as well as unused study medication in the 
original packaging at each study visit. The investigators must instruct subjects on the safe storage 
and transport of used and unused syringes / PENs.  
Temporary interruptions of study drug(s) administration are discouraged; patients are to remain on 
treatment for the entire duration of the trial; and the dose of peg-IFN should not be changed during 
the trial, unless dose reduction is indicated because of laboratory abnormalities/adverse events 
(c.f. Section 4.1.8 for instructions for dose reduction). The patients must be counselled regarding 
the importance of not missing doses of peg-IFN. 
However, in the case that a patient does miss a dose, they should apply the next injection 
immediately. The following week, they are to proceed as below: 
 
If the peg-IFN injection was late by 1 or 2 days, the next dose should be administered on 
the usual day 
 
If the peg-IFN injection was late by 3-5 days, they should receive further injections every 5 
to 6 days until their usual day for peg-IFN injection is reached 
 
If the peg-IFN injection was late by 6 days, the next application will be on the next day (1 
dose is skipped) 
 
If the peg-IFN injection was late by ≥7 days, treatment can be restarted at any time by the 
investigator; if necessary, the following injections can be given at 5 or 6 day intervalls to 
achieve a convenient weekday  
The control group won’t receive pegylated interferon alfa-2a (Pegasys®) as add-on treatment. 
Basic treatment (Non-IMP): 
All patients are to continue their medication with lamivudine, adefovir, entecavir or tenofovir or a 
combination of those during the trial until at least the end of follow-up. The known dosing 
instructions, contraindications, side effects and risks for each drug must be taken into account 
according to the manufacturers’ recommendations. Regular laboratory and clinical assessments 
throughout the course of this study are to provide adequate monitoring of potential toxicities. 
4.1.1 General information about investigational medicinal product (IMP) 
International 
nonproprietary name 
(INN) 
Pegylated interferon alfa-2a 


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ATC Code 
L03A B11 
Formulation 
180 µg/ 0,5 ml- Solution for injection in pre-filled syringe / 
pre-filled pen for single use only  
 
Storage 
in the refrigerator at 2 °C to 8 °C (36 °F to 46 °F)  
Marketed Product 
Pegasys® 
Manufacturer 
Roche Pharma AG 
Ingredients 
sodium chloride , polysorbate 80 , benzyl alcohol (10 mg/ 1 
ml), sodium acetate , acetic acid , water for injections 
 
4.1.2 Therapeutic effects 
Pegylated recombinant human interferon alfa-2a is an inducer of the innate antiviral immune 
response. It stimulates the production of effector proteins such as serum neopterin and 2’, 5’-
oligoadenylate synthetase.   
The biological activity of pegylated interferon alfa-2a is derived from its recombinant human 
interferon α-2a moiety. Peginterferon alfa-2a binds to the human type 1 interferon receptor leading 
to receptor dimerization. Receptor dimerization activates multiple intracellular signal transduction 
pathways initially mediated by the JAK/STAT pathway. Given the diversity of cell types that 
respond to interferon α-2a, and the multiplicity of potential intracellular responses to interferon 
receptor activation, peginterferon alfa-2a is expected to have pleiotropic biological effects in the 
body.   
In the stable HCV cell culture model system (HCV replicon), ribavirin inhibited autonomous HCV 
RNA replication with an effective concentration (EC) value of 11-21 µm. In the same model, PEG-
IFN α-2a also inhibited HCV RNA replication, with an EC value of 0.1 - 3 ng/mL.  
4.1.3 Special warnings and precautions for use 
Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been 
observed in some patients during Pegasys® therapy, and even after treatment discontinuation 
mainly during the 6-month follow-up period. Other CNS effects including aggressive behaviour 
(sometimes directed against others such as homicidal ideation), bipolar disorders, mania, 
confusion and alterations of mental status have been observed with alpha interferons. Patients 
should be closely monitored for any signs or symptoms of psychiatric disorders. If such symptoms 
appear, the potential seriousness of these undesirable effects must be borne in mind by the 
prescribing physician and the need for adequate therapeutic management should be considered. If 
psychiatric symptoms persist or worsen, or suicidal ideation is identified, it is recommended that 
treatment with Pegasys® be discontinued, and the patient followed, with psychiatric intervention as 
appropriate. Patients with existence of, or history of severe psychiatric conditions: If treatment with 
Pegasys® is judged necessary in patients with existence or history of severe psychiatric conditions, 
this should only be initiated after having ensured appropriate individualised diagnostic and 
therapeutic management of the psychiatric condition.  
 
4.1.4 Known side effects of pegylated interferon alfa-2a 
Serious adverse events: 
Serious adverse events in hepatitis B and hepatitis C trials included neuropsychiatric disorders 
(homicidal ideation, suicidal ideation, suicide attempt, suicide, psychotic disorder and 
hallucinations), serious and severe bacterial infections (sepsis), bone marrow toxicity (cytopenia 
and rarely, aplastic anemia), cardiovascular disorders (hypertension, supraventricular arrhythmias 
and myocardial infarction), hypersensitivity (including anaphylaxis), endocrine disorders (including 
thyroid 
disorders 
and 
diabetes 
mellitus), 
autoimmune 
disorders 
(including 
idiopathic 
thrombocytopenic purpura, thrombotic thrombocytopenic purpura, psoriasis, lupus, rheumatoid 
arthritis and interstitial nephritis), pulmonary disorders (dyspnea, pneumonia, bronchiolitis 
obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis), colitis (ulcerative and 


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hemorrhagic/ischemic colitis), pancreatitis, ophthalmologic disorders (decrease or loss of vision, 
retinopathy including macular edema and retinal thrombosis/hemorrhages, optic neuritis and 
papilledema), pancytopenia (in combination with azathioprine), and peripheral neuropathy (in 
combination with telbivudine). 
Adverse reactions reported during post-approval use of  therapy with pegylated interferon alfa-2a 
include dehydration, hearing impairment, hearing loss, serious skin reactions, including erythema 
multiforme major, infections (bacterial, viral and fungal), and serous retinal detachment, and pure 
red cell aplasia. 
Most common adverse events: 
The most common adverse events reported for pegylated interferon alfa-2a and ribavirin 
combination therapy observed in clinical trials were fatigue/asthenia (65%), headache (43%), 
pyrexia (41%), myalgia (40%), irritability/anxiety/nervousness (33%), insomnia (30%), alopecia 
(28%), neutropenia (27%), nausea/vomiting (25%), rigors (25%), anorexia (24%), injection-site 
reaction (23%), arthralgia (22%), depression (20%), pruritus (19%) and dermatitis (16%). In clinical 
trials of 48-week treatment duration, the adverse event profile of pegylated interferon alfa-2a in 
chronic hepatitis B was similar to that seen in chronic hepatitis C pegylated interferon alfa-2a 
monotherapy use, except for exacerbations of hepatitis. The most common adverse events 
reported for pegylated interferon alfa-2a, observed in clinical studies, were pyrexia (54%), 
headache (27%), myalgia (26%), fatigue (24%), alopecia (18%) and anorexia (16%). 
Transient ALT elevations are common during hepatitis B therapy with pegylated interferon alfa-2a. 
Twenty-five percent and 27% of subjects experienced elevations of 5 to 10 x ULN and 12% and 
18% had elevations of >10 x ULN during treatment of HBeAg negative and HBeAg positive 
disease, respectively. Flares have been accompanied by elevations of total bilirubin and alkaline 
phosphatase and less commonly with prolongation of PT and reduced albumin levels. Eleven 
percent of subjects had dose modifications due to ALT flares and <1% of subjects were withdrawn 
from treatment. ALT flares of 5 to 10 x ULN occurred in 13% and 16% of subjects, while ALT flares 
of >10 x ULN occurred in 7% and 12% of subjects in HBeAg negative and HBeAg positive disease, 
respectively, after discontinuation of pegylated interferon alfa-2a therapy.  
Peripheral neuropathy has been reported when alpha interferons were given in combination with 
telbivudine. In one clinical trial, an increased risk and severity of peripheral neuropathy was 
observed with the combination use of telbivudine and pegylated interferon alfa-2a as compared to 
telbivudine alone. The safety and efficacy of telbivudine in combination with interferons for the 
treatment of chronic hepatitis B has not been demonstrated.  
For details of adverse reactions see Summary of Product Characteristics24. 
Contraindications: 
Pegylated interferon alfa-2a is contraindicated in patients with hypersensitivity to pegylated 
interferon alfa-2a or any of its components, autoimmune hepatitis, and hepatic decompensation 
(Child-Pugh score greater than 6; class B and C) in cirrhotic patients before or during treatment, 
with severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease in the 
previous six months. The combination of Pegasys® with telbivudine is also contraindicated.  
4.1.5 Dosage schedule 
In this trial the dosage and duration of Pegasys® is 180 micrograms once weekly for 48 weeks by 
subcutaneous administration in the abdomen or thigh which is consistent with the recommended 
dosage and duration for both HBeAg-positive and –negative chronic hepatitis B.  
4.1.6 Treatment interruptions 
Temporary interruptions of study drug(s) administration are discouraged; patients are to remain on 
treatment for the entire duration of the trial; and the dose of peg-IFN should not be changed during 
the trial, unless dose reduction is indicated because of laboratory abnormalities/adverse events 


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(c.f. Section 4.1.8 for instructions for dose reduction). The patients must be counselled regarding 
the importance of not missing doses of peg-IFN. 
4.1.7 Overdose instruction  
Overdoses involving between two injections on consecutive days (instead of weekly interval) up to 
daily injections for 1 week (i.e., 1260 micrograms/week) have been reported. None of these 
patients experienced unusual, serious or treatment-limiting events. Weekly doses of up to 540 and 
630 micrograms have been administered in renal cell carcinoma and chronic myelogenous 
leukaemia clinical trials, respectively. Dose limiting toxicities were fatigue, elevated liver enzymes, 
neutropenia and thrombocytopenia, consistent with interferon therapy. 
4.1.8 Dose Adjustment for adverse reactions 
When a Pegasys® dose modification is required for moderate to severe adverse reactions (clinical 
and/or laboratory), initial dose reduction to 135 μg should be performed. However, in some cases, 
dose reduction to 90 μg may be needed. 
Following improvement of the adverse reaction, re-escalation of the Pegasys® dose may be 
considered (refer to warnings, precautions, and adverse reactions in the Pegasys® medication 
guide). 
Hematological: 
Pegasys® Hematological Dose Modification Guidelines           
Laboratory Values 
Reduce Pegasys® Dose to: 
Discontinue Pegasys® if 
ANC   
 
 
 
  
≥750/mm3: Maintain 180 μg 
< 750/mm3: Reduce to 135 μg 
< 500/mm3: Treatment should be 
suspended 
until 
ANC 
values 
return to more than 1000/mm3 
Re-institute at 90μg and monitor 
ANC 
Platelet 
 
≥ 50.000/mm3: Maintain 180 μg 
< 50.000/mm3: Reduce to 90 μg 
<25.000/mm3 
Liver function: 
In patients with progressive or persistent ALT increases > 10 x ULN and >2 x baseline values, the 
dose of Pegasys® should be reduced to 135μg and more frequent monitoring of liver function 
should be performed. If ALT increases are further progressive despite dose reduction or 
accompanied by increased bilirubin or evidence of hepatic decompensation, therapy should be 
immediately discontinued. After Pegasys® dose reduction or withholding, therapy can be resumed 
after ALT flares subside. 
4.1.9 Treatment assignment 
The trial medication will be administered only to subjects included in this trial.  
Subjects withdrawn from the trial retain their identification codes (e.g. randomisation number). New 
subjects will always receive a new identification code. 
4.1.10 Treatment after the end of the trial 
After the end of the trial, patients who experienced a complete HBs-seroconversion (i.e. who 
become HBsAg negative and anti-HBs positive) will stop all antiviral therapy. For patients with HBe 
seroconversion a continuation of nucleos(t)ides for at least 6 months is recommended. HBeAg 
negative patients without HBs-seroconversion will continue therapy with nucleos(t)ides as 
previously. 
4.1.11 Packaging and labelling 
Packaging and labelling of trial medication will be conducted by Roche Pharma AG. 


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The trial medication will be labelled according to §5 GCP regulation.  
Pegylated interferon alfa-2a 180 µg (Pegasys®) is provided as 0,5 ml- Solution for injection in pre-
filled syringe / pre-filled pen for single use only. Each pre-filled syringe / pen is packed in a single 
covering box. 
IMP assignment and traceability as required by GCP-V § 5 (1) will be realised by accurate 
documentation of drug accountability and compliance on an accompanying document. 
4.1.12 Drug storage, supplies and accountability 
The investigator will take inventory and acknowledge the receipt of all shipments of the trial 
medication. All trial medication must be kept in a locked area with access restricted to designated 
trial staff.  
Pegasys® should be stored in the refrigerator at 2 °C to 8 °C (36 °F to 46 °F). Do not freeze or 
shake. Protect from light. Pre-filled syringes / pre-filled pens are for single use only. The 
investigator will also keep accurate records of the quantities of trial medication dispensed, used, 
and returned by each subject on the drug accountability form. 
The site monitor will periodically check the supplies of trial medication held by the investigator to 
verify the correct accountability of all trial medication used. At the end of the trial, all unused trial 
medication will be completely returned to Roche Pharma AG in case no other procedure is agreed.  
It will be assured that a final drug accountability report is prepared and maintained by the 
investigator. 
4.1.13 Procedures for monitoring subject compliance 
Trial medication will be dispensed to the subjects by the investigator.  
Subjects will be instructed to bring all trial medication to the trial site at every visit (including all 
empty containers and unused trial medication). Compliance will be assessed by counting of empty 
containers and unused medication. All empty containers will be disposed by the trial center after 
verification by the monitor. Details will be recorded in the CRF and on the drug accountability form 
in the investigator site file. 
4.2 Not permitted medication  
The following concomitant treatments are not permitted during the trial: 
 
Telbivudine 
 
Systemic corticosteroids, if used for longer than 14 days, or other immunsuppressive 
medications (e.g. cyclosporines, tacrolimus, methotrexate etc.) 
 
Systemic cytostatic chemotherapy 
 
Immune-modulating agents such as IL-2, anti-TNF-antibodies or rituximab 
 
Nephrotoxic agents such as aminoglycoside antibiotics, amphotericin B, foscarnet, 
ganciclovir, NSAID, or other agents with significant nephrotoxic potential 
 
Hepatotoxic agents such as anabolic steroids, isoniacid, itraconazole, ketoconazole, 
rifabutin, rifampin, or other agents with significant hepatotoxic potential 
If a subject needs treatment with any excluded concomitant medication, the sponsor should be 
consulted prior to the initiation of the new medication.  
All concomitant medication, including vitamin supplements and herbal remedies must be recorded.  
5 TRIAL SCHEDULE 
After patients have been informed about the trial, written informed consent in accordance with GCP 
and the local legislation must be obtained prior to any study related procedures taking place. 
Patients will be assigned a patient screening number which must be recorded in eCRF.  


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Screening (visit 1) should take place within 28 days before baseline (visit 2). Patients should 
undergo a re-screening (visit 1.1) if start of treatment is delayed to more than 28 days after Visit 1. 
Patients who have a laboratory test value outside the range specified by the inclusion criteria may 
have the test repeated to determine eligibility; however, the result must be available prior to Visit 2 
(Day 1). 
(Screening) Visit 1 (week -4 to -1) 
The following data will be obtained/checked and documented: 
 
Informed consent 
 
Evaluation of eligibility criteria  
 
Demographics:  Age (date of birth), gender, ethnic origin/nationality, height and body weight 
 
Medical History: Possible mode and assumed year of infection (perinatal, injection drug 
use, sexual, occupational, transfusion, unknown, other)  
 
Recording of concomitant medication 
 
Alcohol consumption (regular alcohol consumption, average number of units/drinks per day) 
 
Prior and concomitant medication for HBV: Standard interferon, pegylated interferon, 
nucleoside/nucleotide analogues: start of therapy, dosage regimen (start and end dose), 
cessation of therapy. In addition herbal drugs and vaccination for HBV 
 
HBV disease characteristics: HBV genotype (A-H) (if available) 
 
Complete physical examination, including measurement of vital signs  
 
12-lead resting-ECG measurement 
 
hepatic ultrasound or CT scan or MRI 
 
HBV-PCR 
 
HBs antigen  / anti-HBs 
 
Virology: 
o HBeAg, anti-HBe, anti-HBc  
o Samples for serological assessment of HBV genotype (if not available) 
o HCV, HDV, HIV testing 
 
Routine laboratory test (hematology and clinical chemistry III) 
 
Urine drug screening and urinalysis 
 
Urine pregnancy test for women of childbearing potential 
 
Liver assessment (if available): Results from liver biopsy and documentation of the 
histopathological scoring system used (e.g. METAVIR, Ishak, Knodell, Scheuer), and from 
non-invasive methods, e.g. liver elastography (specify kPa assessed by FibroScan). 
(Baseline) Visit 2 (week 0) 
If upon completion of screening and, if necessary, re-screening the patient has been determined 
eligible by the investigator to enter the trial, the patient will be randomised and assigned a 
randomisation number. For this, the investigator has to request the treatment allocation via a web-
based randomisation tool at Visit 2 (week 0). Sites must enter the treatment allocation on the 
appropriate eCRF pages.  
 
Targeted physical examination including vital signs 
 
Randomisation 
 
Routine laboratory tests (hematology and clinical chemistry I) 
 
HBs antigen / anti-HBs 
 
Samples for immunology 
 
Recording of AEs and concomitant medication  


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Start of treatment with pegylated interferon alfa-2a. Administration of first dose should be under the 
supervision of the investigator (or a designee) at the study center. This is to minimise dosing 
errors.  
Visit 5, 8, (week 12, 24) – treatment group 
Visit 3, 4  (week 12, 24) – control group 
 
Targeted physical examination  
 
Routine laboratory tests (clinical chemistry II) 
 
HBV-PCR  
 
HBs antigen / anti-HBs 
 
Urine pregnancy test for women of childbearing potential (Treatment group: visit 5, 8, 
control group: visit 4 only) 
 
Recording of AEs and concomitant medication  
Visit 3, 4, 6, 7, 9, 10, 11, 12, 13 (week 4, 8, 16, 20, 28, 32, 36, 40, 44) – treatment group 
Visit 5 (week 36) – control group 
 
Targeted physical examination 
 
Routine laboratory tests (clinical chemistry I) 
 
HBs antigen / anti-HBs 
 
Urine pregnancy test for women of childbearing potential (only treatment group: visit 11) 
 
Samples for immunology at week 4 and 8 for treatment group only 
 
Recording of AEs and concomitant medication  
(End of treatment) Visit 14 (week 48) – treatment group 
(End of treatment) Visit 6 (week 48) – control group 
 
Complete physical examination 
 
Routine laboratory tests (clinical chemistry II) 
 
HBV-PCR 
 
HBs antigen / anti-HBs 
 
Samples for immunology 
 
Urine pregnancy test for women of childbearing potential 
 
Recording of AEs and concomitant medication  
(End of follow-up) Visit 15 (week 72) - treatment group 
(End of follow-up) Visit 7 (week 72) - control group 
 
Complete physical examination  
 
Routine laboratory tests (clinical chemistry II) 
 
HBV-PCR 
 
HBs antigen / anti-HBs 
 
Recording of AEs and concomitant medication  
 
Trial completion form 
 


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6 TRIAL METHODS 
Physical examination 
Vital signs (body temperature, heart rate and blood pressure) and weight will be determined at 
every visit, height at screening only.  
Blood pressure measurement should be performed in a consistent manner after the patient has 
been sitting for five minutes. A manual cuff should be used on the same arm each time blood 
pressure is measured. 
Complete physical examinations will be performed at screening, Week 48, Week 72, and Early 
Discontinuation (if applicable). Symptom-directed physical examination will be performed at all 
other visits.  
As an increased incidence of polyneuropathy was observed during combination therapy with 
pegylated interferon alfa-2a and telbivudine, special attention should be paid to the development of 
polyneuropathy or other neurological symptoms in subjects on combination therapy. Investigators 
need to question patients about development of hyp- or dysesthesia, muscle weakness or any 
other neurological symptoms. If neurological symptoms occur, they need to be documented as 
adverse events, and the patients will then be referred to a neurologist for further examination.   
Ultrasound or CT scan 
All subjects must undergo hepatic ultrasound or CT scan or MRI to rule out HCC within 6 months 
before taking part in this study.  
 
Cardiologic Evaluations 
A standard 12-lead ECG will be performed at screening visit. 
Laboratory tests 
Blood samples will be collected and assessed as scheduled (see section 5).  
HBV-PCR, HBsAg and Anti-HBs are measured centrally at the department of clinical chemistry at 
University Medical Center of JoGu University Mainz (Zentrallabor der Universitätsmedizin Mainz). 
To this aim, samples of EDTA blood and serum (8-10 ml each) will be collected the trial site, frozen 
(- 80°C), and sent to Mainz via courier (overnight transport at room temperature).  
All other laboratory tests, including HBeAg, anti-HBe, anti-HBc, HCV, HDV, HIV testing, routine 
hematology, clinical chemistry, and urine screening tests (drug screening and urinalysis) will be 
performed locally in each study center by an accredited laboratory (accredition by the Zentralstelle 
der Länder für Gesundheitsschutz bei Arzneimitteln und Medizinprodukten). Urine pregnancy test 
for women of childbearing potential will be performed using commercially available tests at the trial 
site. 
Routine laboratory tests: 
I  
= erythrocytes, hemoglobin, hematocrit, platelets, total leukocytes and differential, AST, 
ALT, total bilirubin, gamma-GT, alkanine phostphatase, total bilirubin (and conjugated bilirubin if 
total bilirubin is >1.5 x ULN), LDH, sodium, potassium, calcium, creatinine (and calculated 
clearance), blood urea nitrogen (BUN), uric acid, glucose, PT, INR 
II 
= erythrocytes, hemoglobin, hematocrit, platelets, total leukocytes and differential, AST, 
ALT, total bilirubin, gamma-GT, alkanine phostphatase, total bilirubin (and conjugated bilirubin if 
total bilirubin is >1.5 x ULN), LDH, sodium, potassium, calcium, creatinine (and calculated 
clearance), blood urea nitrogen (BUN), uric acid, glucose, PT, INR, albumin, TSH, fT3, fT4 
III  
= erythrocytes, hemoglobin, hematocrit, platelets, total leukocytes and differential, AST, 
ALT, total bilirubin, gamma-GT, alkanine phostphatase, total bilirubin (and conjugated bilirubin if 
total bilirubin is >1.5 x ULN), LDH, sodium, potassium, calcium, creatinine (and calculated 
clearance), blood urea nitrogen (BUN), uric acid, glucose, PT, INR, albumin, TSH, fT3, fT4, AFP, 


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IgG, ANA, SMA, SLA, LKM, AMA, ANCA, ferritin, lipid profile (triglyceride, total cholesterol, HDL, 
LDL), HLA typing, urinalysis  
These laboratory studies include and surpass the manufacturers’ recommendations (summary of 
product characteristics) for the surveillance of patients receiving lamivudine, adefovir, entecavir or 
tenofovir, especially concerning the development of nephropathy.   
 
Additional tests 
Immune monitoring / Immunology 
Blood samples of 50 mL each for PBMC purification and immune monitoring should be acquired 
from all patients at specific time points. PBMC purification using Ficoll will be performed locally at 
each study center according to SOP of the sponsor. PBMC will be transported to Mainz on dry ice. 
Bioinformatic analysis of genetic markers 
In cooperation with a current study at our department at University Medical Center Mainz analysis 
of several genetic markers via microarray is planned in order to identify genes which may be 
associated with HBs antigen loss. For each patient 2 vials of 2 ml of EDTA-blood will be taken at 
baseline and frozen in liquid nitrogen and stored at -80°C. In addition, if available, histology 
samples (10 slices of 5 µm each) will be examined.   
Biomarkers 
Blood samples of15-20 mL each for further anaylsis of potentially predictive biomarkers will be 
collected at week 0, 4, 8, 12, 24, 36, 48 and 72 (treatment group) and 0, 12, 24, 36, 48 and 72 
(control group). Serum samples will be retained and stored at -80°C.  
 
6.1 Assessment of efficacy  
Biological markers of hepatitis B 
To address the primary objective of this study, the decline in quantitative HBsAg during 48 weeks 
of add-on therapy with peg-IFN versus nucleos(t)ides alone, quantitative HBs antigen will be 
measured every four or twelve weeks in the interferon or control arm, respectively. 
To evaluate secondary objectives: 
- 
Serological markers of Hepatitis B will be routinely tested as scheduled (quantitative HBs 
antigen, Anti-HBs, HBe antigen, Anti-HBe) as well as quantitative HBV-DNA and liver 
function tests.  
- 
Since a genomic analysis of the virus is not possible in patients with non-detectable HBV-
DNA serotypic determination of HBV type A-D will be performed25. This assay shows a 
coincident rate with genotyping of 95-100%.  
6.2 Assessment of safety  
6.2.1 Adverse events 
6.2.1.1 Definitions 
Adverse Event (AE) 
According to GCP, an adverse event (AE) is defined as any untoward medical occurrence in a 
subject treated with a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a medicinal investigational product, whether or not related to that product. 


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An AE may be: 
 a new symptom or medical condition 
 a new diagnosis 
 a change in laboratory parameters 
 an intercurrent illness or accident 
 worsening of a medical condition/diseases existing before the start of the clinical trial 
 recurrence of a disease 
 an increase in frequency or intensity of episodic diseases. 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required may be an AE. Planned surgical 
measures permitted by the clinical trial protocol and the condition(s) leading to these measures are 
not AEs, if the condition leading to the measure was present before inclusion in the trial. In the 
latter case the condition should be reported as medical history. 
Change in laboratory parameters: The criteria for determining whether an abnormal test finding 
should be reported as an adverse event are as follows: 
 Test result is associated with accompanying symptoms, and/or 
 Test result requires additional diagnostic testing or medical/surgical intervention, and/or 
 Test result leads to a change in trial dosing outside of protocol-stipulated dose adjustments, or 
discontinuation from the trial, significant additional concomitant drug treatment, or other therapy, 
and/or 
 Test result is considered to be an adverse event by the investigator or sponsor. 
Serious adverse event (SAE) 
A serious adverse event (SAE) is one that at any dose (including overdose): 
 results in death 
 is life-threatening1 
 requires subject hospitalization or prolongation of existing hospitalization² 
 results in persistent or significant disability/incapacity3 or 
 is a congenital anomaly/birth defect 
 is an important medical event4. 
1“Life-threatening” means that the subject was at immediate risk of death at the time of the serious 
adverse event; it does not refer to a serious adverse event that hypothetically might have caused 
death if it were more severe. 
2If the admission is pre-planned (i.e., elective or scheduled surgery arranged prior to start of the 
trial) or not associated with an adverse event (e.g., social hospitalisation for purpose) or results in a 
hospital stay less than 12 hours, the serious criterion “hospitalisation” is not fulfilled. However, it 
should be noted that invasive treatment during a hospitalisation may fulfil the criteria of “medically 
important” and may be reportable as a serious adverse event dependent on clinical judgement. 
3“Persistent or significant disability or incapacity” means that there is a substantial disruption of a 
person’s ability to carry out normal life functions. The irreversible injury of an organ function (e.g., 
paresis, diabetes, cardiac arrhythmia) fulfils this criterion. 
4Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in situations where none of the outcomes listed above occurred. 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 other outcomes listed in 
the definition above should also usually be considered serious. Examples of such events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
convulsions that do not result in subject hospitalization, or the development of drug dependency or 


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drug abuse. A diagnosis of cancer during the course of a treatment should be considered as 
medically important.  
Adverse Reaction (AR) 
An adverse reaction is any noxious and unintended response to an investigational medicinal 
product (the causal relationship between the medicinal product and the adverse event is at least a 
reasonable possibility).  
Serious Adverse Reaction (SAR) 
If there is a causal relationship between a serious adverse event and trial medication then the 
event is called serious adverse reaction (SAR). 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A SUSAR is a serious adverse reaction which is unexpected. 
An unexpected serious adverse reaction is any adverse reaction, the nature or severity of which is 
not consistent with the applicable product information (i.e., the current SPC).  
Clarification of the difference in meaning between "serious" and "severe": 
The terms “serious” and “severe” are not synonymous but are often used interchangeably. The 
term ‘severe’ is often used to describe the intensity (severity) of a specific event; the event itself, 
however, may be of relatively minor significance (such as severe headache). This is not the same 
as “serious”, which is based on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject’s life or functioning. Seriousness (not severity) serves as a 
guide for defining regulatory reporting obligations.” 
6.2.1.2 Assessment of AEs by investigator  
Subjects must be carefully monitored for adverse events by the investigator. The intensity of the 
adverse events and the causal relation to trial medication and/or procedures are to be assessed. 
Intensity 
The intensity of an AE will be assessed by the investigator as follows: 
Mild: 
 
Temporary event which is tolerated well by the subject and does not interfere with 
 
 
normal daily activities. 
Moderate: 
Event which results in discomfort for the subject and impairs his/her normal activity. 
Severe: 
Event which results in substantial impairment of normal activities of subject. 
Causal relation to trial medication/procedures 
The assessment of the relationship of an adverse event to the administration of study drug is a 
clinical decision based on all available information at the time of the completion of the case report 
form. The investigator will evaluate the causal relationship of each adverse event with the 
administration of the investigational product(s) and/or trial procedures according to modified criteria 
of WHO 1991. 
Certain: 
A clinical event, including laboratory test abnormalities, occurring in a 
plausible time relationship to drug administration, and which cannot be 
explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (dechallenge) should be clinically plausible. The event 
must be definitive pharmacologically or phenomenologically, using a 
satisfactory rechallenge procedure if necessary. 
Probable: 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, unlikely to be attributed to concurrent 


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disease or other drugs or chemicals, and which follows a clinically reasonable 
response on withdrawal (dechallenge). Rechallenge is not required to fulfil this 
definition. 
Possible: 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administrations of the drug, but which could also be explained by 
concurrent disease or other drugs or chemicals. Information on drug 
withdrawal may be lacking or unclear. 
Unlikely: 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable, and in which other drugs, chemicals or underlying disease provide 
plausible explanations. 
Not related: 
A clinical event, including laboratory test abnormality that does not follow a 
reasonable temporal sequence from trial participation and that is definitely 
caused by the subject’s clinical state, other modes of therapy or other known 
etiology. 
6.2.1.3 Period of observation 
In this trial, the period of observation for collection of adverse events extends from the time the 
subject has signed the informed consent document up to visit 15 of the treatment group or visit 7 of 
the control group (week 72, End of follow-up).  
If the investigator detects a serious adverse event in a trial subject after the end of the period of 
observation, and considers the event possibly related to the prior trial, he should contact the 
sponsor to determine how the adverse event should be documented and reported. 
6.2.1.4 Documentation of AEs and Follow up 
All AEs reported by the subject or detected by the investigator will be documented on the 
appropriate pages of the case report form (CRF). AEs must also be documented in the subject’s 
medical records.  
The following approach will be taken for documentation: 
 All adverse events (whether serious or non-serious) must be documented on the “Adverse 
Event” page of the CRF. 
 If the adverse event is serious (see Section 6.2.1.1), the investigator must complete, in addition 
to the “Adverse Event Page”, a “Serious Adverse Event Form” at the time the serious adverse 
event is detected. 
Every attempt should be made to describe the adverse event in terms of a diagnosis. If a clear 
diagnosis has been made, individual signs and symptoms will not be recorded unless they 
represent atypical or extreme manifestations of the diagnosis, in which case they should be 
reported as separate events. If a clear diagnosis cannot be established, each sign and symptom 
must be recorded individually. 
All subjects who have adverse events, whether considered associated with the use of the 
investigational products or not, must be monitored to determine the outcome. The clinical course of 
the adverse event will be followed up according to accepted standards of medical practice, until a 
satisfactory explanation is found or the investigator considers it medically justifiable to terminate 
follow-up, but not longer than EoFU. 
Should the adverse event result in death, a full pathologist’s report should be supplied, if possible. 
All questions on the completion and supply of adverse event report forms and any further forms 
issued to the investigator at a later date to clarify unresolved issues should be addressed to the 
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6.2.1.5 Immediate reporting of SAEs by investigator 
SAEs must immediately (within 24 hours of the investigator’s awareness) be reported to: 
IZKS Mainz 
Safety Management 
Langenbeckstr. 2 
55131 Mainz 
 
FAX-No.: 06131-17-9916 
The initial SAE Report should be as complete as possible including the essential details of 
subject’s identification (screening number, random number), the serious adverse event (medical 
term, diagnosis), the trial medication and the assessment of the causal relationship between the 
event and the trial medication. The SAE report must be reviewed and signed by the investigator.  
The investigator should provide related additional information on the clinical course and the 
outcome of each SAE as soon as possible (Follow up report). 
The “Serious Adverse Event Form” is provided in the Investigator Site File. 
The investigator should also inform the trial monitor in all cases.  
Worsening of a sign or symptom of the condition under treatment will normally be measured by 
efficacy parameters. However, if the outcome fulfils the definition of “serious adverse event”, it 
must be reported as such.  
6.2.1.6 Immediate Reporting of pregnancy by investigator 
Any pregnancy diagnosed in a female subject or in the female partner of a male subject during 
treatment with the investigational product must be reported immediately using the “Pregnancy 
Reporting Form” to: 
IZKS Mainz 
Safety Management 
Langenbeckstr. 2 
55131 Mainz 
 
FAX-No.: 06131-17-9916 
 
Pregnancy occuring during the clinical trial, although not considered a SAE, must be reported 
within the same timelines as a serious adverse event. The outcome of a pregnancy should be 
followed up carefully and abnormal outcome of mother or child should be reported if any. 
6.2.1.7 Safety evaluation and Reporting by sponsor 
The sponsor will ensure that all legal reporting requirements are met. According to GCP the 
sponsor is responsible for the continuous safety evaluation of the investigational product(s) and the 
clinical trial. 
On behalf of the sponsor IZKS Mainz will conduct the management of SAEs and the expedited 
reporting as required by German Drug Law (AMG) and GCP regulation (GCP-V). Suspected 
unexpected serious adverse reactions (SUSARs) and safety issues as defined by GCP-V are 
determined for expedited reporting: The competent authorities and the ethics committees should 
be notified as soon as possible but not later than 15 calendar days if the event is non-fatal and 7 
calendar days if it was fatal.  
All investigators will be informed too. The marketing authorization holder of the IMP (Roche 
Pharma AG) will also be informed. 
Work flow and procedures concerning SAE management will be described in a separate document 
(e.g. Safety manual). 


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During the clinical trial the sponsor will submit the annual safety report including a list of all serious 
adverse reactions to the ethics committee(s) and the competent authorities once a year. 
6.2.1.8 Emergency procedures 
During and following a subject’s participation in the trial, the investigator should ensure that 
adequate medical care is provided to a subject for any AEs including clinically significant laboratory 
values. The investigator should inform a subject when medical care is needed for intercurrent 
illness(es) of which the investigator becomes aware. There is no specific antidote or emergency 
treatment. Overdoses involving between two injections on consecutive days (instead of weekly 
interval) up to daily injections for 1 week (ie, 1260 micrograms/week) have been reported. None of 
these patients experienced unusual, serious or treatment-limiting events. Weekly doses of up to 
540 and 630 micrograms have been administered in renal cell carcinoma and chronic 
myelogenous leukaemia clinical trials, respectively. Dose limiting toxicities were fatigue, elevated 
liver enzymes, neutropenia and thrombocytopenia, consistent with interferon therapy. 
6.2.2 Other safety data 
All observations pertinent to the safety of the study medication will be recorded on the CRF and 
included in the final report. 
Safety variables are as follows: laboratory changes, changes in vital signs (blood pressure, heart 
rate and temperature) and, cardiologic evaluation by ECG. 
6.3 Other assessments 
6.3.1 Immune monitoring 
Immune control in chronically HBV infected patients is dependent on HBV specific T cells. In 
chronically HBV infected patients low frequencies of IFN-γ producing CD8+ cells between 0.02 and 
0.08% are observed, in contrast to patients after successful HBV clearance and immune control 
who develop significantly higher HBV specific T cell frequencies between 0.2 and 0.5%26,27. 
Moreover, CD8 T cell responses were more frequently observed in patients being able to control 
HBV replication after interruption of IFN treatment28. This observation indicates that T cell reactivity 
is essential for immune control of HBV infection and might be induced by IFN therapy.  
Therefore, we will include a close monitoring during the treatment course which will require blood 
samples at baseline and after 4, 8, and 48 weeks of pegIFN treatment and at baseline and week 
48 for the control group.  
6.3.2 Bioinformatic analysis of genetic markers 
In cooperation with a current study at our department at University medical Center Mainz analysis 
of several genetic markers via microarray is planned in order to identify genes which may be 
associated with HBs antigen loss.  
6.3.3 Other biomarkers 
Serum samples for further analysis of potentially predictive biomarkers will be acquired from all 
patients at week 0, 4, 8, 12, 24, 36, 48 and 72 (treatment group) and 0, 12, 24, 36, 48 and 72 
(control group).  
6.3.4 Prior and concomitant illnesses 
Relevant additional illnesses present at the time of informed consent are regarded as concomitant 
illnesses and will be documented on the appropriate pages of the case report form (CRF). 
6.3.5 Prior and concomitant treatments 
Relevant additional treatments administered to the subjects on entry to the trial or at any time 
during the trial are regarded as concomitant treatments und must be documented on the 
appropriate pages of the CRF. 


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7 STATISTICS  
Details of the statistical analysis of the data collected in this trial will be documented in a Statistical 
Analysis Plan (SAP) that will be generated by IZKS Mainz and finalized before closing the data 
base. The SAP is based on the protocol including all amendments. The document may modify the 
plans outlined in this protocol; however any major modifications of the primary endpoint definition 
and/or its analysis will also be reflected in a protocol amendment. Any deviation from the original 
statistical plan must be described and justified in the final report. The statistical analysis will be 
conducted by means of SAS®. 
7.1 Sample size 
Based on pilot data, it is assumed that 12% of the patients in the peg-IFN/Nuc group HBsAg will 
drop >1log10 after 48 weeks of combination therapy, while only 0.1% of the patients without 
additional interferon will reach this endpoint.  
Studies in hepatitis C patients reported of a discontinuation rate due to tolerability and safety of 
approximately 10-15%29. As this rate was observed in combination with ribavirin we assume a 
drop-out rate of 10% due to better tolerability and safety in hepatitis B patients.  
The assumed difference in HBsAg loss rates will be detected with a power of 80% by Fisher's 
exact test at a two-sided significance level of 5%, if 153 patients (102 in the interferon arm, 51 in 
the control arm) can be analysed. Taken into account a drop-out rate of 10%, 170 patients will be 
randomised. Patients with no HBs antigen measurement at week 48 will be analysed by their last 
HBs antigen measurement (last observation carried forward). This approach is considered slightly 
conservative but allows all randomised patients to be included into the confirmatory modified 
Intention to treat analysis. 
7.2 Analysis populations 
All subjects who signed informed consent / were assigned a randomisation number are considered 
as enrolled/randomised subjects, even if they did not receive any trial treatment.  
All subjects who received at least one dose of trial treatment and with at least one available post-
baseline assessment of the primary analysis variable will be included in the modified Intention-to-
treat (mITT) population. This population is the primary analysis population. Within mITT population 
analyses subjects will be assigned to the treatment to which they were randomised. 
 
To be eligible for the per protocol population, subjects must fulfil the following criteria: 
 No violation of inclusion criteria 
 Not meeting any exclusion criteria  
 No concomitant treatment with not permitted medication (see section 4.2) 
 Treatment compliance of at least 90% 
 Trial treatment as randomised 
 No deviation from planned visit schedules 
The safety population comprises all subjects who received at least one dose of trial treatment. In 
analyses of the safety population subjects will be assigned to the treatment which they actually 
received. 
7.3 Efficacy analyses 
The primary population for the analyses of efficacy is the mITT Population. 
All hypotheses will be tested on a two-sided level of significance α=0.05. 


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7.3.1 Definition and analysis of primary endpoint  
Null hypothesis: HBsAgRRInterferon = HBsAgRRControl  
Alternative hypothesis: HBsAgRRInterferon ≠ HBsAgRRControl 
 
HBsAgRR denotes HBs antigen response rates. The subscripts show the respective treatment 
group. 
 
The response rates will be compared between the treatment groups by Fisher’s exact test. The 
primary analysis population is the modified Intention to treat population comprising all randomised 
patients for which the primary endpoint can be assessed. 
 
The following supportive analyses are planned: 
The primary analysis (Fisher’s exact test) will be repeated for the Per Protocol Population. 
Furthermore, a logistic regression model including covariates assumed to predict treatment 
response (HBV genotype, age, sex, duration of antiviral therapy before the study) will be applied. 
 
In the primary analysis subjects with missing HBsAg measurements at week 48 will be analysed 
according to the last observation carried forward principle. This approach is considered slightly 
conservative but allows all randomised patients to be included into the confirmatory modified 
Intention to treat analysis. 
7.3.2 Analysis of secondary endpoints 
The primary analysis population for the secondary endpoints is the modified Intention to treat 
population. 
Secondary endpoints will be analysed using appropriate methods depending on the scale of the 
respective parameter. Analyses of secondary endpoints will be interpreted descriptively. 
7.3.3 Analysis of Subgroups 
Age, sex, HBV-Genotype, level of quantitative HBsAg, nucleos(t)ide regimen (substances, 
combination, duration) will be subject to subgroup analyses. 
7.3.4 Interim analyses 
There will be no interim analysis in the sense that the primary endpoint is analysed prematurely 
and a decision about the continuation of the study is derived. 
 
However, it is planned to compare the rates of patients with at least 10% HBsAg loss 24 weeks 
after the start of study treatment compared to baseline between the treatment groups as soon as 
these data are available. The analysis will be interpreted in an explorative manner. Therefore no 
adjustment of the significance level is required. 
 
The influence of this premature analysis on the primary analysis and the predictability of the results 
of the primary analysis based on the results of the premature analysis are expected to be limited 
for the following reasons:  
- 
The recruitment phase will be terminated at the time point of the premature analysis. 
- 
According to the expected accrual time, the analysis will be performed only around 16 
weeks before the end of treatment of the last patient. 
- 
The loss rates in the early response analysis (at least 10% HBsAg loss) and the primary 
analysis (reduction of at least 1log10 HBsAg) are defined differently. 
7.4 Analysis of adverse events 
All summaries and listings of safety data will be performed for the safety population.  
Frequencies of subjects experiencing at least one adverse event (AE) will be displayed by body 
system and preferred term according to MedDRA terminology. Detailed information collected for 
each AE will include: A description of the event, duration, whether the AE was serious, intensity, 


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relationship to trial drug, action taken, clinical outcome. Summary tables will present the number of 
subjects observed with AEs and corresponding percentages. Additional subcategories will be 
based on event intensity and relationship to trial drug.  
A subject listing of all AEs will be prepared. 
7.5 Analysis of clinical laboratory findings 
Listings will be prepared for each laboratory measure and will be structured to permit review of the 
data per subject as they progress on treatment. 
Summary tables will be prepared to examine the changes of laboratory measures over time. 
Additionally, shift tables will be provided to examine the changes of laboratory data from normal 
baseline to values outside the corresponding reference range during/after treatment. 
Changes in vital signs (blood pressure, heart rate and temperature) and, cardiologic evaluation by 
ECG will be analysed descriptively by distributional parameters (such as mean and standard 
deviation) or absolute and relative frequencies. 
8 QUALITY CONTROL AND QUALITY ASSURANCE  
8.1 Requirements for investigational sites and staff 
The investigator should be able to demonstrate (e.g. based on retrospective data) a potential for 
recruiting the required number of suitable subjects within the agreed recruitment period. 
The investigator should have sufficient time to properly conduct and complete the trial within the 
agreed trial period. 
The investigator should have available an adequate number of qualified staff and adequate 
facilities for the foreseen duration of the trial to conduct the trial properly and safely. 
The investigator should ensure that all persons assisting with the trial are adequately qualified, 
informed about the protocol, any amendments to the protocol, the trials treatments, and their trial-
related duties and functions. 
8.2 Direct entries 
Data entries be entered in the CRF as Direct, are listed in the Monitor Manual in the section source 
data control. 
8.3 Direct access to source data/documents  
The investigator/institution must permit trial-related monitoring and auditing by representatives of 
the sponsor, as well as inspections by the appropriate competent authorities and Ethics 
committees, providing direct access to source data/documents (Confidentiality see 10.3). 
The subjects will be informed that representatives of the sponsor, independent ethics committee 
(IEC) or competent authorities may inspect their medical records to verify the information collected, 
and that all personal information made available for inspection will be handled in strictest 
confidence and in accordance with local data protection laws. 
8.4 Investigator site file and archiving 
The investigator will be provided with an investigator site file (ISF) at the start of the trial. The 
investigator will archive all trial data and relevant correspondence in the ISF. The ISF, all source 
data and all documents will be kept filed according to the requirements of the German Drug Law 
and ICH-GCP guidelines after termination of the trial.  
 
It is the responsibility of the investigator to ensure that the subject identification lists are stored for 
at least 15 years beyond the end of the clinical trial. All original subject files must be stored for the 
longest possible time permitted by the regulations at the hospital, research institute, or practice in 


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question. If archiving can no longer be maintained at the site, the investigator will notify the 
sponsor. 
8.5 Monitoring 
Monitoring will be done by personal visits from a clinical monitor according to SOPs of the IZKS 
Mainz.  
To initiate the trial, the monitor will visit all participating local trial centers. The monitor shall ensure 
that the investigators and their staff understand all requirements of the protocol and their regulatory 
responsibilities. 
The monitor will ensure that the investigator will maintain a list of subinvestigators and other 
appropriately qualified persons to whom he or she has delegated significant trial-related duties 
(personnel log).  
Each site will be visited by the monitor at regular intervals to ensure compliance with the trial 
protocol, GCP and legal aspects. The monitor will review the entries into the CRFs for 
completeness and correctness and verify the entries on the basis of the source documents. The 
presence of correct informed consents will be checked for every subject.  
To close the trial, the monitor will visit all trial centres. 
Details will be specified in the monitoring manual for this trial. 
The investigator must allow the monitor to look at all relevant documents and must provide support 
at all times to the monitor. 
8.6 Inspection by authorities and audits 
Competent authorities and by the sponsor authorised persons (auditor) may request access to all 
source documents, CRF, and other trial documentation in case of an inspection or audit. Direct 
access to these documents must be guaranteed by the investigator who must provide support at all 
times for these activities. Source data documents can be copied during inspection or audit in case 
the identity of the subject have been made unrecognizable. 
8.7 Audits  
No audits are planned for this trial. 
9 DATA MANAGEMENT 
9.1 Responsibilities 
Clinical Data Management is conducted by IZKS Mainz according to SOPs. 
In case of discrepancies the data management team is authorised to directly contact the 
responsible person at the trial site. The queries will be implemented into the MACRO database. 
This will allow the trial sites to conduct data corrections more easily and it will also guarantee that 
the queries are filed to the corresponding variables in the database. The investigator has to agree 
the contact per e-mail or phone. 
A detailed methodology for the data management in this trial will be documented in a data 
management plan that will be dated and maintained by IZKS Mainz. This plan has to be signed by 
the sponsor, the head of the data management team and the responsible data manager. The 
document may modify the plans outlined in this protocol; however any major modifications of the 
data handling will also be reflected in a protocol amendment. 
9.2 Data collection 
This trial will be performed using an electronic case report form (eCRF). The investigator and the 
trial site staff will receive system documentation, training and support for the use of the eCRF. In 
case of new trial site staff the training can be performed by personnel of the trial site. 


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For data entry support the IZKS Mainz can be contacted. Each trial site has one responsible 
person who supports IZKS Mainz in the implementation of technical and organisational processes. 
A list of these persons is enclosed in the DMP. 
All protocol-required information collected during the trial must be documented in the eCRF by the 
investigator, or a designated representative. All data entry, modification or deletion will be recorded 
automatically in an electronic audit trail indicating the individual subject, the original value, the new 
value, the reason for change, who made the change and time and date of the change. All data 
changes will be clearly indicated. Former values can be viewed in the audit trail. All electronic data 
will be entered by the site (including an electronic audit trail) in compliance with applicable record 
retention regulations. 
The system will be secured to prevent unauthorized access to the data or the system. Only people 
provided with a user ID and a password will be able to enter or change data. The investigator will 
maintain a list of individuals who are authorized to enter or correct data. 
Computer hardware and software (for accessing the data) will be maintained at or made available 
for the site in compliance with applicable regulations. All technical preconditions for each trial site 
are recorded in the DMP. 
The system is capable of making exact copies of data in legible paper form for inspections and 
audits. The investigator or a designated subinvestigator, following review of the data in the eCRF, 
will confirm the validity of each subject’s data by electronic signature or by signing a paper printout 
of a listing of all subjects enrolled in the trial. 
The architecture of the computer system will be described in the data management plan.  
9.3 Data handling 
During data entry integrity checks help to minimize entry failures. These data entry checks are 
based on the data validation plan, signed by the LKP. The data entry system allows the trial 
monitors to control the entry process with the help of the built-in review functions. Comments and 
requests can be promptly processed by the trial site.  
After completion of data entry the database access rights will be taken away and the database will 
be exported into the data transformation system as mother database. 
Final checks for plausibility, consistency and completeness of the data will be performed. Based on 
these checks, queries will be produced. Any missing data or inconsistencies will be reported back 
to the respective site and clarified by the responsible investigator. If no further corrections are to be 
made in the database it will be declared closed and used for statistical analysis. 
All data management activities will be done according to the current Standard Operating 
Procedures (SOPs) of IZKS Mainz. 
9.4 Storage and archiving of data 
According to GCP, the investigator will archive all trial data (subject identification list, source data) 
and relevant correspondence in the Investigator Site File (ISF). The ISF, all source data and all 
documents itemized in section 8 of the ICH Consolidated Guideline on GCP will be archived after 
finalization of the trial according to the legal regulations. 
The principal investigator will be responsible for storage and archiving of the trial data (source data 
and CRFs). Storage and archiving of the electronic data during the trial will be assured by IZKS 
Mainz. After completion of the trial all electronic data will be handed over to the sponsor. 
10 ETHICAL AND LEGAL ASPECTS  
10.1 Good clinical practice 
The procedures set out in this trial protocol, pertaining to the conduct, evaluation, and 
documentation of this trial, are designed to ensure that all persons involved in the trial abide by 
good clinical practice (GCP) and the ethical principles described in the Declaration of Helsinki 
(1996, 2008). The trial will be carried out in keeping with local legal and regulatory requirements. 


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The requirements of the AMG, the GCP regulation, and the Federal Data Protection Law (BDSG) 
will be kept. 
10.2 Patient information and informed consent 
Before being admitted to the clinical trial, the subject must consent to participate after being fully 
informed about the nature, scope, and possible consequences of the clinical trial. 
The documents must be in a language understandable to the subject and must specify who 
informed the subject.  
A copy of the signed informed consent document must be given to the subject. The original signed 
consent document will be retained by the investigator. 
The investigator will not undertake any measures specifically required only for the clinical trial until 
valid consent has been obtained. 
If the subject has a primary physician the investigator should inform the subject’s primary physician 
about the subject’s participation in the trial and if the subject agrees to the primary physician being 
informed. 
 
After reading the informed consent document and after having been fully informed by the 
investigator (informed consent discussion), the subject must give consent in writing. The subject's 
consent must be confirmed by the personally dated signature of the subject and by the personally 
dated signature of the person conducting the informed consent discussion. 
If the subject is unable to read, oral presentation and explanation of the written informed consent 
form and information to be supplied to subjects must take place in the presence of an impartial 
witness. Consent must be confirmed orally and by the personally dated signature of the subject or 
by a local legally recognized alternative (e.g., the subject's thumbprint or mark). The witness and 
the person conducting the informed consent discussions must also sign and personally date the 
consent document.  
10.3 Confidentiality 
The name of the subjects and other confidential information will not supplied to the sponsor.  
The name of the subjects and other confidential information are subject to medical professional 
secrecy and the regulations of the German law on data protection (Bundesdatenschutzgesetz). 
During the clinical trial, subjects will be identified solely by means of an individual identification 
code (e.g. patient screening number, randomisation number). Trial findings stored on a computer 
will be stored in accordance with local data protection law and will be handled in strictest 
confidence. For protection of these data, organizational procedures are implemented to prevent 
distribution of data to unauthorized persons. The appropriate regulations of data legislation will be 
fulfilled in its entirety. 
The subject will declare in the written consent to release the investigator from the medical 
professional secrecy to allow identification of subject’s name and/or inspection of original data for 
monitoring purposes by health authorities and authorized persons (monitors). 
The investigator will maintain a personal subject identification list (subject numbers with the 
corresponding subject names) to enable records to be identified. 
10.4 Responsibilities of investigator 
The investigator will ensure that all persons assisting with the trial are adequately informed about 
the protocol, any amendments to the protocol, the trial treatments, and their trial-related duties and 
functions. 
The investigator will maintain a list of subinvestigators and other appropriately qualified persons to 
whom he or she has delegated significant trial-related duties. 
Any changes of the authorized trial personnel are to be communicated without delay to the clinical 
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10.5 Approval of trial protocol and substantial amendments 
Before the start of the trial, the trial protocol, informed consent document, and any other 
appropriate documents will be submitted to the independent ethics committee (IEC)/institutional 
review board (IRB). The approval by the IEC should preferably mention the title of the trial, the trial 
code, if applicable the trial site, and the documents they reviewed. It must mention the date on 
which the decision was made and must be officially signed by a committee member. This 
documentation must also include a list of members of the IEC present on the applicable EC 
meeting.  
If applicable, the documents will also be submitted to the competent authority in Germany (BfArM) 
in accordance with the respective local legal requirements. 
Investigational products can only be supplied to the investigator after documentation on all ethical 
and legal requirements for starting the clinical trial has been received by the sponsor (“regulatory 
greenlight”). Before the first subject is enrolled in the trial, all ethical and legal requirements must 
be met. 
Neither the investigator nor the sponsor will alter this trial protocol without obtaining the written 
agreement of the other. The IEC and, if applicable, the competent authorities must be informed of 
all subsequent protocol amendments and administrative changes, in accordance with the 
respective local legal requirements. 
Amendments must be evaluated to determine whether formal approval must be sought and 
whether the informed consent document should also be revised. 
The investigator must keep a record of all communications with the IEC and the competent 
authorities. 
10.6 Continuous information to independent ethics committee/ 
institutional review board 
The EC must be informed by the sponsor of all subsequent protocol amendments which require 
formal approval in accordance with the legal requirements. 
According to the current legal requirements in Germany (GCP-V) the independent EC must be 
informed by the sponsor of SUSARs and of serious AEs which occur during the trial and might 
affect the safety of subjects or the conduct of the trial if not otherwise stated in the vote. 
The EC must be informed by the sponsor of trial process regularly if not otherwise stated in the 
vote. The EC must be informed of the end of the trial in accordance with legal requirements (within 
90 days or within 15 days in case of premature closure of the clinical trial). 
10.7 Submission to local regulatory/competent authorities 
Before the start of trial, the sponsor is responsible for submission of all documents necessary to 
the competent authority for approval. The local regulatory authority responsible for the investigator 
will be informed of the trial. 
10.8 Independent data monitoring committee (IDMC) 
Not applicable. 
10.9 Insurance 
According to § 40 AMG, the sponsor has subscribed to an insurance policy covering, in its terms 
and provisions, its legal liability for injuries caused to participating persons and arising out of this 
research performed strictly in accordance with the scientific protocol as well as with applicable law 
and professional standards. The insurance was taken out at HDI-Gerling Versicherung AG 
(insurance number: 5701030703010, maximum limit: € 500.000,- per participating person). 
Any impairment of health which might occur in consequence of trial participation must be notified to 
the insurance company. The subject is responsible for notification. The insured person will be 


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agreed to all appropriate measures serving for clarification of the cause and the extent of damage 
as well as the reduction of damage. 
During the conduct of the trial, the subject must not undergo other clinical treatment except for 
cases of emergency. The subject is bound to inform the investigator immediately about any 
adverse events and additionally drugs taken. The terms and conditions of the insurance should be 
delivered to the subject. 
10.10 Agreements 
10.10.1 
Financing of the trial 
The trial is funded by Roche Pharma AG. The general conditions of financing for this trial are given 
in separate agreements. 
10.10.2 
Report 
After conclusion of the trial, a report shall be written by the sponsor, in cooperation with the 
coordinating investigator, according to ICH-GCP. The report will include a statistical analysis and 
an appraisal of the results from a medical viewpoint. It will be based on the items listed in this trial 
protocol. 
10.10.3 
Publication policy  
Any publication of the results, either in part or in total (articles in journals or newspapers, oral 
presentation, etc.) by the investigators, their representatives, or by the sponsor, shall require the 
approval of the principal investigator. It is planned to publish the results of the trial as an original 
article in an appropriate medical journal as well as presentation at congresses. The principal 
investigator is first author of the article and will present the data at the major congresses. The 
choice of the journal for the publication will be made by principal investigator in agreement with the 
co-authors. Besides the Principal Investigator, further authors of this article have to meet the 
following points: 
 Substantial contribution to the recruitment of subjects, i.e. one of the five best recruiting centers 
within the trial. 
 Substantial contribution to interpretation of the data. 
 Substantial contribution to drafting the article or revising it critically for important intellectual 
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17. Moucari R, Mackiewicz V, Lada O, et al. Early serum HBsAg drop: a strong predictor of 
sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients. 
Hepatology. 2009;49(4):1151-1157. 
18. Rijckborst V, Hansen BE, Cakaloglu Y, et al. Early on-treatment prediction of response to 
peginterferon alfa-2a for HBeAg-negative chronic hepatitis B using HBsAg and HBV DNA levels. 
Hepatology (Baltimore, Md.). 2010;52(2):454-61. 
19. Marcellin P, Lau GK, Bonino F, 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(12):1206-1217. 
20. Janssen HL, Zonneveld M van, Senturk H, et al. Pegylated interferon alfa-2b alone or in 
combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet. 
2005;365(9454):123-129. 
21. Cao Z, Zhang Y, Ma L, et al. Treatment of HBeAg-positive CHB infection wih peginterferon-
alfa-2a plus lamivudine or adefovir for 96 weeks results in high rates of HBs-Ag clearance / 
seroconversion. AASLD. 2010;Abstract #. 
22. Marcellin P, Avila C, Wursthorn K, et al. 13 TELBIVUDINE (LDT) PLUS PEG-INTERFERON 
(PEGIFN) IN HBEAG-POSITIVE CHRONIC HEPATITIS B ‚Äì VERY POTENT ANTIVIRAL 
EFFICACY BUT RISK OF PERIPHERAL NEUROPATHY (PN). Journal of hepatology. 2010;52:S6-
S7. 
23. Wedemeyer H, Yurdaydìn C, Dalekos GN, et al. Peginterferon plus adefovir versus either drug 
alone for hepatitis delta. The New England journal of medicine. 2011;364(4):322-31. 
24. European Medicines Agency. Pegasys EPAR - Product Information. Available at: 
http://www.ema.europa.eu. 
25. Usuda S. Serological detection of hepatitis B virus genotypes by ELISA with monoclonal 
antibodies to type-specific epitopes in the preS2-region product. Journal of Virological Methods. 
1999;80(1):97-112. 
26. Rehermann BB, Fowler P, Sidney J, et al. The Cytotoxic T Lymphocyte Response to Multiple 
Hepatitis B Virus Polymerase Epitopes During and After Acute Viral Hepatitis. Journal of 
Experimental Medicine. 1995;181(March). 
27. Evans A, Riva A, Cooksley H, et al. Programmed death 1 expression during antiviral treatment 
of chronic hepatitis B: Impact of hepatitis B e-antigen seroconversion. Hepatology (Baltimore, Md.). 
2008;48(3):759-69. 
28. Carotenuto P, Artsen A, Niesters H, Osterhaus A, Pontesilli O. In Vitro Use of Autologous 
Dendritic Cells Improves Detection of T Cell Responses to Hepatitis B Virus ( HBV ) Antigens. 
Journal of Medical Virology. 2009;81:332-339. 
29. Foster GR. Pegylated Interferons for the Treatment of Chronic Hepatitis C Pharmacological 
and Clinical Differences between. Drugs. 2010;70(2):147-165. 
30. Kittner JM, Sprinzl MF, Grambihler A, Weinmann A, Schattenberg JM, Galle PR, Schuchmann 
M. Adding pegulated ineterferon to a current nucleos(t)die therapy leads to HBsAg seroconversion 
in a subgroup of patients with chronic hepatitis B. J Clin Virol. 2012 May;54(1):93-5  
 

SAP_001.pdf: 


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Content 
1 
Background ........................................................................................................................ 3 
1.1 
Study Objectives .......................................................................................................... 3 
1.2 
Study Design ................................................................................................................ 3 
2 
Analysis Populations .......................................................................................................... 5 
2.1 
Definitions ................................................................................................................... 5 
2.2 
Scope ........................................................................................................................... 5 
2.3 
Major Protocol Violations ........................................................................................... 6 
3 
Study Centres ..................................................................................................................... 6 
4 
Analysis Variables .............................................................................................................. 6 
4.1 
Demographics .............................................................................................................. 6 
4.2 
Baseline characteristics ................................................................................................ 6 
4.3 
Primary variable .......................................................................................................... 7 
4.4 
Secondary variables ..................................................................................................... 7 
4.4.1 
Efficacy ................................................................................................................ 7 
4.4.2 
Safety / Tolerability .............................................................................................. 8 
5 
Treatment of Missing Values and Outliers ........................................................................ 8 
5.1 
Missing values ............................................................................................................. 8 
5.2 
Outlier .......................................................................................................................... 9 
6 
Statistical Analyses ............................................................................................................ 9 
6.1 
Disposition of Patients ................................................................................................. 9 
6.2 
Demographics and Baseline characteristics ................................................................ 9 
6.3 
Prior and Concomitant Diseases ................................................................................ 10 
6.4 
Prior and Concomitant Medication ............................................................................ 10 
6.5 
Extent of Exposure to Study Treatment / Compliance .............................................. 10 
6.6 
Primary Analysis ....................................................................................................... 10 
6.7 
Secondary Analyses ................................................................................................... 11 
6.7.1 
Efficacy .............................................................................................................. 11 
6.7.2 
Safety / Tolerability ............................................................................................ 12 
6.7.3 
Other analyses .................................................................................................... 13 
6.8 
Subgroup analyses ..................................................................................................... 13 
6.9 
Interim Analyses ........................................................................................................ 13 
7 
Software ........................................................................................................................... 13 
8 
Appendix .......................................................................................................................... 14 
8.1 
Planned Tables ........................................................................................................... 14 
 


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1 Background 
1.1 Study Objectives 
The primary objective of the trial is to investigate whether the add-on of pegylated interferon 
alfa-2a to a continued treatment with nucleos(t)ide analogues increases the percentage of 
patients who have significant decrease (≥1 log10) of HBs antigen after 48 weeks. 
The secondary objective(s) of the trial are 
 To evaluate the safety and tolerability of pegylated interferon alfa-2a when combined 
with tenofovir, entecavir, lamivudine, adefovir, or a combination of those, 
o Adverse Events (classified into mild/moderate/severe) 
o Vital signs and physical examination 
o Laboratory test abnormalities 
o Laboratory test value changes over time 
 To identify biological variables predicting HBs antigen decrease, e.g.: 
o viral genotype 
o time course of HBs antigen level.  
Scientific objectives of the trial are 
 To determine the effect of pegylated interferon on the frequency and functional 
properties of HBV-specific cytotoxic and regulatory T-cells in responder and non-
responder patients 
 To identify potentially predictive biomarkers 
1.2 Study Design 
The PADD-ON trial is a prospective, randomised, controlled open-label clinical trial with 
parallel treatment groups. Patients will be randomised (2:1 ratio) either to the treatment group 
applying weekly interferon injections additionally to basic nucleos(t)ide therapy or to the 
control group continuing basic nucleos(t)ide therapy without additional trial treatment. 
There will be an individual screening period of approximately 4 weeks. After randomisation, 
the treatment period will take 48 weeks. Follow-up will continue for another 24 weeks. 
170 randomized patients are included in the clinical trial, 112 subjects in the treatment group 
and 58 subjects in the control group. 


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Footnotes: 
1. Virology: HCV, HDV, HIV testing; HBe Ag, anti-HBe, anti-HBc 
2. Physical examination: “C” is a complete physical examination. “T“ is a targeted physical examination 
including measurements of vital signs, and evaluation of organ systems particularly associated with adverse 
event(s) symptoms. 


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3. For patients with early withdrawal from medication, the End of follow-up visit is at 24 weeks after the End of 
treatment visit. 
 
I = erythroctes, hemoglobin, hematocrit, platelets, total leukocytes and differential, AST, ALT, total 
bilirubin, gamma-GT, alkanine phostphatase, total bilirubin (and conjugated bilirubin if  total bilirubin is >1.5 x 
ULN), LDH, sodium, potassium, calcium, creatinine (and calculated clearance), blood urea nitrogen (BUN), uric 
acid, glucose, PT, INR  
 
II = erythroctes, hemoglobin, hematocrit, platelets, total leukocytes and differential, AST, ALT, total 
bilirubin, gamma-GT, alkanine phostphatase, total bilirubin (and conjugated bilirubin if total bilirubin is >1.5 x 
ULN), LDH, sodium, potassium, calcium, creatinine (and calculated clearance), blood urea nitrogen (BUN), uric 
acid, glucose, PT, INR, albumin, TSH, fT3, fT4 
 
III = erythroctes, hemoglobin, hematocrit, platelets, total leukocytes and differential, AST, ALT, total 
bilirubin, gamma-GT, alkanine phostphatase, total bilirubin (and conjugated bilirubin if total bilirubin is >1.5 x 
ULN), LDH, sodium, potassium, calcium, creatinine (and calculated clearance), blood urea nitrogen (BUN), uric 
acid, glucose, PT, INR, albumin, TSH, fT3, fT4, AFP, IgG, ANA, SMA, SLA, LKM, AMA, ANCA, ferritin, 
lipid profile (triglycerides, total cholesterol, HDL, LDL), HLA typing, urinalysis 
4. Immunology/Immune monitoring: Blood samples (50 mL each) for PBMC purification and immune 
monitoring 
5. Biomarkers: blood samples of 15-20 mL each, serum samples to be stored at -80 °C 
6. Genetic Markers: 2 vials of 2 mL EDTA blood to be frozen in liquid nitrogen and stored at -80°C. 
2 Analysis Populations 
2.1 Definitions 
All subjects who signed informed consent / were assigned a randomisation number are 
considered as enrolled/randomised subjects, even if there are no assessments of the analysis 
variables. 
All randomised subjects with at least one available post-baseline assessment of the primary 
analysis variable will be included in the modified Intention-to-treat (mITT) population. 
Within mITT population analyses subjects will be assigned to the treatment to which they 
were randomised. The mITT definition from the study protocol was modified as the wording “all 
subjects who received at least one dose of trial treatment” would include only patients from the 
interferon group into the mITT population. 
 
All subjects of the mITT population without major protocol violations will be included in the 
Per Protocol (PP) population. Major protocol violations are described in section 2.3. 
The safety population comprises all randomised subjects who received at least one dose of 
nucleos(t)ide based treatment. In analyses of the safety population subjects will be assigned to 
the treatment which they actually received. 
Patient 09/004 will be excluded from the analyses in the mITT and the PP population as 
important inclusion criteria were violated (patient is HBeAg positive).  
2.2 Scope 
The analyses of efficacy will be based primarily on the mITT population.  
The primary analysis population for the secondary endpoints except for safety data is the 
mITT population.  
All summaries and tables of safety data will be performed for the safety population. 
Supportive analyses for primary and secondary endpoints will be performed in the PP 
population. 
All data of the enrolled population will be listed. 


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2.3 Major Protocol Violations 
The following criteria will be regarded as major protocol violations. The subjects showing at least 
one of these major protocol violations will be excluded from the PP Population:  
 Violation of inclusion criteria 
 Meeting any exclusion criteria 
 Concomitant treatment with not permitted medication. 
The following concomitant treatments are not permitted during the trial (according to 
the protocol): 
o Telbivudine 
o Systemic corticosteroids, if used for longer than 14 days, or other 
immunsuppressive medications (e.g. cyclosporines, tacrolimus, methotrexate 
etc.) 
o Systemic cytostatic chemotherapy 
o Immune-modulating agents such as IL-2, anti-TNF-antibodies or rituximab 
o Nephrotoxic agents such as aminoglycoside antibiotics, amphotericin B, 
foscarnet, ganciclovir, NSAID, or other agents with significant nephrotoxic 
potential 
o Hepatotoxic agents such as anabolic steroids, isoniacid, itraconazole, 
ketoconazole, rifabutin, rifampin, or other agents with significant hepatotoxic 
potential 
 Compliance less than 90%  
 Trial treatment not as randomised 
3 Study Centres 
Recruitment and treatment of subjects is performed in 24 trial centres in Germany. 
4 Analysis Variables 
4.1 Demographics 
The following demographic data will be documented: 
 Age and date of birth,  
 Gender (female/male),  
 ethnic origin/nationality (European/Asian/African/Other),  
4.2 Baseline characteristics 
 Virology before screening (HBV DNS (IU/mL), HBV DNS negative (Y/N), HBsAg 
(IU/mL) 
 Virology (screening): HBV DNS (IU/mL), HBV DNS negative (Y/N), HBsAg 
(IU/mL); 
anti-HBs, 
HBeAg, 
Anti-HBe, 
Anti-HBc, 
HCV, 
HDV, 
HIV 
(positive/negative) 
 HBV disease characteristics: HBV genotype (A-H/ wildtype; if available), samples for 
serological assessment of HBV genotype (Y/N; if not available) 


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 Urine 
drug 
screening 
(positive/ 
negative; 
if 
available) 
and 
urinalysis 
(normal/abnormal, clinically not relevant/abnormal, clinically relevant; if available) 
 Urine pregnancy test for women of childbearing potential (negative/ positive/ sterile or 
postmenopausal) 
 Medical History: Relevant previous illnesses (Y/N), possible source and assumed year 
of infection (perinatal, injection drug use, sexual, occupational, transfusion, unknown, 
other), year of first diagnosis 
 Imaging of the liver (if available): method (ultrasound/ CT scan/MRI),, presence of 
hepatocellular carcinoma (Y/N), extent of fibrosis (0-6/ unknown), liver elastography 
(kPa) 
 Liver assessment (if available): Results from liver biopsy, extent of fibrosis (0-6/ 
unknown)   
 Alcohol consumption > 20g/d (women)/ >30g/d (men) (Y/N) 
 12-lead resting-ECG measurement (normal/abnormal, clinically not relevant/ 
abnormal, clinically relevant/ not done) 
 Fundoscopy (normal/ abnormal, clinically not relevant/ abnormal, clinically relevant/ 
not done) 
 General physical examination (screening): Different organ systems (normal/ abnormal, 
clinically not relevant/ abnormal, clinically relevant/ not done)  
 Routine laboratory test (screening): hematology and clinical chemistry III)  
 Vital signs (baseline): blood pressure, pulse, temperature, height (cm, only at 
screening), body weight (kg), BMI (kg/m²) 
 Samples for immunology (baseline): biomarker (Y/N), genetic marker (Y/N), 
immunology (Y/N) 
 Targeted physical examination (baseline):Neurologic symptoms (Y/N), neuropathy 
(Y/N), proofed by neurologist (Y/N)) 
 
Additionally, it is documented whether a re-screening was done. If yes, screening values will 
be replaced by re-screening values. 
4.3 Primary variable 
The primary endpoint is the objective response after 48 weeks of combination therapy. The 
response is defined as a confirmed reduction of ≥1log10 in HBs antigen compared to baseline. 
4.4 Secondary variables 
4.4.1 Efficacy 
Efficacy analyses are based on the measurements of HBs antigen and anti HBs concentration 
which will be done at screening, at baseline and on a regular basis during the 48 week 
treatment phase (every four weeks in the interferon arm and every twelve weeks in the control 
arm) as well as at end of follow-up (week 72).  
Secondary efficacy endpoints are: 
 Decline of quantitative HBs antigen at week 12 and 24 
 Rate of patients with at least 10% HBs antigen loss at week 24 compared to baseline 
 HBsAg seroconversion defined as percentage of subjects who become HBsAg 
negative and anti-HBs positive during the observation period 
 HBs antigen levels at all measurement times  


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4.4.2 Safety / Tolerability 
Adverse events and concomitant medication will be documented continuously during the 
study. 
 
Laboratory data will be evaluated at every study visit; the following parameters will be 
assessed: 
Screening (panel III):  
erythroctes, hemoglobin, hematocrit, platelets, total leukocytes and differential, AST, 
ALT, total bilirubin (and conjugated bilirubin if total bilirubin is >1.5 x ULN), 
bilirubin ratio (direct/ indirect), gamma-GT, alkanine phosphatase, LDH, sodium, 
potassium, calcium, creatinine (and calculated clearance), blood urea nitrogen (BUN), 
uric acid, glucose, PT, INR, albumin, TSH, fT3, fT4, AFP, IgG, ANA, SMA, SLA, 
LKM, AMA, ANCA, ferritin, lipid profile (triglycerides, total cholesterol, HDL, 
LDL), HLA typing, urinalysis 
Week 12, 24, 48 and 72 (panel II):  
erythroctes, hemoglobin, hematocrit, platelets, total leukocytes and differential, AST, 
ALT, total bilirubin (and conjugated bilirubin if total bilirubin is >1.5 x ULN), 
bilirubin ratio (direct/ indirect), gamma-GT, alkanine phosphatase, total bilirubin (and 
conjugated bilirubin if total bilirubin is >1.5 x ULN), LDH, sodium, potassium, 
calcium, creatinine (and calculated clearance), blood urea nitrogen (BUN), uric acid, 
glucose, PT, INR, albumin, TSH, fT3, fT4 
Week 0, 4, 8, 16, 20, 28, 32, 36, 40, 44 for IFN patients and Week 0 and 36 for 
control patients (panel I):  
erythroctes, hemoglobin, hematocrit, platelets, total leukocytes and differential, AST, 
ALT, total bilirubin (and conjugated bilirubin if total bilirubin is >1.5 x ULN), 
bilirubin ratio (direct/ indirect), gamma-GT, alkanine phosphatase, LDH, sodium, 
potassium, calcium, creatinine (and calculated clearance), blood urea nitrogen (BUN), 
uric acid, glucose, PT, INR 
The following vital signs will be evaluated at every study visit: 
Body temperature, heart rate, blood pressure, weight and BMI (height only at 
screening) 
 
Urine pregnancy tests will be performed for women with childbearing potential at screening 
and EoT for both groups, at week 12, 24, 36 and 48 in the treatment group and week 48 in the 
control group. 
 
Cardiologic evaluation by 12-lead ECG will be done at screening. 
 
A complete physical examination including vital signs will be done at screening, end of 
treatment (EoT) and end of follow-up (EoFU). A targeted physical examination will be done 
at baseline, and every four or twelve weeks in the interferon or control arm, respectively. 
 
HBV-PCR will be performed at week 0, 12, 24, 48 and 72.   
5 Treatment of Missing Values and Outliers 
5.1 Missing values 
The last observation carried forward method (LOCF) will be used for the handling of missing 
data due to drop-out when analysing the primary endpoint.  


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LOCF for primary analysis: In order to avoid bias and ensure the comparability of the two 
treatment groups, only data from visits which took place after similar time intervals in the two 
groups will be included in the primary analysis (visits in week 12, 24, 36 and 48), meaning 
that only HBsAg values potentially obtained at week 12, 24 or 36 will be carried forward in 
case of missing values at week 48. There will be no baseline values carried forward. 
Modified LOCF for sensitivity analysis: All LOCF analyses will be repeated with the LOCF 
method applied to the last visit available meaning that in the interferon group every last visit 
(except the baseline visit) can be carried forward, not only the ones in week 12, 24 or 36.  
 
5.2 Outlier 
There will be no methods employed for detecting outliers.  
6 Statistical Analyses 
The default summary statistics for quantitative variables will be the number of observations 
(n), mean, standard deviation (SD), median, first quartile (Q1), third quartile (Q3), minimum 
and maximum for those patients with data available.  
For qualitative variables, the number (n) and percentage (%) of patients with non-missing data 
per category will be the default summary presentation. If appropriate, the number of missing 
values will be displayed as a “Missing” category.  
All variables will be displayed by treatment group and with a total column.  
Listings of all data available will be provided. 
6.1 Disposition of Patients 
The following patient disposition variables will be presented by numbers and percentages: 
 Informed consent given to study participation / study treatment 
 Informed consent given to biomarker analysis 
 Informed consent given to genotypic analysis 
 Informed consent given to transfer of anonymised biomaterial  
 Inclusion and exclusion criteria 
 Size of analysis populations (Safety, mITT, PP) 
 Study completion according to protocol 
 Main reason for premature discontinuation of study treatment 
 Follow-up visit according to protocol (interferon group) 
 Main Reason for follow-up visit not according to protocol (interferon group) 
 Participation at every study visit (if the date is available, participation at the visit is 
assumed) 
 Participation at every main study visit (screening, week 0, 12, 24, 36, 48 and 72) 
 Type of protocol violation 
6.2 Demographics and Baseline characteristics 
All parameters (except date of birth, virology before screening, HBV-DNA [IU/mL] at 
screening, assumed year of infection and year of first diagnosis) mentioned in chapter 4.1 and 
4.2 will be summarised descriptively. Appropriate exploratory p-values of t-test (unequal 
variances) or chi-square test to test on differences between treatment groups will be shown. 
 


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Additionally the time since infection will be calculated by:  
(year of screening – year of infection) + 1. 
If date of infection differs from date of first diagnosis, the time since first diagnosis will be 
calculated as well: 
(year of screening – year of first diagnosis) + 1. 
Exploratory p-values of t-test (unequal variances) to test on differences between treatment 
groups will be shown. 
6.3 Prior and Concomitant Diseases 
Concomitant diseases will be coded by MedDRA (Medical Dictionary for Regulatory 
Activities) terminology and presented by number and percentages within preferred term and 
system organ class. 
The number of patients with at least one concomitant disease will be displayed by number and 
percentages. 
6.4 Prior and Concomitant Medication 
Concomitant medication will be coded using the current WHO drug dictionary version and 
will be presented within ATC-2 and ATC-4 level.  
Concomitant medication for HBV (basic nucleos(t)ide treatment) and concomitant medication 
not for HBV will be documented and tabulated separately. 
Patients with at least one concomitant medication will be displayed by number and 
percentages.  
6.5 Extent of Exposure to Study Treatment / Compliance 
Extent of exposure: The dose of injection is documented for the interferon treatment arm on a 
weekly basis. Descriptive statistics will be provided for the overall cumulative dose. 
Compliance will be calculated by dividing the number of used interferon injections by the 
planned number of injections. This number is set to 47 (most patients did not receive another 
injection in week 48 where the EoT visit took place). Still a higher number than 47 injections 
in total is possible as in certain cases the EoT visit took place after more than 48 weeks. ( . 
This parameter will be used as compliance parameter for definition of major protocol 
violation. 
Additionally, the number of visits without re-screening and follow-up visits will be calculated 
per patient and treatment group. Descriptive statistics and exploratory p-value (t-test with 
unequal variances) will be provided for the number of visits per patient given as percentage 
based on all possible visits per treatment group until EoT (interferon group: 14 visits, control 
group: 6 visits).  
6.6 Primary Analysis 
Null hypothesis: HBsAgRRInterferon = HBsAgRRControl 
Alternative hypothesis: HBsAgRRInterferon ≠ HBsAgRRControl 
HBsAgRR denotes HBs antigen response rates. The subscripts show the respective treatment 
group. 
Response is defined as significant decrease (≥1 log10) of HBs antigen after 48 weeks 
compared to baseline. The response rates will be compared between the treatment groups by 


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Fisher’s exact test (two-sided, level of significance α=0.05). Additionally a Cochran-Mantel-
Haenszel test stratifying for screening HBsAg levels will be performed, if the number of 
patients in the respective strata is sufficient. The primary analysis population is the modified 
Intention to treat population.  
Subjects with missing HBsAg measurements at week 48 (EoT) will be analysed according to 
the LOCF principle in the primary analysis as specified in section 5.1 (“LOCF for primary 
analysis). This approach is considered slightly conservative but allows including all patients 
with at least one valid HBsAg measurement in week 12, 24, 36 or 48 to be included into the 
confirmatory modified Intention to treat analysis. The analysis will be repeated with the 
modified LOCF approach specified in section 5.1 (“LOCF for sensitivity analysis”). 
Further supportive analyses are planned: 
The primary analysis will be repeated using all available data as observed (no LOCF will be 
applied). Drop-outs before week 48 will be considered as non-responders. 
Also the primary analysis (Fisher’s exact test, Cochran-Mantel-Haenszel test) will be repeated 
for the PP population with and without application of the LOCF method (both LOCF 
definitions). 
As sensitivity analysis a logistic regression model including the factor treatment and the 
covariate HBsAgScreen (HBsAg level at screening < 20.000IU/ mL vs. ≥ 20.000 IU/mL) will 
be applied on each analysis population. 
Furthermore, a logistic regression model including covariates assumed to predict treatment 
response (age, sex, duration of antiviral therapy before the study) will be applied. 
 
6.7 Secondary Analyses 
6.7.1 Efficacy 
The primary population for the analyses of efficacy is the mITT Population. If there is a 
difference of at least 5% between PP population and mITT population regarding the number 
of patients, all secondary efficacy analyses will be repeated for the PP population. 
All hypotheses will be tested on a two-sided level of significance α=0.05 and results will be 
interpreted in an exploratory manner. 
Missing values will not be replaced. 
6.7.1.1 
HBs antigen at week 12 and 24 
The decline of quantitative HBs antigen at week 12 and 24 will be analysed using an 
ANCOVA model, including treatment and baseline HBs antigen as parameters in the model. 
6.7.1.2 
HBs antigen rate at week 24 
The rate of patients with at least 10% HBs antigen loss at week 24 compared to baseline will 
be analysed by Fisher’s exact test (results of interim analysis). Drop-outs before week 24 will 
be considered as non-responders. 
6.7.1.3 
HBs antigen seroconversion 
HBs antigen seroconversion is defined as percentage of subjects who become HBs antigen 
negative (< 10 IU/ml) and anti-HBs positive (≥10 IU/l) at least once during the observation 
period (baseline - EoFU).  In order to compare the two treatment groups a Cochran-Mantel-


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Haenszel test or Fisher’s exact test will be performed (depending on the number of patients in 
the respective strata).  
Additionally, patients with HBs antigen seroconversion will be displayed by group and visit. 
This will be repeated for all patients who become HBs antigen negative. 
6.7.1.4 
HBs antigen over time 
The HBs antigen concentration and changes to baseline will be analysed descriptively by 
visit. Whenever applicable, exploratory p-values (t-test) for the comparison between treatment 
groups will be provided. Mean antigen concentrations per time will also be displayed 
graphically. Additionally, a spaghetti plot will be produced that depicts the HBs antigen 
concentration over time for each individual. 
6.7.2 Safety / Tolerability 
6.7.2.1 
Adverse Events 
Frequencies of subjects experiencing at least one adverse event (AE) will be displayed by 
body system and preferred term according to MedDRA terminology. Detailed information 
collected for each AE will include: A description of the event, duration, whether the AE was 
serious, intensity, relationship to trial drug, action taken, clinical outcome.  
Frequencies of patients experiencing at least one serious adverse event (SAE) will be 
displayed by body system and preferred term according to MedDRA terminology. 
Further tables will present the number of subjects observed with AEs specified by  event 
intensity and relationship to trial drug. 
A summary table will be produced showing the number of patients with 
- any AEs 
- any SAEs 
- any fatal AEs 
- any severe AEs 
- any related AEs 
- any related severe AEs 
- any related serious AEs 
- any fatal related AEs 
- any AEs leading to premature study discontinuation 
- any AEs leading to actions regarding the study medication 
6.7.2.2 
Laboratory Parameters 
Listings will be prepared for each laboratory parameter and will be structured to permit 
review of the data per subject as they progress on treatment. 
Summary tables will be prepared to examine the changes of laboratory parameters over time. 
Laboratory measurements and the changes to baseline will be analysed descriptively by visit. 
Exploratory p-values (t-test or chi-square test) will be shown whenever applicable. 
Additionally, shift tables will be provided to examine the changes of laboratory data 
(clinically relevant Y/N) from baseline to EoT and from baseline to EoFU. 
6.7.2.3 
Vital Signs 
Vital signs (blood pressure, heart rate, weight, BMI and temperature) and corresponding 
changes to baseline in vital signs will be analysed descriptively by distributional parameters 
(such as mean and standard deviation). 


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Exploratory p-values for the comparison of treatment groups will be provided, whenever 
applicable. 
6.7.2.4 
Physical examination 
Results of the complete physical examination and the targeted examination will be tabulated 
by visit, respectively. Exploratory p-values (chi-square test) for the comparison of treatment 
groups will be shown. 
6.7.3 Other analyses 
Blood samples for immune monitoring / immunology, for bioinformatics analysis of genetic 
markers will be obtained at the baseline visit. Blood samples for identification of biomarkers 
will be obtained every four or twelve weeks respectively in the interferon or control arm, 
respectively. The corresponding analyses, for example the identification of potentially 
predictive biomarkers will not be carried out by the IZKS. 
6.8 Subgroup analyses 
Age, sex, level of quantitative HBsAg at baseline, nucleos(t)ide regimen (substances at 
baseline, combination, duration) will be subject to subgroup analyses for the primary 
endpoint.  
 
If appropriate, logistic regressions will be applied, including treatment, subgroup parameter 
and interaction between treatment and subgroup parameter in the model. 
6.9 Interim Analyses 
There will be no interim analysis in the sense that the primary endpoint is analysed 
prematurely and a decision about the continuation of the study is derived. 
However, it is planned to compare the rates of patients with at least 10% HBsAg loss 24 
weeks after the start of study treatment compared to baseline between the treatment groups as 
soon as these data are available. The analysis will be interpreted in an explorative manner. 
Therefore no adjustment of the significance level is required. 
The influence of this premature analysis on the primary analysis and the predictability of the 
results of the primary analysis based on the results of the premature analysis are expected to 
be limited for the following reasons: 
 The recruitment phase will be terminated at the time point of the premature analysis. 
 According to the expected accrual time, the analysis will be performed only around 
16weeks before the end of treatment of the last patient. 
 The loss rates in the early response analysis (at least 10% HBsAg loss) and the 
primary analysis (reduction of at least 1log10 HBsAg) are defined differently. 
Details of the interim analysis are documented in an additional SAP. 
7 Software 
All analyses will be performed using the Statistical Analysis Software (SAS), Version 9.4.  


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8 Appendix 
8.1 Planned Tables  
No 
Title 
Population 
 
Patient Disposition (including In- and Exclusion Criteria) 
Enrolled 
 
Patient Discontinuation 
Randomised 
 
Important Protocol Violations 
Randomised 
 
Demographics and Baseline Characteristics 
mITT/ PP 
 
Concomitant Diseases 
mITT 
 
Concomitant Medication 
mITT 
 
Concomitant Medication for HBV (Basic Nucleos(t)ide Treatment) mITT 
 
Exposure to Study Medication 
mITT 
 
Compliance (Based on Used Medication) 
mITT 
 
Compliance (Based on Visits) 
mITT 
 
 
 
 
Primary Analysis: Comparison of Responder Rates after 48 Weeks 
(LOCF) 
mITT/ PP 
 
Sensitivity Analysis: Comparison of Responder Rates after 48 
Weeks (modified LOCF) 
mITT/ PP 
 
Sensitivity Analysis: Comparison of Responder Rates after 48 
Weeks (no LOCF) 
mITT/ PP 
 
Sensitivity Analysis: Logistic Regression of Responder Rates after 
48 Weeks 
mITT/ PP 
 
 
 
 
Secondary Analysis: Decline of HBsAg Concentration at Week 12 
and Week 24  
mITT/ (PP)* 
 
Secondary Analysis: Rate of Patients with at least 10% HBsAg 
Loss  after 24 Weeks 
mITT/ (PP)* 
 
Secondary Analysis: Subjects with HBsAG seroconversion 
(overall) 
mITT 
 
Secondary Analysis: Subjects with HBsAG seroconversion (over 
time) 
mITT 
 
Secondary Analysis: Subjects becoming HBsAG negative (overall) mITT 
 
Secondary Analysis: Subjects becoming HBsAG negative (over 
time) 
mITT 
 
Secondary Analysis: HBsAG Concentration and Changes to 
Baseline by Visit 
mITT/ (PP)* 
 
 
 


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Adverse Events (Summary Table) 
Safety 
 
Adverse Events 
Safety 
 
Serious Adverse Events 
Safety 
 
Adverse Events by Severity (Group A) 
Safety 
 
Adverse Events by Severity (Group B) 
Safety 
 
Adverse Events by Relationship to Trial Medication (Group A) 
Safety 
 
Adverse Events by Relationship to Trial Medication (Group B) 
Safety 
 
Laboratory Parameters over Time (Summary Table) 
Safety  
 
Laboratory Parameters– Changes to Baseline 
Safety 
 
Shift Tables: Changes of Laboratory Data (Clinical Relevant Y/N) 
from Baseline to EoT and EoFU  
Safety 
 
Vital Signs over Time (Summary Table) 
Safety  
 
Complete physical Examination (Summary Table) 
Safety 
 
Targeted Physical Examination (Summary Table) 
Safety 
 
Blood Samples for Immunology/ Markers 
Safety 
 
 
 
 
Subgroup Analyses: Logistic Regression of Responder Rates after 
48 Weeks 
Safety 
*Analyses in the PP population will only be carried out if the number of patients differs > 5% 
between mITT and PP population.