Clinical trial NCT03852433
Conditions: Chronic Hepatitis Delta
Sponsor: Gilead Sciences
Start date: 2019-05-31; Completion date: 2022-09-28
Enrollment: 175 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the efficacy of bulevirtide in combination with pegylated interferon in participants with chronic hepatitis delta (CHD).

Detailed description:

Arms: arm 1: Participants will receive PEG-IFN alfa 180 microgram (mcg) once a week subcutaneously for 48 weeks with additional 48 weeks follow-up. arm 2: Participants will receive bulevirtide 2 mg once a day subcutaneously incombination with PEG-IFN alfa 180 mcg once a week subcutaneously for 48 weeks followed by bulevirtide 2 mg once a day for 48 weeks and additional 48 weeks follow-up. arm 3: Participants will receive bulevirtide 10 mg once a day subcutaneously in combination with PEG-IFN alfa 180 mcg once a week subcutaneously for 48 weeks followed by bulevirtide 10 mg once a day for 48 weeks and additional 48 weeks follow-up. arm 4: Participants will receive bulevirtide 10 mg once a day subcutaneously for 96 weeks with additional 48 weeks follow-up
Interventions: intervention 1: Bulevirtide intervention 2: Peginterferon Alfa-2a (PEG-IFN alfa)
Intervention descriptions: intervention 1: Administered via subcutaneous injections intervention 2: Administered via subcutaneous injections

Protocol documents:
Prot_000.pdf: 
  
CLINICAL STUDY PROTOCOL
Study Title:
A Multicenter, Open-label, Randomized Phase 2b Clinical 
Study to Assess Efficacy and Safety of Bulevirtide in 
Combination with Pegylated Interferon alfa-2a in Patients 
with Chronic Hepatitis Delta
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive 
Foster City, CA 94404
USA
Protocol Identification:
MYR204
Version Number and 
Date:
EudraCT number:
ClinicalTrials.gov
Identifier:
Version 5.0 dated 08-Feb-2022
2019-001485-15
NCT03852433
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the 
property or under control of Gilead Sciences, Inc., and is provided to you in confidence 
as an investigator, potential investigator, or consultant, for review by you, your staff, and 
an applicable institutional review board or independent ethics committee. The 
information is only to be used by you in connection with authorized clinical studies of the 
investigational drug described in the protocol. You will not disclose any of the 
information to others without written authorization from Gilead Sciences, Inc., except to 
the extent necessary to obtain informed consent from those persons to whom the drug 
may be administered.


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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................2
LIST OF IN-TEXT TABLES .........................................................................................................................................4
LIST OF IN-TEXT FIGURES........................................................................................................................................5
CONTACT INFORMATION.........................................................................................................................................8
LIST OF ABBREVIATIONS.........................................................................................................................................9
SYNOPSIS....................................................................................................................................................................11
1.
INTRODUCTION................................................................................................................................................22
1.1.
Hepatitis Delta.........................................................................................................................................22
1.2.
Treatment Options for Hepatitis Delta ....................................................................................................23
1.3.
Background on Bulevirtide......................................................................................................................24
1.3.1.
Description of the Study Drug...............................................................................................24
1.3.2.
Summary of Clinical Data.....................................................................................................24
1.4.
Study Rationale .......................................................................................................................................31
1.4.1.
Rationale for Participant Population .....................................................................................32
1.4.2.
Rationale for Selection of the Dose of the Study Drug.........................................................32
1.5.
Benefit/Risk Assessment.........................................................................................................................32
2.
STUDY OBJECTIVES ........................................................................................................................................34
2.1.
Objectives................................................................................................................................................34
2.2.
Endpoints.................................................................................................................................................34
3.
OVERALL STUDY DESIGN .............................................................................................................................37
3.1.
Randomization.........................................................................................................................................38
3.2.
Blinding ...................................................................................................................................................38
4.
SELECTION OF STUDY POPULATION..........................................................................................................39
4.1.
Inclusion Criteria.....................................................................................................................................39
4.2.
Exclusion Criteria....................................................................................................................................40
4.3.
Withdrawal Criteria.................................................................................................................................42
4.4.
Replacement of Participants....................................................................................................................43
4.5.
Premature Termination of Study .............................................................................................................43
5.
TREATMENTS....................................................................................................................................................44
5.1.
Treatments Administered ........................................................................................................................44
5.1.1.
Bulevirtide .............................................................................................................................44
5.1.2.
Peginterferon Alfa-2a ............................................................................................................45
5.2.
Labelling of Bulevirtide and Peginterferon Alfa-2a................................................................................45
5.3.
Dosing and Administration......................................................................................................................45
5.3.1.
Supplying Participants with Bulevirtide and Peginterferon Alfa-2a.....................................45
5.3.2.
Administration of Bulevirtide................................................................................................46
5.3.3.
Administration of Peginterferon Alfa-2a...............................................................................47
5.3.4.
Dose Adjustment Guidelines.................................................................................................47
5.3.5.
Dose Adjustment Guidelines for Bulevirtide ........................................................................47
5.3.6.
Dose Adjustment Guidelines for Peginterferon Alfa-2a .......................................................48
5.3.7.
Dose Adjustment Guidelines for Peginterferon Alfa-2a in Case of ALT 
Increases................................................................................................................................49
5.4.
Accountability Procedures.......................................................................................................................49
5.5.
Treatment Compliance ............................................................................................................................50
5.6.
Concomitant Therapy ..............................................................................................................................50
5.6.1.
Treatment With Nucleoside/Nucleotide Analogues..............................................................50


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5.6.2.
Prohibited Treatments ...........................................................................................................51
6.
STUDY PROCEDURES......................................................................................................................................52
6.1.
Early Discontinuation Visit .....................................................................................................................52
6.2.
Restrictions During the Study .................................................................................................................52
6.3.
Demographic and Other Baseline Characteristics...................................................................................54
6.3.1.
Demographics........................................................................................................................54
6.3.2.
Medical History.....................................................................................................................54
6.3.3.
Prior and Concomitant Therapy ............................................................................................54
6.3.4.
Weight, Height, Body Mass Index ........................................................................................54
6.3.5.
Pregnancy Test ......................................................................................................................55
6.3.6.
Drug Screening......................................................................................................................55
6.3.7.
Breath Alcohol Test...............................................................................................................55
6.3.8.
Abdominal Ultrasound ..........................................................................................................55
6.3.9.
Serum Alpha-fetoprotein.......................................................................................................55
6.3.10.
Serology, HDV RNA, HCV RNA and HBeAg Test at Screening........................................55
6.4.
Efficacy Procedures.................................................................................................................................56
6.4.1.
Virology Tests .......................................................................................................................56
6.4.2.
ALT .......................................................................................................................................56
6.4.3.
HBV/HDV genotyping..........................................................................................................56
6.4.4.
NTCP Polymorphism and Resistance Tests..........................................................................56
6.4.5.
Serum Alpha-2-Macroglobulin .............................................................................................59
6.4.6.
Liver Biopsy ..........................................................................................................................59
6.4.7.
Transient Elastometry............................................................................................................59
6.5.
Safety Procedures ....................................................................................................................................60
6.5.1.
Physical Examination ............................................................................................................60
6.5.2.
Vital Signs .............................................................................................................................62
6.5.3.
Electrocardiogram .................................................................................................................63
6.5.4.
Hematology, Biochemistry, Coagulogram, Vitamin D and TSH..........................................63
6.5.5.
Total Blood Bile Salts ...........................................................................................................65
6.5.6.
Urinalysis...............................................................................................................................65
6.5.7.
Adverse Events......................................................................................................................66
6.6.
Other Procedures .....................................................................................................................................66
6.6.1.
Immunogenicity.....................................................................................................................66
6.6.2.
Pharmacokinetics...................................................................................................................66
6.7.
Participant Diary......................................................................................................................................67
6.8.
The Quality of Life Questionnaires.........................................................................................................67
6.9.
Liver Related Clinical Events..................................................................................................................67
7.
ADVERSE EVENTS ...........................................................................................................................................68
7.1.
Definitions ...............................................................................................................................................68
7.1.1.
Adverse event (AE) ...............................................................................................................68
7.1.2.
Serious Adverse Event (SAE) ...............................................................................................68
7.1.3.
Adverse Event of Special Interest (AESI).............................................................................69
7.1.4.
Abnormal Laboratory Values................................................................................................70
7.1.5.
Abnormal Vital Sign Values .................................................................................................70
7.1.6.
Adverse drug reaction (ADR) ...............................................................................................71
7.1.7.
Unexpected adverse drug reaction.........................................................................................71
7.2.
Classification of an Adverse Event .........................................................................................................71
7.2.1.
Severity of Event ...................................................................................................................71
7.2.2.
Relationship to Study Medication .........................................................................................72
7.2.3.
Adverse Event Outcome........................................................................................................73
7.2.4.
Adverse Event Assessment and Follow-up ...........................................................................73
7.3.
Reporting procedure ................................................................................................................................73
7.3.1.
Adverse Event Reporting Period...........................................................................................73
7.3.2.
Adverse Event Reporting ......................................................................................................74


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7.3.3.
Serious Adverse Event Reporting .........................................................................................74
7.4.
Events of Special Interest ........................................................................................................................75
7.5.
Hepatic Safety Adjudication Committee.................................................................................................75
7.6.
Reporting of Pregnancy...........................................................................................................................75
8.
STATISTICAL CONSIDERATIONS.................................................................................................................77
8.1.
Analysis Populations ...............................................................................................................................77
8.2.
Description of Statistical Methods ..........................................................................................................77
8.2.1.
Demographic and Baseline Measurements ...........................................................................77
8.2.2.
Analysis of Efficacy ..............................................................................................................77
8.2.3.
Analysis of Safety..................................................................................................................78
8.2.4.
Determination of Sample Size...............................................................................................79
8.2.5.
Interim, Follow-up and Final Analyses.................................................................................80
9.
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .............................................81
10.
QUALITY ASSURANCE AND QUALITY CONTROL ...................................................................................82
10.1.
Periodic Monitoring.................................................................................................................................82
10.2.
Audit and Inspection................................................................................................................................82
11.
ETHICS / PROTECTION OF HUMAN SUBJECTS..........................................................................................83
11.1.
Ethical Standard.......................................................................................................................................83
11.2.
Independent Ethics Committee (IEC) and/or Institutional Review Board (IRB)....................................83
11.3.
Informed Consent Process.......................................................................................................................83
11.4.
Participant and Data Confidentiality .......................................................................................................84
12.
DATA HANDLING AND RECORD KEEPING................................................................................................85
12.1.
The Entering of Data Into the eCRF........................................................................................................85
12.2.
The Query Process...................................................................................................................................85
12.3.
Data Collection and Management Responsibilities.................................................................................85
12.3.1.
User ID ..................................................................................................................................86
12.3.2.
Audit Trail .............................................................................................................................86
12.4.
Study Records Retention .........................................................................................................................86
12.5.
Protocol Deviations .................................................................................................................................86
12.6.
Publication and Data Sharing Policy.......................................................................................................86
13.
FINANCING AND INSURANCE.......................................................................................................................88
13.1.
Financing .................................................................................................................................................88
13.2.
Insurance..................................................................................................................................................88
14.
LITERATURE REFERENCES ...........................................................................................................................89
APPENDIX 1. CONFIRMATION OF PARTICIPANTS’ ELIGIBILITY..................................................................92
LIST OF IN-TEXT TABLES
Table 1.
Schedule of Events ..................................................................................................................17
Table 2.
Participants with HDV RNA response and combined response at week 24 
(MYR202 study, mITT population) ........................................................................................29
Table 3.
Tables for Clinical Abnormalities ...........................................................................................62


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LIST OF IN-TEXT FIGURES
Figure 1.
Study Plan................................................................................................................................38


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SIGNATURE PAGE 1 (SPONSOR)
Protocol Title: A Multicenter, Open-label, Randomized Phase 2b Clinical Study to Assess 
Efficacy and Safety of Bulevirtide in Combination with Pegylated Interferon alfa-2а in Patients 
with Chronic Hepatitis Delta.
The signature below constitutes approval of this protocol by the signatory and provides the 
necessary assurances that this study will be conducted according to all stipulations of the protocol.
                    [See appended electronic signature]       [See appended electronic signature]
Signature: _______________________________        Date: ______/______/______
                            day/month/year
Medical Monitor, Clinical Development
Gilead Sciences, Inc.
PPD


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SIGNATURE PAGE 2 (PRINCIPAL INVESTIGATOR)
Protocol Title: A Multicenter, Open-label, Randomized Phase 2b Clinical Study to Assess 
Efficacy and Safety of Bulevirtide in Combination with Pegylated Interferon alfa-2а in Patients 
with Chronic Hepatitis Delta.
The signature of the below constitutes agreement of this protocol by the signatory and provides 
the necessary assurance that this study will be conducted at his/her investigational site as outlined 
in the protocol, Good Clinical Practice, and all international and local regulations that apply for 
this study including all statements regarding confidentiality.
Institution title:
________________________________________________
________________________________________________
________________________________________________
Institution address:
________________________________________________
________________________________________________
________________________________________________
Investigator’s name:
________________________________________________
________________________________________________
Signature:
_____________________________
Date:  
_____________________________


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CONTACT INFORMATION
Study sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
For correspondence:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
Central laboratories and other 
contacts:
Central laboratories, their addresses and other 
contact information are provided in a contact list. 
This list will be regularly updated as needed; the 
most current version is available in the Sponsor’s 
trial master file and site file.


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LIST OF ABBREVIATIONS
AASLD
American Association for the Study of Liver Diseases
AE
Adverse event
AESI
Adverse Event of Special Interest
ADR
Adverse drug reaction
ALT
Alanine transaminase
aPTT
Activated partial thromboplastin time
AST
Aspartate transaminase
BID
Twice daily
BMI 
Body mass index
cccDNA
covalently closed circular DNA
CHB
Chronic hepatitis B
CHD
Chronic hepatitis delta
CI 
Confidence interval
COVID-19
Coronavirus disease 2019
CRA
Clinical research associate 
CRF
Case report form
CRO
Contract research organisation
CRP
C-reactive protein
CTCAE
Common Terminology Criteria for Adverse Events
EASL
European Association for the Study of the Liver
ECG
Electrocardiogram
eCRF
Electronic case report form
ELISA
Enzyme-linked immunosorbent assay
EOS
End of study
EOT
End of treatment
EQ-5D
EuroQol 5-Dimentions
EU
European Union
FAS
Full analysis set
FSS
Fatigue Severity Scale
FU
Follow-up
GCP
Good Clinical Practice
GGT
Gamma glutamyl transferase
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HDV
Hepatitis delta virus
HIV
Human immunodeficiency virus
HPLC-MS
High performance liquid chromatography-mass spectrometry
HQLQ™
The Hepatitis Quality of Life Questionnaire™
HSAC
Hepatic Safety Adjudication Committee


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ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
INR
International Normalization Ratio
IRB
Institutional Review Board
LoD
Limit of detection
LLOQ
Lower limit of quantification
kPa
Kilopascal
MedDRA
Medical Dictionary for Regulatory Activities
mcg
Microgram
MMRM
Mixed effect repeated measurement models
NA
Nucleos(t)ide analogue
NCI
National Cancer Institute (USA)
NOCB
Next observation carried backward
NTCP
Sodium-taurocholate cotransporting polypeptide
OATP
Organic anion transporting polypeptide
PCR
Polymerase chain reaction
PEG-IFN alfa
Pegylated interferon alfa-2a
PI
Principal Investigator
PP
Per-protocol set
PT
Preferred Term 
RBC
Red blood cell
QD
Once daily
REML
Restricted maximum likelihood
RNA
Ribonucleic acid
SAE
Serious adverse event
SC
Subcutaneously
SCR
Screening
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR 24
Sustained virological response 24
SVR 48
Sustained virological response 48
TDF
Tenofovir disoproxil fumarate
TSH
Thyroid stimulating hormone (thyrotropic hormone)
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
US, USA
United States, United States of America
WBC
White blood cell


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SYNOPSIS
Title of Study:
A Multicenter, Open-label, Randomized Phase 2b Clinical Study to Assess 
Efficacy and Safety of Bulevirtide in Combination with Pegylated Interferon 
alfa-2a in Patients with Chronic Hepatitis Delta
Protocol 
Identification:
MYR204
Study sites:
Approximately 25 study sites in approximately 4 countries globally which may 
include Russia, France, Moldova, Romania
Phase of 
Development:
Phase 2b
Objectives:
Primary:
The primary objective of this study is to evaluate the efficacy of bulevirtide 
administered subcutaneously at a dose of 2 mg or 10 mg in combination with 
pegylated interferon alfa-2a once weekly relative to 10 mg bulevirtide 
monotherapy in participants with chronic hepatitis delta.
Secondary:

To assess the safety of bulevirtide.
 
Methodology:
This is a randomized, open label, active controlled, parallel group multicenter 
Phase 2b study that will evaluate the efficacy and safety of bulevirtide at daily 
doses of 2 and 10 mg in combination with pegylated interferon alfa-2a (PEG-IFN 
alfa) compared to monotherapy with bulevirtide at daily dose of 10 mg and 
monotherapy with PEG-IFN alfa-2а in participants with CHD.
Diagnosis and 
Main Criteria for 
Inclusion:
Adult male and female participants with chronic HDV infection, detectable HDV 
RNA and elevated ALT at Screening.
Treatments:
Arm A:
Peginterferon alfa-2a for 48 weeks with additional 48 weeks follow-up
Arm B:
Bulevirtide 2 mg/day in combination with peginterferon alfa-2a for 48 weeks 
followed by bulevirtide 2 mg/day for 48 weeks and additional 48 weeks follow-
up
Arm C:
Bulevirtide 10 mg/day in combination with peginterferon alfa-2a for 48 weeks 
followed by bulevirtide 10 mg/day for 48 weeks and additional 48 weeks follow-
up 
Arm D:
Bulevirtide 10 mg/day for 96 weeks with additional 48 weeks follow-up
Mode of 
Administration:
The study is open label. Treatments are administered as follows:
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Concomitant 
medication: 
Criteria for 
Evaluation: 
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Bulevirtide 10 mg: Two injections ofbulevittide each 5 mg. Two injections are 
perfo1med one after another without time lag between injections. These injections 
are pe1fo1med subcutaneously (s.c.) daily, eve1y 24±1 hours. 
Bulevirtide 2 mg: One injection ofbulevittide 2 mg. Injection is pe1fo1med s.c. 
daily, eve1y 24±1 hours. 
PEG-IFN alfa: One injection of PEG-IFN alfa 180 mcg. Injections are 
perfo1med s.c. once a week. 
Nucleoside / nucleotide analogue indicated for the treatment of chronic HBV 
infection should be given dming screening, treatment and/or follow-up period if 
requfred for control of the underlying chronic HBV infection, according to the 
cmTent clinical practice guidelines (EASL and AASLD). The Sponsor will be 
providing tenofovfr (tablets) if the dmg cannot be made available for paiticipants 
through routine medical care. In paiticipants in whom tenofovir is 
contraindicated, entecavfr (tablets) will be provided. 
Primary Efficacy Endpoint 
Sustained vfrological response 24 (SVR 24) defined as undetectable HDV RNA 
(HDV RNA < lfrnit of detection [LoD]) at week 24 after the scheduled end of 
treatment (follow-up week 24 [FU-24], i.e., study week 120 for Alms B, C and 
D). 
Secondary Efficacy Endpoints 
• Undetectable HDV RNA at week 48 (all aims), 96 (Alms B, C and D) 
• Combined sustained response at week 24 and 48 after the scheduled end of 
treatment where combined response is defined as fulfilment of two conditions 
simultaneously: 
Undetectable HDV RNA or decrease by 2:: 2 log10 IU/mL from baseline. 
ALT n01malization 
• Sustained vfrological response 48 (SVR 48) defined as undetectable HDV 
RNA at week 48 after the scheduled end of treatment 
• Change from baseline in liver stiffness as measured by elastography at week 
48, 96, and 144 
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Criteria for 
Evaluation 
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Safety endpoints 
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• Frequency and nature of adverse events (based on assessments of clinical 
events, physical examination, vital signs, electrocardiogram and laborato1y 
tests) 
• Changes in vital signs 
• Changes in PR, QRS, QT, QT-inte1val conected for herut rate (QTc, Bazett), 
and herut rate based on assessments of electrocardiogram 
• Changes in laborato1y tests (hematology, coagulogram, biochemistry, blood 
bile salts, vitamin D) 
Immunogenicity variables 
• Appearance and concentration of buleviitide antibodies 
Phannacokinetic variables 
• Plasma concentr·ation ofbuleviitide 
Other variables 
• HDV /HBV genotyping 
• NTCP polymorphism 
• Resistance testing (HBV genotypic assay with focus on the HBV envelope, 
Phenotypic resistance assay and HDV genotypic assay) 
• HBeAg and HBeAg antibodies status at all postbaseline assessments (for 
pruticipants with positive HBeAg at Screening) 
• Other pru·ameters in liver biopsy samples (may include but not limited to: 
quantitative analysis of HDV RNA, HBV DNA, HBV RNA, interferon-
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stimulated genes, NTCP; semi-quantitative analysis of HBsAg and HDAg 
with immunohistochemistry)
Statistical 
Methods:
Sample size
The primary efficacy analysis of this study is the estimation of the difference in 
rates between the combination of pegylated interferon + bulevirtide 10 mg (Arm 
C) and bulevirtide 10 mg monotherapy (Arm D) of sustained virological response 
(SVR 24) defined as undetectable HDV RNA at week 24 after the scheduled end 
of treatment i.e. at study week 120. With 48 participants per treatment group a 
two-sided continuity corrected 95%-confidence interval for the difference of the 
SVR 24 rates will extend less than 22.5% from the observed difference. The 
sample size will be slightly increased to 50 participants per treatment group to 
account for a few potential early withdrawals before exposure. 
The treatment group with the combination of pegylated interferon + bulevirtide 
2 mg will be of the same size. The treatment group with the pegylated interferon 
will include 25 participants. Hence 175 participants will be randomized.
Analysis populations

Enrolled set: All participants screened and enrolled (signed Informed 
Consent) into this study.

Randomized set: All enrolled and randomized participants.

Full analysis set (FAS): All participants randomized who received study 
medication (pegylated interferon and/or bulevirtide) at least once after 
randomization.

Per-protocol (PP) set: All participants of the FAS for whom no protocol 
deviations are judged to have an impact on the analysis of the primary 
efficacy endpoint of SVR24. Details will be specified in the statistical 
analysis plan and final decision on exclusion from PP set will be made 
in a data review meeting before data base lock.

Safety population: All participants who had been exposed to study 
medication (pegylated interferon and/or bulevirtide).
Analyses based on the randomized set and the FAS will use the randomized 
treatment. Analyses based on the PP population and the Safety population will 
use the actual treatment received.
Demographic and baseline measurements
All demographic and background characteristic variables will be summarized 
by treatment group and overall to describe the study population.
The data will be presented for all participants in the FAS and the PP 
population. Presentation for Safety, and Randomized set (if applicable) will be 
done if the corresponding set size differs from the FAS set size by more than 
10%. 
Analysis of efficacy
Continuous variables will be summarized in terms of descriptive statistics 
including number of observations, mean, standard deviation, minimum, 
maximum and quartiles. Categorical variables will be summarized in terms of 


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Statistical Methods 
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frequencies and percentages. Where data are collected over time, both the 
obse1ved data and the change from baseline will be summarized by treatment 
group at each visit. 
P1imaiy analysis 
The prima1y efficacy analysis of this study is the estimation of the difference in 
rates between the combination of pegylated interferon + buleviitide 10 mg (Alm 
C) and bulevirtide 10 mg mono therapy (Alm D) of sustained virological 
response (SVR 24) defined as undetectable HDV RNA at week 24 after the 
scheduled end of treatment i.e. at study week 120. 95%-confidence inte1val with 
exact unconditional confidence limits using the score statistic will be presented 
for the rate differences. Clopper-Peai·son 95%-confidence inte1vals will be 
calculated for the single rates. The p-value of a two-sided Fisher test will be 
calculated. 
Participants with missing FU-24 assessment in HDV RNA will be handled as 
non-responders unless it is related to coronavims disease 2019 (COVID-19) in 
which case missing values will be imputed using the next obse1vation caiTied 
backwai·d (NOCB) approach. 
The prima1y analysis will be based on the FAS. The analysis will be repeated 
for the PP set and in case of differences between the FAS and the randomized 
set also for the randomized set to assess consistency and robustness of results. 
The influence of covariables e.g. presence of ciIThosis and region will be 
investigated using logistic models. 
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Statistical Methods 
(continued):
Analysis of safety
Adverse events
Adverse events (AE) will be coded using MedDRA and will be presented by 
primary System Organ Class (SOC) and Preferred Term. The analysis will 
focus on the treatment-emergent AEs (TEAE), i.e., AEs which started or 
worsened after start of treatment and no later than 30 days after permanent 
discontinuation of treatment. The frequency of TEAEs will be summarized by 
incidences. In these summaries, each participant will be counted only once 
within each preferred term and SOC. 
Frequencies of TEAEs will also be presented by relationship to study treatment 
and by maximum severity. Additional analyses will be performed for SAE, 
TESAE and AEs leading to dose reduction and AE leading to discontinuation.
Vital signs 
Vital signs will be described by summary statistics for measured values and 
changes from baseline by visit.
Laboratory parameters
Laboratory parameters will be described by summary statistics for measured 
values and changes from baseline by visit.
The clinical assessment of laboratory variables (abnormal high/ clinically 
relevant, abnormal high/not clinically relevant, within normal limits, abnormal 
low/not clinically relevant, abnormal low/clinically relevant) will be tabulated 
by visit for each clinical laboratory analyte in frequency tables. Additionally, 
for each laboratory parameter shifts in assessments from baseline to week 48 
and week 96 visit will be presented (shift tables).
ECG
The ECG assessment summary categories will be tabulated by visit. 
Additionally, shifts in assessments from baseline to visits will be presented 
(shift tables).
Descriptive summaries of actual values and changes from baseline will be 
presented for ECG measures of PR interval, QRS interval, QT interval, QT-
interval corrected for heart rate (QTc, Bazett), and heart rate by visit.
Also, the number and percent of participants in each treatment group with QTc 
values 451 - 480 ms, 481 - 500 ms or >500 ms and the number and percent of 
participants in each treatment group who experienced a change vs. baseline >30 
ms or a change >60 ms will be presented by visit.
Immunogenicity
The production of bulevirtide antibodies will be presented by visit.
Pharmacokinetics 
Plasma concentration of bulevirtide will be described by descriptive statistics
Other safety assessments
Other safety variable will be described by appropriate descriptive statistics. 


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Table 1. 
Schedule of Events 
Study phase 
Screening 
48 (or 96)-week Treatment phase* 
48-week Follow-up phase* 
V (Visit) / 
SCR 
Vl 
V2 - V8 
V9 - V14 
FU l 
FU2-5 
FU 6 
W (Week) / D (Day) 
/EOS 
D-28 to D-
WO/ 
±2 days 
±2 days 
± 3 days 
±3 days 
±7 days 
Procedures 1 
1 ** 
D1 
All groups: W4, W8, 
Only Arms B, C and D: 
A:W52 
A:W56, W64, W72, 
A: W96 
W16, W24, W32, W40, 
W52, W56, W64, W72, 
B, C, D: WlOO 
W84 
B,C,D: 
W48 
W84, W96 
B, C, D: W104, W112, 
W144 
W120, W132 
CLINICAL AND INSTRUMENTAL EVALUATIONS 
Informed consent 2 
X 
Demographics 3 
X 
Medical histo1y, prior therapy 4 
X 
Weight, height, BMI 
X 
X 
X 
X 
X 
X 
X 
(height and BMI at SCR only) 
Physical examination 5 
X 
X6 
X 
X 
X 
X 
X 
Assessment of local reactions at the 
X 
X 
X 
X 
injection sites 
Complete eye examination 
X 
As clinically indicated 
Vital signs 7 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogram (ECG) 
X 
X (W8, W24, W48) 
X(W72, W96) 
X (A: W72; B, C and 
X 
D: W120) 
Abdominal ultrasound 
X 
Transient elastometiy (Fibroscan) 
X 
X(W48) 
X (W96) 
X (A: W72; B, C and 
X 
D: W120) 
Breath alcohol test 
X 
X 
Inclusion/Exclusion criteria 
X 
X 
Adverse events (including liver related 
clinical 
events 
starting 
from 
the X(SAE only) 
X 
X 
X 
X 
X 
X 
randomization) 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
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Study phase 
Screening 
48 (or 96)-week Treatment phase* 
48-week Follow-up phase* 
V (Visit) / 
SCR 
Vl 
V2 - V8 
V9 - V14 
FU l 
FU2-5 
FU6 
W (Week) / D (Day) 
/EOS 
D-28 to D-
WO / 
±2 days 
±2 days 
± 3 days 
±3 days 
±7 days 
Procedures 1 
1 ** 
D1 
All groups: W4, W8, 
Only Arms B, C and D: 
A:W52 
A:W56, W64, W72, 
A: W96 
W16, W24, W32, W40, 
W52, W56, W64, W72, 
B, C, D: WlOO 
W84 
B,C,D: 
W48 
W84, W96 
B, C, D: W104, W112, 
W144 
W120, W132 
TREATMENT DISPENSING/RETURN 
Randomization 8 
X 
Study treatment dispensing 9 
x9 
x9 
x9 
Study treatment return and treatment 
X 
X 
compliance assessment 
Participant Dia1y Dispensing/Review/ 
X 
X 
X 
Collection 
Quality oflife questionnaires (EQ-5D, 
X 
X (W24, W40, W48) 
X(W72, W96) 
X(W72) 
X 
FSS, HQLQ™) 
LOCAL LABORATORY/STUDY SITE 
Urine pregnancy test 10 
X 
X 
X 
X 
X 
X 
X 
Urine dmg screening test 
X 
ANALYSIS PERFORMED IN CENTRAL LABORATORY I SAMPLES TO BE SENT TO CENTRAL LABORATORY AT ONCE 
Serology (anti-HIV, anti-HCV, anti-
X 
HDV) 
HCV RNA (ifanti-HCV positiveatSCR.) 
X 
HBeAg and HBeAg antibodies 
X 
Urinalysis 
X 
X6 
X 11 
X 11 
X 
X 
X 
Hematology 12 
X 
x6 
X 
X 
X 
X 
X 
Biochemistry (full panel) 13 
X 
x6 
X(W24, W48) 
X(W72, W96) 
X 
Biochemistry (abbreviated panel) 14 
X (W4, W8, W16, W32, 
X (W52, W56, W64, 
X 
X 
W40) 
W84) 
Coagulogram 15 
X 
x6 
X (W8, W24, W40, 
X (W64, W72, W84, 
X (W72, W120) 
X 
W48) 
W96) 
Total blood bile salts 
X 
X 
X 
X 
X 
X 
Alpha-fetoprotein test 
X 
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Study phase 
Screening 
48 (or 96)-week Treatment phase* 
48-week Follow-up phase* 
V (Visit) / 
SCR 
Vl 
V2 - V8 
V9 - V14 
FU l 
FU2-5 
FU6 
W (Week) / D (Day) 
/EOS 
D-28 to D-
WO / 
±2 days 
±2 days 
±3 days 
±3 days 
±7 days 
Procedures 1 
1 ** 
Dl 
All groups: W4, W8, 
Only Arms B, C and D: 
A:W52 
A:W56, W64, W72, 
A: W96 
W16, W24, W32, W40, 
W52, W56, W64, W72, 
B, C, D: WlOO 
W84 
B,C,D: 
W48 
W84, W96 
B, C, D: W104, W112, 
W144 
W120, W132 
VitaminD 
X 
X(W24, W48) 
X(W72, W96) 
X (W72, W120) 
X 
TSH16 
X 
X (W8, W24, W48) 
Senun alpha-2-macroglobulin 
X 
X(W48) 
X (W96) 
X(W120) 
X 
HBV DNA for pts. not receiving 
X 
Nucleoside / nucleotide analogues 
ANALYSIS PERFORMED IN CENTRAL VIROLOGY LABORATORY I SAMPLES TO BE SENT TO CENTRAL LABORATORY AT ONCE 
HDVRNA 
X 
II 
ANALYSIS PERFORMED IN CENTRAL VIROLOGY LABORATORY I SAMPLES TO BE STORED AT SITE 
HDV genotyping 
X 
HDVRNA 
X 
X 
X 
X 
X 
X 
HBV DNA (HBV genotyping at first 
X 
X 
X 
X 
X 
X 
positive HBV DNA) 
HBsAg 
X 
X 
X 
X 
X 
X 
HBsAg antibodies 17 
X 
X(W24, W48) 
X(W72, W96) 
X (A: W72; B, C and 
X 
D: W120) 
HBeAg and HBeAg antibodies 18 
X 
X(W48) 
X (W96) 
X 
ANALYSIS PERFORMED IN CENTRAL LABORATORY I SAMPLES TO BE STORED AT SITE 
Immunogenicity (bulevi.ttide antibodies) 
X 
X (B, C and D: W16, 
X(W72, W96) 
X (B, C and D: W120) 
X 
19 
W24, W48) 
NTCP polymorphism20 
X 
Resistance tests (HBV genome 
sequencing, Phenotypic assay, HDV 
x21 
x21 
x21 
x21 
x
21 
x 21 
genome sequencing) 21 
Pharmacokinetics 22 
x22 
x22 
X22 
Liver biopsy 
x23 
X (A: W72; B, C, and 
D: W120) 24 
EQ-5D - EuroQol 5-Dimentions; FSS - Fatigue Severity Scale; HQLQTM - The Hepatitis Quality of Life Questionnaire™. 
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* Duration of treatment is 48 weeks for Arm A and 96 weeks for Arms B, C and D. For participants of Arm A the Follow-up period starts after W48 of 
treatment. For participants of Arms B, C and D the Follow-up period starts after W96 of treatment. See study design for detailed information on duration 
of treatment in different groups.
**Screening can be shorter than 28 days as soon as eligibility of participant is confirmed.
1. Detailed description of all study procedures can be found in Section 6 of this protocol.
2. Signed and dated informed consent must be obtained before any procedure specific to this protocol.
3. Demographics includes: date of birth, sex, race, smoking/alcohol/drugs abuse history and current use.
4. Information about diseases, conditions and surgeries related to the liver is collected for a lifelong period; Information about other diseases, conditions 
and surgeries is collected if they have occurred within 5 years before the Screening or regardless of the time if they are considered to be relevant by 
Investigator. All previous treatment for viral hepatitis should be recorded. Prior therapy for other diseases is collected for therapies that participant 
receives currently and therapies that were discontinued within 3 months before Screening.
5. A complete physical examination is performed at Screening (SCR), Randomization (V1), week 24, week 48, week 96 and week 144. A complete 
physical examination includes evaluation of general appearance, skin, head, eyes, ears, nose and throat, lymph nodes, respiratory, cardiovascular, 
gastrointestinal including hepatobiliary assessment, musculoskeletal, endocrine system, nervous systems, and urogenital system. At all other visits, a 
symptom directed physical examination is performed.
6. If at Screening was done over 14 days ago.
7. Vital signs include body temperature, heart rate and blood pressure. Vital signs are measured as indicated in Table 1 and when clinically indicated.
8. Participants eligible for the study are randomized after completion of all procedures scheduled for Screening and Day 1 related to confirmation of 
participant’s eligibility (See Section 4). All other procedures of Day 1 (except sample collection for pharmacokinetic and assessment of adverse events 
including assessment of injection site reaction) should be performed before study drug administration.
9. Participants should be instructed NOT to administer bulevirtide at home at days of visits to study sites. At these days bulevirtide is administered at study 
site in accordance with schedule of events for assessment of immunogenicity and pharmacokinetics of the study drug.
10. Only for women of childbearing potential.
11. Urinalysis is not needed at W4, W52 (for B, C and D arms only. Assessment for Arm A at FU1 is required).
12. Hematology includes: hemoglobin, hematocrit, reticulocytes, RBC, platelet count, WBC with differential (absolute counts and percentage for 
neutrophils, eosinophils, basophils, monocytes, and lymphocytes).
13. Full biochemistry (total protein, albumin, ALT [this sample will be used to obtain ALT results for efficacy assessment as described in Section 6.5.4], 
AST, GGT, P-amylase, alkaline phosphatase, lipase, total bilirubin, direct bilirubin, total cholesterol, creatinine, urea, glucose, potassium, sodium, 
chloride, phosphorus, and CRP). 
14. Abbreviated biochemistry (albumin, ALT [this sample will be used to obtain ALT results for efficacy assessment as described in Section 6.5.4], AST, 
GGT, total bilirubin, direct bilirubin, creatinine, lipase, P-amylase, CRP). 
15. Coagulogram includes prothrombin time, INR and aPTT.
16. Only for Arms A, B, C 
17. Collection of anti-HBsAg samples at designated time points; testing only if HBsAg becomes undetectable.
18. Collection and testing of HBeAg and HBeAg antibodies only if participant is HBeAg positive at SCR.


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19. Samples for immunogenicity assessment should be taken before administration of the study drug(s), for B, C and D arms only.
20. Blood samples for determination of NTCP polymorphism are collected at Day 1 for all the participants. NTCP polymorphism will be performed in 
central laboratory for participant who are either non-responders or have viral breakthrough as detailed in Section 6.4.4 of this protocol.
21. Dedicated samples for phenotypic assay are collected only at Day 1. For other resistance tests (HBV genome sequencing and HDV genome sequencing) 
and phenotypic assay at the other timepoints back-up virology samples are used. Full Resistance tests are performed in participants for whom results of 
HDV RNA testing in central laboratory indicate lack of response (non-responders) or viral breakthrough as detailed in Section 6.4.4 of this protocol.
22. Pharmacokinetics samples are taken only for Arms B, C and D. One sample at each visit 1h±15 min post bulevirtide dose.
23. At Screening liver biopsy is performed after confirmation of eligibility. If a liver biopsy was performed within 1 year prior to Screening, and a participant 
can provide biopsy records and appropriate biopsy specimens, the available specimens can be used for the baseline evaluation and biopsy at Screening 
is not required. Otherwise liver biopsy at screening is performed if feasible provided that participant is considered to be eligible after the review of all 
eligibility criteria.
24. Liver biopsy should be performed within ± 7 days from the date of the visit for participants who do not have medical contraindications for the procedure. 
If baseline liver biopsy samples are not available (were not provided to central laboratory or were considered as non-evaluable by central laboratory) 
subsequent liver biopsy should not be performed. 


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1. 
INTRODUCTION 
1.1. 
Hepatitis Delta 
Hepatitis delta is liver inflammation caused by infection with hepatitis D vim s (HDV), which 
requires the presence of hepatitis B vims surface antigen (HBsAg) for its complete replication 
and transmission. HDV is a hepatotropic vims with a small RNA genome also containing the 
hepatitis delta antigen (HDAg). HDV is necessarily associated with Hepatitis B vims (HBV) 
infection, as HDV ribonucleoprotein buds through the HBsAg secreto1y pathway. HDV genome 
is a single-stranded RNA of 1,680 bases; it has historical homology with viroids or plant vims 
satellite RNA (1). The HDAg consists of2 isofonns, the small 24 kD protein which is required 
for the replication, and the larger 27 kD protein which is needed for virion fo1mation. Eight 
genotypes of HDV exist, whereas genotype 1 is the most coilllllon in the world and in Europe 
(2). 
In general, HDV is a highly pathogenic vims causing acute and chronic liver disease. Although 
benign course of the disease has been described (3), patients with hepatitis delta usually have 
progressive liver disease leading to compensated or decompensated cinhosis. Evidence was 
repo1i ed in the literature, that unlike HBV, HDV can be associated with direct cytotoxicity which 
may hasten the fibrosis process (4,5). However, the iilllllune system plays the major role in the 
clearance of the infected hepatocytes; levels of HDV viremia are not directly associated with 
histological changes (6). There is no histological feature distinctive of hepatitis delta from other 
types of viral hepatitis. Biopsy specimens of patients with chronic hepatitis delta exhibit po1ial 
and peripo1ial inflailllllation, fragmentaiy necrosis, often accompanied by fibrosis and ciIThosis. 
Mai·ked intraglobular infiltration by mononuclear cells and degenerative changes in hepatocytes 
is seen (7). Clinically, hepatitis delta may cause acute or fulminant hepatitis, chronic infection 
may lead to asymptomatic caiTier state or evolve to rapidly progressive chronic liver disease. 
Chronic Hepatitis delta (CHD) develops in 70-90% of patients with HDV superinfection. The 
liver disease associated with HDV mns a more progressive course than chronic hepatitis B 
(CHB) and may lead to ciIThosis within 2 years in 10-15% of patients (8). Hepatitis delta is 
considered the most severe fonn of viral hepatitis in humans (9), and is associated with 
progression of liver disease, development of cinhosis and decompensation (10, 11 ). 
In regions endemic for HDV infection, the liver disease is representing 
a major health cai·e challenge. A study from Italy has shown existence of HDV antibodies in as 
many as 40% of patients with liver ciIThosis in 1987. Although this number has declined to 11 % 
in 2000 (13), the HOV-caused disease is still a significant burden. A longitudinal study has 
shown that 20% of hepatitis delta patients develop a liver-related first tune event during the 
median follow-up time of 4 years, vs only 8.5% of HBV monoinfected patients (14). At baseline, 
19.8% of the patients of this cohort had ciIThosis, compai·ed to 7.3% of CHB patients. HDV was 
a cause of death for 60% of patients in a 28-yeai· study from Italy (15). HDV co-infection is 
associated with faster progression to fibrosis and ciIThosis, eai·lier onset of hepatic complications 
and likelihood of liver transplantation (3,16,17). Liver ciIThosis and cancer occur 10-15 yeai·s 
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earlier in HBV/HDV co-infection and the 5-year mortality of co-infected individuals is twice that 
of HBV monoinfection (18). Chronic HDV infection causes cirrhosis and hepatocellular 
carcinoma (HCC) with annual rates of 4% and 2.8%, respectively (15).
In average, 5-10% of HBsAg-positive patients who admit to tertiary centers are tested positive 
for HDV in the EU. The calculation of total number of people affected by hepatitis delta in the 
EU has yielded the estimate of 145,000 persons. Accounting for EU population of 505,665,700 
(2013), the prevalence of the condition is estimated to be 2.9 in 10,000 people which is below the 
Orphan Drug designation threshold.
The estimated HDV prevalence in the United States (US) is based on limited data from literature. 
A recent study utilizing data of a tertiary center database revealed HDV prevalence of 8% among 
HBsAg carriers (19). 11% of injection drug users were tested positive for HDV in Baltimore; in 
those with chronic HBV infection, 50% were HDV positive (20). In average, 5-10% of HBsAg 
positive patients who admit to tertiary centers are tested positive for HDV. The calculation of 
total number of people affected by hepatitis delta in the US has yielded the estimate of 63,800 
persons (worst-case scenario). This is below the Orphan Drug designation threshold of 200,000 
people affected by the condition.
1.2.
Treatment Options for Hepatitis Delta 
The therapeutic options for HDV co-infected patients have been limited. Previously, only 
interferons show some degree of efficacy in a small proportion of patients with approximately 
25% of virological and biochemical response. Antiviral agents active against HBV do not work 
against HDV (17).
Several clinical trials were recently performed investigating the use of pegylated interferon alpha 
in hepatitis delta. The two large trials in this indication, HIDIT-1 and HIDIT-2, did show only 
very modest long-term virological results. In the HIDIT-1 clinical trial, pegylated interferon was 
tested in combination with nucleotide analogue adefovir dipivoxil versus either drug along in 91 
chronically HDV infected participants (21). At test week 48, 23% of participants on combination 
therapy, 24% on pegylated interferon monotherapy, and no participants on adefovir reached 
HDV RNA negativation. The effect was sustained through week 24. However, the follow-up 
study revealed that from 16 individuals who have reached HDV RNA negativity at the end of 
treatment, 9 tested positive within the median follow-up of 4.5 years (0.5-5.5 years) (22). In the 
HIDIT-2 clinical trial, 120 participants received pegylated interferon alpha with or without 
tenofovir disoproxil fumarate for 96 weeks. The prolongation of the interferon treatment to 96 
weeks and addition of nucleotide analogue Tenofovir did not improve sustained virological 
response rates: 30% of participants in the combination arm and 23% of participants in the 
monotherapy arm were HDV RNA negative 24 weeks after the end of treatment. Of note, 20 
participants (16%) did not complete at least week 80 of treatment. A trial involving 49 
participants treated with pegylated interferon alpha 2b has shown 33% of HDV RNA 
negativation at the end of treatment (48 weeks) and 25% at the end of follow-up (23).


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1.3.
Background on Bulevirtide
1.3.1.
Description of the Study Drug
Bulevirtide is a myristoylated N-terminal and amidated C-terminal 47-amino acid lipopeptide. 
The drug substance is available as acetate salt. Drug formulation is lyophilized powder for 
injections. Bulevirtide is supplied in sterile vials. The vial content has to be reconstituted in 1 mL 
sterile water for injection prior to administration. Bulevirtide is given by subcutaneous injection.
Bulevirtide blocks the entry of HBV into hepatocytes by binding to and inactivating an essential 
HBV/ HDV entry receptor described as sodium-taurocholate cotransporting polypeptide (NTCP) 
receptor. Bulevirtide acts at a post attachment step probably misdirecting the entry route of 
HBV/ HDV to an unproductive cellular pathway.
Bulevirtide (2 mg) is conditionally approved under the brand name Hepcludex® in the European 
Union (EU) and other countries in Europe and is fully approved as Myrcludex B® in Russia for 
the treatment of CHD in adults with compensated liver disease.
1.3.2.
Summary of Clinical Data
Six clinical studies have been conducted on bulevirtide so far and one clinical study is currently 
ongoing:

Study MYR101: An Open-Label, Single Center Phase 1a Clinical Trial to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of Myrcludex B in Healthy Volunteers 
[completed]

Study MYR102: Assessment of a Potential Drug-Drug Interaction Between the Novel 
Antiviral Drug Candidate Myrcludex B and the Nucleotide Analogue Reverse Transcriptase 
Inhibitor Tenofovir [completed]

Study MYR201 (Part I): A Phase 1b/2a randomized, open-label clinical trial of daily 
bulevirtide versus Entecavir in participants with HBeAg negative chronic hepatitis B 
(Russia) [completed]

Study MYR201 (Part II): Randomized open-label substudy of daily bulevirtide plus 
pegylated interferon-alpha-2a in participants with HBeAg negative chronic hepatitis B co-
infected with hepatitis delta (Russia) [completed]

Study MYR202: A multicenter, open-label, randomized clinical study to assess efficacy and 
safety of 3 doses of bulevirtide for 24 weeks in combination with tenofovir compared to 
tenofovir alone to suppress HBV replication in participants with chronic hepatitis D 
(Germany, Russia) [completed]

Study MYR203: A multicenter, open-label, randomized, comparative, parallel-group Phase 2 
study to assess the efficacy and safety of the combination of bulevirtide and pegylated 
interferon-alpha-2a as compared with pegylated interferon-alpha-2a monotherapy in 
participants with chronic hepatitis B with delta-agent (Russia) [completed]


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
Study MYR301: A Multicenter, Open-label, Randomized Phase 3 Clinical Study to Assess 
Efficacy and Safety of Bulevirtide in Patients with Chronic Hepatitis Delta [ongoing]
MYR101 Study
A Phase I single-dose study (MYR101) was conducted in 36 healthy male participants. Selected 
dose groups were 0.3 μg, 3 μg, 10 μg, 100 μg, 800 μg, 3 mg, 5 mg, 10 mg, and 20 mg for 
intravenous application and subcutaneous administration was carried out with 800 μg, 5 mg, and 
10 mg. Each dose was administered to a cohort of 3 consecutive participants. For all cohorts and 
both administration routes administration of bulevirtide was uneventful and well tolerated. After 
administration, there were no relevant changes in vital signs (blood pressure, heart rate, 
respiratory rate, and body temperature), 12-lead ECGs, and safety laboratory values. Overall, 
85 adverse events (AEs) were observed in 29 individuals, none of these was serious. Events were 
equally distributed between cohorts and no organ system was predominantly affected. Seventy-
four events were mild in nature, nine moderate, and only two were severe (Grade 3) according to 
CTCAE 4.0 criteria (increased lipase; increased amylase). Anti-drug antibodies were measured 
until 6 months after exposure and were negative for all individuals.
Bulevirtide has been well tolerated in all participants, no SAE and no dose limiting toxicities 
occurred. The AEs were mostly mild in nature and self-limiting and no pattern suggesting a 
relationship with bulevirtide or unexpected off-target effects were seen. There was no dose-
dependency of AE frequency or severity. This matches the observations from animal studies, 
where bulevirtide exhibited a highly specific and exclusive binding to hepatocyte. Therefore, 
bulevirtide had a good safety profile even in the cohorts with high doses in this trial.
Bulevirtide showed strong dose dependent pharmacokinetics; the area-under-the-time-plasma 
concentration curve increased disproportionally while the clearance and volume of distribution 
decreased with higher doses. The bioavailability of the drug after subcutaneous administration 
was estimated to be 88%. The release after subcutaneous administration was best described by a 
parallel slow and fast first-order process, where 59% of the bioavailable dose was absorbed fast 
and the remaining 41% of the dose was absorbed slowly with absorption half-lives of 1.3 h and 
5.4 h, respectively. A simulation of the impact of various doses of bulevirtide on the occupancy 
of the binding target revealed that at doses of 10 mg most of the binding target was occupied 
>80% for at least twenty hours in a simulated steady-state after subcutaneous administration.
MYR102 Study
A Phase 1 drug interaction study (MYR102) in healthy participants investigated the influence of 
receptor-saturating dose on pharmacokinetics of anti-HBV drug tenofovir. Twelve healthy 
participants received 245 mg of oral tenofovir disoproxil for 5 days alone followed by 6 days of 
co-administration of 10 mg subcutaneous bulevirtide. Plasma samples were collected and 
bulevirtide, tenofovir, and plasma bile salts were quantified. Repeatedly, a 30 μg midazolam 
microdose was administered to determine the impact of the antivirals on CYP3A activity.
The combination of bulevirtide and tenofovir was well tolerated. A total of 28 adverse events 
occurred in 10 out of 12 participants, 12 of which were considered to be at least possibly related 
to tenofovir or bulevirtide treatment (anemia [2], first-degree atrioventricular block [1], diarrhea 


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[1], nausea [1], injection site hypersensitivity [2], increased ALT [5], increased amylase [1], 
increased AST [1], increased lipase [2], muscular weakness [1], and headache [1]). With the 
exception of one Grade 3 increase in lipase levels, all treatment-related adverse events were 
mild. Lipase levels showed marked day to day fluctuations in this participant. Two participants 
experienced localized hypersensitivity reactions for about 30 min after each administration of 
bulevirtide (erythema, pruritus) without accompanying signs of systemic anaphylaxis.
Bulevirtide did not have a significant effect on tenofovir pharmacokinetics including renal 
tenofovir clearance. Bulevirtide pharmacokinetic parameters after first and repeated dosing were 
comparable to those observed in two other clinical studies with the substance. Therefore, a 
clinically relevant influence of tenofovir on bulevirtide concentrations seems unlikely. Estimated 
metabolic clearance of midazolam exhibited a downward trend with a gradual decrease during 
the course of the study. Geometric mean values were 1022 mL/min (95% CI: 801.5, 1303) 
without co-medication, 869.1 mL/min (679.8, 1111) under tenofovir, and 724.8 mL/min (592.5, 
886.7; p-value 0.02 vs. baseline) under tenofovir and bulevirtide treatment.
Differences were significant between baseline and co-administration of tenofovir and bulevirtide, 
but not between tenofovir monotherapy (baseline immediately before start of bulevirtide) and 
combination therapy. Therefore, our results did neither confirm nor rule out an influence of 
bulevirtide on CYP3A activity. The small and clinically irrelevant inhibition of CYP3A activity 
by tenofovir or its prodrug might account for the statistically inconclusive results. 
Coadministration of regular tenofovir doses with bulevirtide was well tolerated and revealed no 
clinically relevant change in either drug`s pharmacokinetics or CYP3A activity, suggesting that 
these drugs can be safely combined without dose modification.
MYR201 Study (Part I – Chronic Hepatitis B)
This was an 
 randomized, open-label, multicenter, active-controlled, parallel-group 
study of daily bulevirtide versus Entecavir in participants with HBeAg negative chronic 
hepatitis B. Participants of both sexes at the age of 18–65 years with HBeAg negative chronic 
hepatitis B and mild to moderate disease activity confirmed by HBV DNA ≥ 10 000 copies/mL 
and ALT level ≥ 1.5  ULN and ≤ 6 x ULN were enrolled into this study. A total of 48 
participants were randomized into 6 treatment groups, each of 8 participants:
Cohort A (n=8): Bulevirtide 0.5 mg daily subcutaneously (SC) for 12 weeks + 12 weeks 
follow-up
Cohort B (n=8): Bulevirtide 1 mg daily SC for 12 weeks + 12 weeks follow-up
Cohort C (n=8): Bulevirtide 2 mg daily SC for 12 weeks + 12 weeks follow-up
Cohort D (n=8): Entecavir 0.5 mg daily orally for 24 weeks
Cohort E (n=8): Bulevirtide 5 mg daily SC for 12 weeks + 12 weeks follow-up
Cohort F (n=8): Bulevirtide 10 mg daily SC for 24 weeks + 12 weeks follow-up
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Safety and tolerability, plasma pharmacokinetic parameters, immunogenicity and virological 
responses were assessed in this trial. Levels of HBsAg, HBV DNA and ALT were used to assess 
efficacy.
A dose-dependent decrease in viral load was reported at week 12 of treatment. Six (6) of 8 
participants (75%) of the 10 mg bulevirtide cohort had a decline in serum HBV DNA of more 
than 1 log10 IU/mL in comparison to baseline. The participants of the 10 mg bulevirtide cohort 
continued the treatment for 24 weeks, maintaining HBV DNA levels achieved at week 12. At 
lower dose levels, no per cohort dose dependency was observed; per cohort, at most 25% of 
lower dose participants achieved > 1 log10 IU/mL HBV DNA reduction at week 12. Normal ALT 
was reported in 50-75% of participants receiving bulevirtide at week 12, irrespective of dose 
level. No effect on HBsAg was observed.
A total of 69 adverse events were reported during the study. Overall, in the bulevirtide treatment 
groups the AEs were predominantly clustered in the same 4 SOCs: ‘General disorders and 
administration site condition’; ‘Investigations’; ‘Skin and subcutaneous tissues disorders’; 
‘Blood and lymphatic system disorders’. In the Entecavir treatment group all the AEs were in the 
3 SOCs: ‘General disorders and administration site condition’; ‘Infections and infestations’; 
‘Respiratory, thoracic and mediastinal disorders’.
A total of 45 adverse events were considered as related with bulevirtide. In general, treatment-
related AEs were of mild severity (a total of 41 events). The events of moderate severity were 
erythema, gamma-glutamyltransferase increased, reticulocyte increased, injection site dermatitis. 
Neither treatment group had any reports of AEs judged to be severe. There were 2 AEs 
considered to be serious: drug withdrawal syndrome reported for 1 participant of the 1 mg 
bulevirtide cohort and 1 participant of the 2 mg bulevirtide cohort. There were no participants 
who prematurely discontinued participation in the study due to AE/SAE. There were no deaths in 
the study.
Levels of bile salts are important secondary pharmacodynamics parameter, as a bile salts 
transporter NTCP is the target of bulevirtide. A dose-dependent, asymptomatic increase of bile 
salts which are NTCP substrates (i.e. taurocholate and glycocholate) was detected; whereas 
lithocholic acid (non-substrate for NTCP) levels were not affected. Antibodies to bulevirtide 
were detected in 58% of participants of bulevirtide dose groups. No correlation was observed 
between the appearance of antibodies and pharmacodynamic parameters. Elevated levels of bile 
salts, which are a secondary pharmacodynamic parameter and are indicative for drug-target 
binding, were detected independent of antibody positivity. Virological and biochemical response 
was not different in participants who were antibody-positive versus antibody-negative.
MYR201 Study (Part II – Chronic Hepatitis Delta)
This was a randomized, open-label, single-center, active-controlled, parallel-group study. 
Participants of both sexes at the age of 18–65 years with HBV/HDV co-infection confirmed by 
the presence of HBsAg for at least 6 months and positive HDV antibodies status for at least 3 
months before screening, as well as positive results for HDV RNA within the screening period 
were enrolled in the study. A total of 24 participants were randomized in 1:1:1 ratio into the 3 
treatment arms:


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Arm A (n=8): Bulevirtide 2 mg daily subcutaneous injection (SC) for 24 weeks, followed by 
PEG IFN alfa-2a for 48 weeks + 24 weeks follow-up
Arm B (n=8): Bulevirtide 2 mg daily SC and PEG IFN alfa-2a for 24 weeks, followed by 
monotherapy with PEG IFN alfa-2a for 24 weeks + 24 weeks follow-up
Arm C (n=8): PEG IFN alfa-2a for 48 weeks + 24 weeks follow-up
Safety and tolerability, immunogenicity and virological responses were assessed in this trial. 
Levels of HBsAg, HBV DNA, HDV RNA and ALT were used to assess efficacy.
The 24-week therapy with bulevirtide both in Arm A and Arm B was not associated with higher 
number of HBsAg responders (defined as HBsAg decline of ≥ 0.5 log10 IU/mL) as compared 
with Arm C.
Combination therapy with bulevirtide 2 mg and PEG IFN alfa-2a for 24 weeks showed the 
highest rate of fast HBV DNA responders (defined as HBV DNA decline by > 1 log10 IU/mL; 
6/8 participants). Overall, both bulevirtide-containing regimens (Arm A and B) showed more 
considerable HBV DNA response as compared with PEG IFN alfa-2a monotherapy (Arm C). At 
week 48, there were 5/8 responders in Arm A, 4/8 in Arm B and 3/8 in Arm C. At week 72 there 
were 5/8 responders in Arm B. At the end of follow-up, the number of responders decreased in 
all treatment groups: there were 3/8 responders in Arm A, 3/8 responders in Arm B and 2/8 
responders in Arm C (FAS).
All treatment regimens demonstrated a considerable number of HDV RNA responders (defined 
as HDV RNA decline by > 1 log10 IU/mL) at week 24. Monotherapy with bulevirtide showed 
response rates comparable to response rates observed in participants treated with PEG IFN alfa-
2a (6/7 participants). The combination treatment of bulevirtide + PEG IFN alfa-2a demonstrated 
the highest response rate, thus indicating a potential synergistic effect (7/8 participants). HDV 
RNA became undetectable in 2 of 7 participants treated with bulevirtide (Arm A) and PEG IFN 
alfa-2a (Arm C) and in 5 of 8 participants treated with bulevirtide + PEG IFN alfa-2a (Arm B). 
Further during the treatment there was an obvious decrease in the number of responders after the 
cessation of bulevirtide in Arm A and Arm B, while no changes were observed in Arm C.
The highest rate of ALT responders was observed after the 24-week monotherapy with 
bulevirtide (Arm A); however further switching to PEG IFN alfa-2a led to the decrease of ALT 
response. No considerable difference was observed between Arm B and Arm C.
All randomized participants (24/24, 100.0%) experienced at least one AE during the study. A 
total of 226 AEs were reported: 85 AEs in Arm A, 59 AEs in Arm B and 82 AEs in Arm C. The 
AEs were predominantly clustered in the same 3 SOCs: ‘Blood and lymphatic system disorders’, 
‘Investigations’, ‘General disorders and administration site condition’. The preferred terms with 
the most AEs reported were leucopenia, neutropenia, thrombocytopenia, each reported in more 
than 5 participants from each treatment group. The most common biochemical abnormalities 
were AST and ALT increased with the higher incidence observed in Arm A (6 and more 
participants) as compared with Arm B and C (3 participants). Influenza-like illness was the most 
reported adverse event within the SOC “General disorders and administration site conditions”.


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The majority of AEs were of mild or moderate in intensity. A few participants experienced 
severe AEs during the study: 1 participant in Arm B and 2 participants in each Arm A and Arm 
C. Severe AEs were hematological (leucopenia, neutropenia, thrombocytopenia) and 
biochemical (ALT, AST, GGT increased) abnormalities.
There was a 100% incidence (8/8 participants) of the PEG IFN-alpha 2a-related AEs in each 
treatment group, while the incidence of the bulevirtide-related AEs comprised 37.5% (3 
participants) in Arm A and 12.5% (1 participant) in Arm B. Those related to PEG IFN-alpha 2a 
were leucopenia, neutropenia, thrombocytopenia, anemia, ALT, AST, GGT, bilirubin increased, 
aPTT prolonged, influenza-like illness, fatigue, pyrexia, dizziness, irritability and rash. The 
bulevirtide-related AEs included single cases of hematological disorders (leucopenia, 
neutropenia, thrombocytopenia and eosinophilia).
There were no deaths or other SAEs during the study. One participant discontinued the study due 
to AE: participant from Arm B who experienced rash of moderate intensity that was judged to be 
related to PEG IFN-alpha 2a.
There was on-treatment immune response observed for both bulevirtide-containing regimens 
(Arm A and B). Overall, there were 4 participants in Arm A and 7 participants in Arm B that had 
positive immunogenicity response (increase of bulevirtide antibodies by >2 fold as compared to 
baseline). After the cessation of bulevirtide, there was a significant decline of anti-drug 
antibodies titers. There were no obvious signs of the influence of immunogenicity on safety and 
efficacy results found in Arm A and B.
MYR202 Study (Completed)
MYR202 study aimed to evaluate the efficacy and safety of bulevirtide at daily doses of 2, 5 or 
10 mg in combination with tenofovir disoproxil fumarate (TDF) compared to TDF alone in 
participants with chronic hepatitis D.
The primary efficacy endpoint was HDV RNA response at week 24 defined as undetectable 
HDV RNA or decrease by ≥2 log10 IU/mL from baseline. Combined response was defined as 
fulfilment of two conditions simultaneously: undetectable HDV RNA or decrease by 
≥ 2 log10 IU/mL from baseline; ALT normalization. The percentage of participants with HDV 
RNA response and combined response at week 24 is shown in Table 2. There was significantly 
higher percentage of participants with HDV RNA response at week 24 in all bulevirtide groups 
compared to TDF group (p<0.0001 for all bulevirtide groups).
Table 2.
Participants with HDV RNA response and combined response at week 24 
(MYR202 study, mITT population)
Bulevirtide 2 mg + 
TDF (N=28)
Bulevirtide 5 
mg + TDF 
(N=32)
Bulevirtide 10 
mg + TDF 
(N=30)
TDF 
(N=28)
Participants with HDV RNA 
response at week 24, n (%)
15 (53.6)*
15 (46.9)*
24 (80.0)*
1 (3.6)


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Participants with combined HDV 
RNA / ALT response at week 24, n 
(%)
6 (21.4)
8 (25.0)**
11 (36.7)***
0
* p<0.0001 compared to TDF (Wald test for superiority by margin of 5%)
** p<0.05 compared to TDF (Fisher’s exact test)
*** p<0.001 compared to TDF (Fisher’s exact test)
Reference: 32
MYR203 Study (Completed)
MYR203 study aimed to evaluate the efficacy and safety of bulevirtide at daily doses of 2, 5 or 
10 mg in combination with pegylated interferon, bulevirtide at daily dose of 2 mg, and 
bulevirtide at a daily dose of 5 mg BID in combination with TDF compared to pegylated 
interferon alone, in participants with chronic hepatitis D.
A total of 90 participants were randomized into 6 treatment groups, each of 15 participants:
Group A: pegylated interferon 180 μg
Group В: bulevirtide 2 mg + pegylated interferon 180 μg
Group С: bulevirtide 5 mg + pegylated interferon 180 μg
Group D: bulevirtide 2 mg
Group E: bulevirtide 10 mg (10 mg once a day) + pegylated interferon 180 μg
Group F: bulevirtide 10 mg (5 mg BID) + TDF
The primary efficacy endpoint was defined as the proportion of participants with a negative PCR 
result of HDV RNA (HDV RNA negativation) at week 72 (end of the follow-up period).
At week 72, the primary efficacy endpoint was achieved by 8/15 (53.3%; 95% CI: 26.6-78.7%), 
5/15 (33.3%; 95% CI: 11.8-61.6%) and 4/15 (26.7%; 95% CI: 7.8-55.1%) of the participants 
treated with bulevirtide 2 mg + pegylated interferon (Group B), bulevirtide 5 mg BID + TDF 
(Group F) and bulevirtide 5 mg + pegylated interferon (Group C), respectively. One participant 
from each of the other bulevirtide groups, Group D and Group E, achieved the primary endpoint 
(1/15 [6.7%; 95% CI: 0.2-31.9%]). No participant (0/15 participants) treated with pegylated 
interferon only (Group A) achieved the respective HDV RNA response. 
MYR301 Study (Ongoing)
MYR301 is an ongoing study that is comparing the efficacy and safety of bulevirtide 
administered as delayed treatment (followed by 10 mg/day after 48 weeks) versus immediate 
treatment (2 mg or 10 mg/day) for the treatment of CHD in participants with compensated 
cirrhosis or without cirrhosis.
Participants were randomized in a 1:1:1 ratio to 1 of the following 3 treatment groups for the 
treatment period, which is 144 weeks:


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
Treatment Group A: Delayed treatment with bulevirtide 10 mg/day for 96 weeks after an 
observational period of 48 weeks with an additional follow-up period of 96 weeks

Treatment Group B: Immediate treatment with bulevirtide 2 mg/day for 144 weeks with a 
further follow-up period of 96 weeks

Treatment Group C: Immediate treatment with bulevirtide 10 mg/day for 144 weeks with a 
further follow-up period of 96 weeks
Randomization was stratified for liver cirrhosis status (no/yes).
The primary efficacy endpoint was the proportion of participants achieving combined response at 
Week 48. Combined response was defined as fulfilment of 2 conditions simultaneously:

Undetectable (< limit of detection [LOD]) HDV RNA or decreased by ≥ 2 log10 IU/mL from 
baseline

ALT normalization
At Week 48, there was a clear treatment effect for participants receiving bulevirtide 2 mg or 
bulevirtide 10 mg when compared with participants in the delayed treatment group. The 
proportion of participants who achieved combined response in the active treatment groups was as 
follows:

Bulevirtide 2 mg treatment group: 44.9% (95% CI: 30.7% to 59.8%); p < 0.0001 when 
compared with delayed treatment (2.0% [95% CI: 0.0% to 10.4%])

Bulevirtide 10 mg treatment group: 48.0% (95% CI: 33.7% to 62.6%); p < 0.0001 when 
compared with delayed treatment (2.0% [95% CI: 0.0% to 10.4%])
The differences in proportions (96% CI) of responders at Week 48 for the combined response 
between each of the BLV treatment groups and the delayed treatment group were as follows; the 
differences were statistically significant for both BLV treatment groups:

Bulevirtide 2 mg treatment group versus delayed treatment group: 42.9% (96% CI: 27.0% to 
58.5%; p < 0.0001)

Bulevirtide 10 mg treatment group versus delayed treatment group: 46.0% (96% CI: 30.5 to 
61.4%; p < 0.0001)
Refer to the bulevirtide Investigator's Brochure for details on nonclinical and clinical studies.
1.4.
Study Rationale
There is currently no approved drug for treatment of CHD. Pegylated interferon alfa -2a (PEG-
IFN alfa) is approved for treatment of chronic HBV infection which is required for the 
propagation of HDV, and used to treat participants with HDV infection with evidence of some 
virologic efficacy (21-23). Interferon has a complex mode of action, whereas direct antiviral 


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effects and immunomodulatory mechanisms have been described. Bulevirtide is an entry 
inhibitor has demonstrated significant virologic and biochemical activity in participants with 
HDV infection during the Phase 2 clinical trials. A combination of the both drugs demonstrated 
significant synergistic effects in the 201 clinical trial. It is therefore warranted to further 
investigate the combination therapy with the aim of improvement of sustained virologic response 
rates.
Graphic representation of the study design is shown in Figure 1.
1.4.1.
Rationale for Participant Population
In participants with HDV infection therapeutic options are very limited or absent, as no drug is 
approved for treatment of this condition. In previous clinical trials administration of bulevirtide 
in participants with HDV infection resulted in a significant decrease in HDV RNA and ALT 
values (see Section 1.3.2).
To ensure balance between groups, stratification by the presence of liver cirrhosis will be 
employed. Participants should receive nucleoside / nucleotide analogues at screening, treatment 
and/or follow-up period if required for control of the underlying chronic HBV infection, if 
indicated by the current clinical practice guidelines (EASL and AASLD). Inclusion of the 
described population is considered to be ethically appropriate and justified by data obtained in 
the previous study.
Participants with ALT ≥ 10  upper limit of normal (ULN), creatinine clearance < 60 mL/min, 
total bilirubin ≥ 34.2 µmol/L, HCV or HIV coinfection, hepatocellular carcinoma, 
decompensated liver disease, other significant or unstable disease will not be allowed to enter the 
study.
1.4.2.
Rationale for Selection of the Dose of the Study Drug
The dose of 10 mg was selected for monotherapy and for the combination arm with PEG-IFN as 
this dose has demonstrated the highest HDV virologic response rates in the 202 clinical trial. The 
2 mg dose in combination with PEG-IFN demonstrated synergistic effects in 201 study. The 
PEG-IFN monotherapy cohort will be added as a mode of action / effect contribution arm.
In order to further increase SVR rates in this difficult to treat indication, the "tale" of 48 weeks of 
bulevirtide therapy will be introduced after the completion of 48 weeks combination.
1.5.
Benefit/Risk Assessment
Bulevirtide has undergone extensive nonclinical testing. Detailed information on potential risks 
associated with NTCP inhibition is provided in the risk-benefit section of the "Investigator`s 
Brochure". Several clinical studies evaluating pharmacokinetics, immunogenicity, safety and 
efficacy of bulevirtide have been completed (see Section 1.3.2). An important risk identified in 
clinical trials was hepatitis exacerbation after bulevirtide cessation. Monitoring of ALT levels, 
liver function, HDV RNA, HBV DNA is recommended after the end of the study or the event of 
early study termination. The available clinical data supports a clinical benefit in the proposed 
target population given the demonstrated favorable effects of bulevirtide in terms of HDV RNA 
decline, ALT normalization and liver stiffness amelioration.


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The risks associated with pegylated interferon treatment are generally mild, not treatment-
limiting and well-established. The most common side effects include fatigue, fever, headache, 
injection-site reactions, rigors, myalgia, arthralgia, nausea, weight decrease, anorexia, 
depression, insomnia, irritability, alopecia, rash, dry skin. Influenza-like symptoms are common 
and develop more often in patients who are using high doses of pegylated interferon (28). These 
data are in alignment with the results obtained by Janssen et al (2005). They have also 
established that the most common side-effects associated with pegylated interferon treatment are 
flu-like symptoms, headache, fatigue, and local reaction at the injection site (29).
The design of this study contains adequate measures to mitigate risk factors and adequate safety 
monitoring to protect the participants. In the context of the progressive, severe, and debilitating 
nature of CHD, the balance between risks that have been identified from cumulative safety data 
for bulevirtide and anticipated efficacy/benefits remains favorable.
The Sponsor realizes that extraordinary measures may need to be implemented and trials 
management may need to be adjusted due to unexpected risks which may increase due to 
external unavoidable circumstances, including coronavirus disease 2019 (COVID-19) pandemic 
spread in the world, e.g. for participants safety, trial participants being in self-
isolation/quarantine, limited access to public places (including hospitals) due to the risk of 
spreading infections, and health care professionals being committed to critical tasks.
Clinical trial nosology is Chronic Hepatitis Delta, which is a life-threatening disease with no 
currently approved therapeutic options. As the overall well-being and best interests of the 
participant should be considered, in trials for patients with life-threatening or severely 
debilitating conditions, in general it is of the best interest for the participants to remain receiving 
the trial treatment. Unplanned interruption of the bulevirtide treatment may lead to negative 
medical consequences including hepatitis flairs. The treatment interruption should be avoided 
and each case of interruption, where it is inevitably, should be closely monitored for safety of the 
participants.
The investigators, in coordination with the Sponsor, should assess the risks of any changes 
considered in the trial for each single participant and each single procedure with regard to the 
safety of the participant and the integrity of the trial data, with priority given to the safety of the 
participant. The safety of the participant is of primary importance and risks of participation in the 
trial, in particular with added challenges due to COVID-19, should be weighed against 
anticipated benefit for the participant and society.


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2.
STUDY OBJECTIVES
2.1.
Objectives
Primary objective:
The primary objective of this study is to evaluate the efficacy of bulevirtide administered 
subcutaneously at a dose of 2 mg or 10 mg in combination with pegylated interferon once 
weekly relative to 10 mg bulevirtide monotherapy in participants with chronic hepatitis delta.
Secondary objectives:

To assess the safety of bulevirtide.
2.2.
Endpoints
Primary efficacy endpoint:
Sustained virological response 24 (SVR 24) defined as undetectable HDV RNA (HDV RNA 
< LoD) at week 24 after the scheduled end of treatment (follow-up week 24 [FU-24], i.e., study 
week 120 for Arms B, C and D).
Secondary efficacy endpoints:

Undetectable HDV RNA at week 48 (all arms), 96 (Arms B, C and D).

Combined sustained response at week 24 and 48 after the scheduled end of treatment where 
combined response is defined as fulfilment of two conditions simultaneously:
Undetectable HDV RNA or decrease by ≥ 2 log10 IU/mL from baseline.
ALT normalization

Sustained virological response 48 (SVR 48) defined as undetectable HDV RNA at week 48 
after the scheduled end of treatment.

Change from baseline in liver stiffness as measured by elastography at week 48, 96, and 144.
CCI
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Safety endpoints:

Frequency and nature of adverse events (based on assessments of clinical events, physical 
examination, vital signs, electrocardiogram and laboratory tests)

Changes in vital signs 

Changes in PR, QRS, QT, QT-interval corrected for heart rate (QTc, Bazett), and heart 
rate based on assessments of electrocardiogram 

Changes in laboratory tests (hematology, coagulogram, biochemistry, blood bile salts, 
vitamin D)
Immunogenicity variables:

Appearance and concentration of bulevirtide antibodies 
Pharmacokinetic variables:

Plasma concentration of bulevirtide
Other variables:

HDV/HBV genotyping

NTCP polymorphism

Resistance testing (HBV genotypic assay with focus on the HBV envelope, Phenotypic 
resistance assay and HDV genotypic assay)

HBeAg and HBeAg antibodies status at all postbaseline assessments (for participants with 
positive HBeAg at Screening)

Other parameters in liver biopsy samples (may include but not limited to: quantitative 
analysis of HDV RNA, HBV DNA, HBV RNA, interferon-stimulated genes, NTCP; semi-
quantitative analysis of HBsAg and HDAg with immunohistochemistry)


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3.
OVERALL STUDY DESIGN
This is a randomized, open-label, active-controlled, parallel-group multicenter Phase 2b study 
that will evaluate the efficacy and safety of bulevirtide at daily doses of 2 and 10 mg in 
combination with PEG-IFN alfa-2a compared to monotherapy with bulevirtide at daily dose of 
10 mg in participants with CHD.
This study will be conducted at approximately 25 sites across approximately 4 countries globally 
which may include Russia, France, Moldova, Romania. A total of 175 participants will be 
randomized.
Participants will be assessed for eligibility to enter the study during a 4-week Screening period. 
Eligible participants will be randomized at Visit 1 in a 1:2:2:2 ratio with stratification for the 
presence of liver cirrhosis (no/yes) to receive PEG-IFN alfa-2a (Arm A), combination of PEG-
IFN alfa-2a with bulevirtide 2 mg/day (Arm B), combination of PEG-IFN alfa-2a with 
bulevirtide 10 mg/day (Arm C) or bulevirtide 10 mg/day (Arm D) respectively. 
At week 48 all participants that received PEG-IFN alfa-2a (Arms A, B and C) discontinue its 
use. Participants in Arm A are followed for additional 48 weeks. Participants in Arms B, C and 
D continue treatment with bulevirtide at initially assigned dose until week 96 and they are 
followed until week 144 (See Figure 1).
The total duration of treatment period is 48 weeks for Arm A and 96 weeks for Arms B, C and 
D. After completion of the treatment period, participants are followed for additional 48 weeks. 
The total amount of time to complete the study is 96-100 weeks (inclusive of the Screening, 
Treatment, and Follow-Up Periods) for Arm A and 144-148 weeks for Arms B, C and D. A 
scheme of the study design is presented in Figure 1. The schedule of events to be conducted 
during the Treatment Period and the Follow-Up Period is presented in Table 1. Treatment and all 
study procedures will be performed on an outpatient basis (except for hospitalization for biopsy 
procedure, if required).


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Figure 1.
Study Plan
The study will be considered to have started when the first participant has provided signed 
informed consent, and will be considered to have finished after the last participant has completed 
the last follow-up visit.
3.1.
Randomization
Participants eligible for the study are randomized after completion of all procedures scheduled 
for Screening and Day 1 related to confirmation of participant’s eligibility (See Section 4). All 
other procedures of Day 1 (except sample collection for pharmacokinetic and assessment of 
adverse events including assessment of injection site reaction; See Table 1) should be performed 
before study drug administration.
Participants eligible for the study will be allocated into the treatment group through an electronic 
randomization system. Electronic randomization system must be accessed as close to the 
initiation of study treatment as possible to avoid randomization of participants who ultimately 
decide not to participate in the trial.
A manual will be provided to investigator with instructions detailing how to work with electronic 
randomization system. Investigators must be trained to use electronic randomization system 
before randomization.
Randomization will be performed with 1:2:2:2 allocation ratio with stratification for the presence 
of liver cirrhosis (no/yes); each participant will be assigned a unique randomization code.
3.2.
Blinding
This is an open label study for study participants and investigators at study sites. Central 
laboratories (except the laboratories for pharmacokinetic, immunogenicity, NTCP polymorphism 
and Resistance tests) will be blinded to actual treatment allocation.
Arm A ~
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4.
SELECTION OF STUDY POPULATION
This is an international study and it is expected that participants will be enrolled at 
approximately 25 study sites across approximately 4 countries. A total of 175 participants will be 
randomized. Enrolment will stop as soon as the target number of randomized participants is 
reached.
Before randomization of study participant eligibility must be confirmed by the Medical Monitor. 
Investigator should record all relevant information about the study participant in electronic case 
report form (eCRF) (all forms with information related to assessment of eligibility) and provide 
blinded copy of medical record confirming positive serum HDV antibody results or PCR results 
for serum/ plasma HDV RNA for at least 6 months before Screening and other relevant medical 
information if required to confirm participant’s eligibility.
The laboratory results from Day 1 are not supposed to be used for participant’s eligibility 
assessment.
All inclusion and exclusion criteria should be confirmed according to Appendix 1 to the 
Protocol.
4.1.
Inclusion Criteria
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria:
1) Provision of signed and dated informed consent form.
2) Male or female, aged 18-65 years (inclusive). 
3) Positive serum HDV antibody results or PCR results for serum/ plasma HDV RNA for at 
least 6 months before Screening. 
4) Positive PCR results for serum/ plasma HDV RNA at Screening. 
5) Alanine transaminase level >1  ULN, but less than 10  ULN. 
6) Serum albumin >28 g/L.
7) Thyroid stimulating hormone (TSH) within normal ranges (including on medication for 
control of thyroid function)
8) Negative urine pregnancy test for females of childbearing potential. 
9) Inclusion criteria for female participants: 
a) Postmenopausal for at least 2 years, or 


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b) Surgically sterile (total hysterectomy or bilateral oophorectomy, bilateral tubal ligation, 
staples, or another type of sterilization), or 
c) Abstinence from heterosexual intercourse throughout the treatment period, or 
d) Willingness to use highly effective contraception (double barrier method or barrier 
contraception in combination with hormonal or intrauterine contraceptive) throughout the 
treatment period and for 6 months after the last dose of the study medication. 
10) Male participants must agree to use a highly effective contraception (double barrier method 
or barrier contraception in combination with hormonal or intrauterine contraceptive used by 
female partners) and not to donate sperm throughout the treatment period and for 6 months 
after the last dose of the study medication.
4.2.
Exclusion Criteria
An individual who meets any of the following criteria cannot take part in this study:
1) Child-Pugh hepatic insufficiency score of B-C or over 6 points. NOTE: Child-Pugh hepatic 
insufficiency score of 6 points is allowed. Only participants with compensated cirrhosis are 
allowed. Uncomplicated oesophageal varices allowed; Participants with current bleeding or 
ligation, or history of bleeding or ligation within the last 2 years are excluded.
2) HCV or HIV coinfection. Participants with HCV antibodies can be enrolled, if screening 
HCV RNA test is negative.
3) Creatinine clearance < 60 mL/min as estimated using Cockcroft-Gault formula.
4) Total bilirubin ≥ 34.2 µmol/L. [Participants with higher total bilirubin values may be 
included after the consultation with the Study Medical Monitor, if such elevation can be 
clearly attributed to Gilbert’s syndrome associated with low-grade hyperbilirubinemia.]
5) Evidence of an active or suspected malignancy, or an untreated pre-malignancy disorder, or a 
history of malignancy within the last 5 years (with the exception of successfully treated 
carcinoma of the cervix in situ and successfully treated basal cell carcinoma and squamous 
cell carcinoma not less than 1 year prior to screening [and no more than 3 excised skin cancer 
within the last 5 years prior to screening]) or history of hepatic carcinoma.
6) Systemic connective tissue disorders.
7) NYHA (New York Heart Association) class III-IV congestive heart failure.
8) Participants with uncontrolled arterial hypertension: systolic blood pressure > 150 mm Hg 
and/ or diastolic blood pressure > 100 mm Hg at Screening.
9) Previous or unstable concurrent diseases or conditions that prevent participant’s enrolment 
into the study.


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10) Participants with mental disorders or social circumstances that preclude them from following 
protocol requirements.
11) Current or previous decompensated liver disease, including coagulopathy, hepatic 
encephalopathy and esophageal varices hemorrhage.
12) One or more additional known primary or secondary causes of liver disease, other than 
hepatitis B (e.g., alcoholism, autoimmune hepatitis, malignancy with hepatic involvement, 
hemochromatosis, alpha-1 antitrypsin deficiency, Wilson’s Disease, other congenital or 
metabolic conditions affecting the liver, congestive heart failure or other severe 
cardiopulmonary disease, etc). Gilbert’s syndrome, a benign disorder associated with low-
grade hyperbilirubinemia, will not exclude participants from participation in this trial. 
Autoimmune hepatitis stigmata attributed to HDV infection in the opinion of the investigator 
are allowed.
13) White blood cells (WBC) count < 3000 cells/mm3 (<1500 if African participants).
14) Absolute neutrophil count < 1500 cells/mm3 (<1000 if African participants).
15) Platelet count < 90,000 cells/mm3.
16) Hemoglobin < 12 g/dL.
17) Use of prohibited psychotropic agents at Screening.
18) Use of interferons within 6 months before Screening.
19) History of solid organ transplantation.
20) Current alcohol abuse or alcohol abuse within 6 months prior to enrolment in this study; 
current drug addict or history of drug use within 2 years prior to Screening.
21) History of disease requiring regular use of systemic glucocorticosteroids (inhalative 
glucocorticosteroids are allowed) or other immunosuppressants.
22) Pregnant or breast-feeding females.
23) Participation in another clinical study with investigational drugs within 30 days prior to 
randomization.
24) Receipt of bulevirtide previously, e.g. in clinical trials.
25) Inability to follow protocol requirements and undergo all protocol procedures. NOTE: 
Participants with medical contraindication for liver biopsy are allowed to participate in this 
study. Such participants will exempt from liver biopsy requirements in this study.
26) Participants receiving prohibited treatment at Screening cannot be included into the study 
unless this treatment is withdrawn prior to randomization.


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27) Contraindications, intolerance or hypersensitivity to interferons alfa, genetically engineered 
E.coli medications, polyethylene glycol or other components of peginterferon alfa-2а.
28) Presence or history of severe retinopathy, significant diabetic or hypertensive retinopathy.
29) Uncontrolled diabetes mellitus.
30) Uncontrolled cardiovascular disorders within 6 months before screening.
31) History of autoimmune disorder (e.g. myositis, hepatitis, thrombotic thrombocytopenic 
purpura, idiopathic thrombocytopenic purpura, severe psoriasis, rheumatoid arthritis, 
interstitial nephritis, thyroiditis, and systemic lupus erythematosus)
32) Presence or history of significant psychiatric disorder (e.g. severe depression, suicide 
attempt, severe neurosis or cognitive disorder).
33) Presence or history of chronic lung disease with respiratory malfunction.
4.3.
Withdrawal Criteria
Participants are free to withdraw from participation in the study at any time upon request. 
However, Investigator will make every reasonable effort to document exact reasons for 
participant’s decision to withdraw and enter them into eCRF.
Participants may be withdrawn from the study in the following circumstances:
1) Informed consent withdrawal by the participant.
2) Investigator believes that it is not in the participant’s best interests to continue participation 
in the study.
3) Investigator decides to withdraw the study participant due to a serious protocol 
deviation/violation.
4) Concurrent disease or progression of the underlying disease that, in the opinion of 
Investigator, can significantly affect evaluation of participant’s clinical status.
5) In case of suspected pancreatitis, the treatment with the study medication should be stopped 
and further diagnostic procedures undertaken. 
6) Use of prohibited medication is required.
7) Unacceptable toxicities, or a reaction that, in the Investigator’s opinion, precludes further 
study procedures or requires discontinuation of the participant from the study.
8) Pregnancy during the study.
9) Participant is lost to follow-up.


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Investigator is responsible for obtaining and documenting the reason(s) for participant’s 
withdrawal from the study after randomization and entering all relevant information into eCRF, 
including detailed information about the reason for the participant’s withdrawal from the study 
when participants agrees to provide such information. If the participant was withdrawn due to an 
AE, the primary term or a laboratory test must be reported in the eCRF, and Investigator must 
make every effort to accurately report all AE characteristics.
Investigator should report information about withdrawn participants to the Sponsor and the 
Clinical research associate (CRA) within 24 hours.
4.4.
Replacement of Participants
Study participants will not be replaced.
4.5.
Premature Termination of Study
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to investigator and 
regulatory authorities. If the study is prematurely terminated or suspended, the Principal 
Investigator (PI) will promptly inform the Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB) and will provide the reason(s) for the termination or suspension; the PI will 
also promptly inform the study participants and will assure appropriate therapy and follow-up.
Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants 

Insufficient compliance to protocol requirements 

Data that are not sufficiently complete and/or evaluable


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5.
TREATMENTS
5.1.
Treatments Administered
5.1.1.
Bulevirtide
Brief description of study drug bulevirtide is presented below. Additional information can be 
found in Investigator’s Brochure. The product will be supplied in sterile vials to be reconstituted 
in 1 mL water for injection prior to administration.
Drug formulation: Lyophilized powder for injections.
Composition
Active ingredient: Bulevirtide, 5.0 or 2.0 mg/vial.
Excipients: sodium carbonate, sodium hydrocarbonate, mannitol, hydrochloric acid, and sodium 
hydroxide are used for solution of the drug substance before aseptic filling and lyophilization. 
Pharmaceutically pure substances are used.
Physical form: white to off-white powder.
Appearance of the solution: clear and colorless.
Packaging
Container: 2 R injection vial, colorless glass, European Pharmacopoeia (Ph. Eur.) Hydrolytic 
class I. 
Closure: Lyophilization rubber stopper for 2R vials, Ph. Eur. Type I (diameter 13 mm). 
Closure: 13 mm bordered cap, aluminum with plastic disc.
Single use vials.
Storage
At the central depot, during transportation and at study site, the drug should be stored at 20±5°C 
in the dark place with temperature monitoring.
At home, it is allowed for study participants to store the drug at +2-8°С (in the refrigerator).
Temporary storage of the drug at room temperature up to 25°C for not more than three days is 
allowed.
In case of other deviations of the cold chain conditions such deviation should be promptly 
reported to the Sponsor and the product should be placed to quarantine and should not be used 
prior to Sponsor’s authorization.


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After reconstitution of vial contents with water for injection the drug remains stable for 
120 minutes at room temperature.
5.1.2.
Peginterferon Alfa-2a
Drug formulation: Solution for subcutaneous administration.
Composition
Active ingredient: Peginterferon alfa-2a 180 mcg/0.5 mL. 
Excipients: acetic acid, benzyl alcohol, polysorbate 80, sodium acetate, sodium chloride, and 
water for injection.
Appearance: Colorless to slightly yellowish solution.
Packaging
Peginterferon alfa-2a will be supplied in commercially available package.
Storage
Refer to package insert for information on storage of Peginterferon alfa-2a.
5.2.
Labelling of Bulevirtide and Peginterferon Alfa-2a
Labelling of packages of the study products, apart from the compulsory information 
(pharmaceutical form of the product, amount in the package, storage conditions and shelf life, 
manufacturer data, release date and batch number), will include the following note “For clinical 
studies”, study protocol No., and other information as required by local regulations.
5.3.
Dosing and Administration
5.3.1.
Supplying Participants with Bulevirtide and Peginterferon Alfa-2a
Investigator or designated person is responsible for supplying participant with the study drugs 
(bulevirtide and Peginterferon alfa-2a).  
Participants randomized to receive bulevirtide at 2 mg daily dose are supplied with sufficient 
quantity of the study drug and materials assuming that for each day of the treatment period the 
following is needed:

1 vial with bulevirtide 2 mg,

1 vial with sterile water for injection (minimum 1 mL),

1 disposable syringe (with 2 needles),

Alcohol pads for disinfection


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Participants randomized to receive bulevirtide at 10 mg daily dose are supplied with sufficient 
quantity of the study drug assuming that for each day of the treatment with bulevirtide the 
following is needed:

2 vials with bulevirtide 5 mg,

2 vials with sterile water for injection (minimum 1 mL),

2 disposable syringes (with 2 needles each),

Alcohol pads for disinfection
If, in the case of external unavoidable circumstances, including COVID-19 pandemic spread in 
the world, it is not possible for participant to visit the site for drug(s) supplying, upon consent of 
the participants and by the decision of investigator, the drug(s) may be delivered to the 
participant.
5.3.2.
Administration of Bulevirtide
Bulevirtide is administered by study participants at home and by the responsible person at site. 
Bulevirtide is administered at study sites on days of visits to study sites and at home for all other 
days. Participants should be instructed NOT to administer bulevirtide at home at days of visits to 
study sites. At these days study drug is administered at study site in accordance with schedule of 
events for assessment of immunogenicity and pharmacokinetics of the study drug (i.e. sample for 
immunogenicity assessment is taken before administration of bulevirtide and sample for 
pharmacokinetics is taken 1h±15 min post bulevirtide dose).
Study site staff will instruct participants on procedures for storage, preparation and subcutaneous 
administration of the study drugs. Instructions for participants will be provided within the 
participant diary.
Participants randomized to receive bulevirtide at 2 mg daily dose administer bulevirtide by 1 
subcutaneous injection. Participants randomized to receive bulevirtide at 10 mg daily dose 
administer bulevirtide by 2 subcutaneous injections (5 mg of bulevirtide twice). For participants 
randomized to receive bulevirtide at 10 mg daily dose two injections are performed one after 
another without time lag between injections. Bulevirtide is administered daily. 
Participant should schedule constant time for daily injection of study drug during the first week 
of treatment (given the time of visits to the study sites) and then should follow the estimated 
schedule of injection during all period of the study.
The interval between injections should be 24±1 hours. The exact time for the next injection 
should be calculated from the previous injection with possible deviation ±1 hour. Deviation ±3 
hours is allowed for days of visits to study sites.
To prepare study drug for injection content of each bulevirtide vial assigned for administration at 
current day is reconstituted with 1 mL of the supplied solvent and self-administered with the 
supplied syringe. Study drug should be reconstituted immediately before injection. Reconstituted 
solution is stable for 2 hours.


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The injection sites are: the outer surface of the shoulder, anterolateral thigh surface or the 
anterolateral surface of the abdominal wall with developed subcutaneous fat. During the 
treatment period, injection sites may be changed.
5.3.3.
Administration of Peginterferon Alfa-2a
Peginterferon alfa-2a is administered at a dose 180 mcg. Injections are performed SC once a 
week for 48 weeks. Peginterferon alfa-2a should follow the rules described in current approved 
version of label text/prescription information for Peginterferon alfa-2a.
Peginterferon alfa-2a is administered in outpatient setting.
At days of simultaneous administration of peginterferon alfa-2a and bulevirtide, bulevirtide 
should be administered first and Peginterferon alfa-2a should be administered after bulevirtide. If 
bulevirtide is delayed due to the visit to the study site Peginterferon alfa-2a should be also 
delayed.
SC injections of Peginterferon alfa-2a and bulevirtide are performed at different anatomical 
regions.
5.3.4.
Dose Adjustment Guidelines
It is possible that some participants will encounter transient or prolonged adverse effects during 
their participation in the trial engendering the need to adjust test drug dosage. To minimize the 
effects of these modifications on the evaluation of the safety, tolerability, and efficacy of test 
drug regimens, the principles in the following sections will be used to adjust the dose of test 
drugs.
Treatment Interruption
If missing of one several doses of bulevirtide or PEG-IFN alfa is considered necessary to manage 
adverse events, such cases should be promptly discussed with the Sponsor.
If treatment interruption or permanent withdrawal of either bulevirtide or PEG-IFN is considered 
for participants receiving combination of these drugs, such cases should be promptly discussed 
with the Sponsor. Treatment with bulevirtide as monotherapy can be continued according to the 
scheduled regimen if participant’s condition allows continued participation in this study.
5.3.5.
Dose Adjustment Guidelines for Bulevirtide
General Aspects
If Investigator believes that the participant requires temporary interruption in the bulevirtide 
treatment, he/she should discuss it with the Study Medical Monitor.
In case the treatment is interrupted the investigator should maintain the participant’s safety 
supervision, including the ALT monitoring.


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Dose Adjustments
Dose adjustments are not allowed in this study.
Missed Dose
In case of a missed dose the following procedure is to be followed.
If a participant remembered of the missed dose before 4 hours have lapsed from the daily 
administration time frame, the dose should be administered. The next day, the planned dose 
should be administered at the initially set up time.
If more than 4 hours have passed from the planned time point, the dose should not be 
administered and should be considered missed, and the next day the planned dose should be 
administered at the initially set up time. The missed dose should be reported in a Participant 
Diary and case report form (CRF).
Treatment Adherence
Participant Diary (see Section 6.7) will be in place to monitor dosing and adherence for each 
participant.
5.3.6.
Dose Adjustment Guidelines for Peginterferon Alfa-2a
Dose Adjustment Guidelines for Peginterferon Alfa-2a due to Intolerance
If in the opinion of the Investigator the treatment with Peginterferon alfa-2a should be suspended 
or prematurely terminated due to intolerance, the participant can continue his participation in the 
study.
Follow information provided in current approved version of label text/prescription information 
for instructions on dose adjustment of Peginterferon alfa-2a due to AEs.
Once the participant’s unit dose has been decreased, the investigator may attempt to increase the 
dose back to or toward that which was originally assigned only if the event or circumstance 
responsible for the dosage adjustment has resolved or improved.
If four or more consecutive doses of Peginterferon alfa-2a are held or otherwise not administered 
(i.e., the participant has not received test medication for more than 28 days), the participant will 
be considered intolerant of the test medication or non-compliant, whichever is more appropriate 
to the clinical situation. No additional test drug may be administered to such participants without 
explicit permission from the sponsor.
Missing doses and Missed doses
If consistent with participant safety, doses should not be held or eliminated. This 
recommendation stems from concerns that extended periods of lowered drug concentrations in 
the blood may be associated with the replication of the more resistant clones of the virus, 
resulting in a lack of sustained response at the conclusion of therapy.


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When the investigator considers it prudent to hold a dose, consideration needs to be given to 
informing the sponsor of the missed scheduled dose and the reasons the dose was withheld. 
Investigators should consider if adjusting the dose, either transiently or permanently, might be 
appropriate rather than holding a dose.
If a Peginterferon alfa-2a dose is delayed but eventually administered, the following guidelines 
should be utilized for the next scheduled dose(s):
Dose delayed 1 or 2 
days:
Administer on usual dosing day of the week (e.g., if Monday is the usual 
dosing day and the dose is delayed until Wednesday, the next dose may 
be administered as usual on Monday).
Dose delayed 3-5 
days:
Administer subsequent doses every 5th or 6th day until the participant 
is back to his or her original schedule (e.g., if Monday is the usual 
dosing day and the dose is delayed until Saturday, the next dose should 
be administered on Thursday, the following dose on Tuesday, then the 
dose after that as usual on Monday).
Dose delayed 6 days:
Hold the dose for that week then continue on the usual schedule the 
following week (e.g., if Monday is the usual dosing day but the 
participant is not ready to be dosed until the following Sunday, the dose 
is considered to have been held and the next injection should be for the 
following week’s dose on Monday).
Dose delayed ≥7 
days:
The investigator may reintroduce test drug at any time and, if necessary, 
dose the participant every 5th or 6th day until the participant resumes 
weekly dosing on their usual scheduled day.
5.3.7. Dose Adjustment Guidelines for Peginterferon Alfa-2a in Case of ALT Increases
Participants experiencing ALT flares (e.g. progressive ALT elevations of >10  ULN) should 
receive more frequent monitoring of liver function until the ALT levels are stabilized. PEG-IFN 
alfa dose should be reduced in participants experiencing progressive or clinically significant 
ALT increase. If ALT increases are progressive despite reduction of PEG-IFN alfa dose or are 
accompanied by increased bilirubin or evidence of hepatic decompensation (i.e. 
hypoalbuminemia, increases in coagulation times), PEG-IFN alfa should be immediately 
discontinued.
5.4.
Accountability Procedures
Drug supplies should be stored in a secure area, accessed by authorized personnel only.
Drug inventory and accountability logs including details of the study drug received and 
dispensed to the participant, batch and participant numbers must be kept.


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5.5.
Treatment Compliance
Both participant’s diary information and drug accountability information will be used to estimate 
treatment compliance. Information about each study drug administration (i.e. time of 
administration and administered dose) will be captured in participant’s diary by participant. All 
empty vials and syringes of the study drugs and unused drugs are returned by participant to 
investigator at each visit. Participant’s diary information and drug accountability information 
(i.e. number of dispensed vials and/ or syringes with the study drug and the number of returned 
empty vials and/ or syringes of the study drugs) is entered in eCRF at each visit of participant to 
study site.
5.6.
Concomitant Therapy
All concomitant medications taken during study participation will be recorded on the eCRF. 
Medications to be reported in the eCRF are concomitant prescription medications, over-the-
counter medications and non-prescription medications.
5.6.1.
Treatment With Nucleoside/Nucleotide Analogues
The following rules should be followed:
1) Participants who receive the treatment with nucleoside/nucleotide analogue (NA) for chronic 
HBV infection at screening will continue their treatment as prescribed.
2) For participants not on NA treatment at screening, such treatment should be initiated at 
Baseline visit or later in the study, if indicated by current EASL/AASLD treatment 
guidelines.
In particular, NA treatment should be considered if one of following conditions is met:

HBV DNA >2,000 IU/mL, ALT >ULN and/or at least moderate liver necroinflammation or 
fibrosis, or

Liver cirrhosis with any detectable HBV DNA level, or

Participants with HBV DNA >20,000 IU/mL and ALT >2  ULN should start treatment 
regardless of the degree of fibrosis, or

Family history of cirrhosis or HCC, or

Presence of extrahepatic manifestations
The Sponsor will be providing tenofovir (tablets) if the drug cannot be made available for 
participants through routine medical care. In participants in whom tenofovir is contraindicated, 
entecavir (tablets) will be provided.


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5.6.2.
Prohibited Treatments
Treatment with the following drugs will not be permitted unless discussed with and approved by 
the Study Medical Monitor.

Systemic glucocorticosteroids (inhaled glucocorticosteroids are allowed)

Immunomodulatory agents (drugs intended for treatment of common cold are allowed)

Antiviral drugs for HBV and/or HDV treatment, apart from study treatment and allowed 
nucleoside / nucleotide analogues 

Hematopoiesis -stimulating agents are allowed during interferon therapy only

Sulfasalazine

Ezetimibe

Cyclosporine

Substrates of organic anion transporting polypeptide (OATP)1B1 and OATP1B3: 
Atorvastatin, Bosentan, Docetaxel, Fexofenadine, Glecaprevir, Glyburide (glibenclamide), 
Grazoprevir, Nateglinide, Paclitaxel, Paritaprevir, Pitavastatin, Pravastatin, Repaglinide, 
Rosuvastatin, Simeprevir, Simvastatin (acid), Olmesartan, Telmisartan, Valsartan, 
Voxilaprevir [35, 36, 37, 38]

Irbesartan

Ritonavir


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6.
STUDY PROCEDURES
Schedule of study procedures is given in Table 1. Additional unscheduled visits and procedures 
may be performed in following cases:

If additional procedures are considered by Investigator to be necessary for monitoring 
participant’s condition,

In case of abnormal laboratory results,

In case of sample sent to central laboratory was considered to be not analysable,

In case of necessity of dispensing of additional study materials and/ or study drug(s)
In case of early discontinuation of the study by study participant early discontinuation visit 
should be scheduled and performed. Procedures for early discontinuation visit are listed in 
Section 6.1.
6.1.
Early Discontinuation Visit
Early discontinuation visit should be performed for participants who discontinue the study 
prematurely. The visit should be scheduled and performed at the earliest convenience after the 
decision to discontinue participant from the study. Participants prematurely withdrawn during the 
treatment period should complete procedures of Visit 14/ week 96.
Participants prematurely withdrawn during the follow-up period should complete procedures of 
Visit FU 6 / EOS.
6.2.
Restrictions During the Study
Diet restrictions
Participants must attend study sites after fasting for at least 9 hours (water and concomitant 
medications are permitted) for the purpose of conducting the biochemistry.
Restrictions in concomitant treatment
Information is presented in Section 5.6.
Contraception
Female participants
Women of childbearing potential must agree to use an adequate method of contraception 
throughout the treatment period and for 6 months after the last dose of the study medication.
Women of childbearing potential are females who have experienced menarche and do not meet 
the criteria of Not being of childbearing potential.


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Women Not of childbearing potential are females who are postmenopausal or permanently 
sterilized (i.e. bilateral tubal legation greater than or equal to one menstrual cycle prior 
randomization, or have undergone a hysterectomy or bilateral oophorectomy). Postmenopausal is 
defined as 24 consecutive months with no menses without an alternative medical cause.
Adequate contraceptive precautions include one highly effective form of contraception or two 
effective forms of contraception.
The following contraception forms are considered highly-effective:

True abstinence when this is in line with the preferred and usual lifestyle of the participant. 
[Periodic abstinence (e.g., calendar, ovulation, symptothermal post-ovulation methods) and 
withdrawal are not acceptable methods of contraception].

Male partner is vasectomized (surgically sterilized). The vasectomized male partner should 
be the sole partner.
The following contraception forms are considered effective:

Placement of intrauterine device or intrauterine system. Consideration should be given to the 
type of device being used, as there are higher failure rates quoted for certain types, e.g., steel 
or copper wire.

Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository.

Hormonal contraceptive.
It should be noted that two forms of effective contraception are required. A double barrier 
method is acceptable which is defined as condom and occlusive cap (diaphragm or cervical/vault 
caps) if used together with spermicidal foam/gel/film/cream/suppository.
Should the female participant become sexually active while participating in the study, she must 
agree to use a double barrier method of contraception providing she is of childbearing potential.
Male participants
Male participants who have female partner of childbearing potential must use an adequate 
method of contraception (as described above) and not to donate sperm throughout the treatment 
period and for 6 months after the last dose of the study medication.
The procedures to be followed if a female participant or female partner of a male participant 
becomes pregnant while enrolled in the study are described in Section 7.5.


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6.3.
Demographic and Other Baseline Characteristics
6.3.1.
Demographics
The following demographic details as permitted by local regulations are to be collected during 
Screening:

Date of birth

Sex

Race

Smoking/alcohol/drugs abuse history and current use
6.3.2.
Medical History
The following reporting periods should be followed:

Information about diseases, conditions and surgeries related to the liver is collected for a 
lifelong period,

Information about other diseases, conditions and surgeries is collected if they have occurred 
within 5 years before the Screening or regardless of the time if they are considered to be 
relevant by Investigator.
The cirrhosis status including Child-Pugh Score (points) should be recorded in the source 
documents and eCRF for cirrhotic participants within the Medical history collection at 
Screening.
6.3.3.
Prior and Concomitant Therapy
All previous treatment for viral hepatitis should be recorded in the eCRF. Prior therapy for other 
diseases is collected for therapies that participant receives currently and therapies that were 
discontinued within 3 months before Screening.
Any medical treatment present at Screening or started after the first administration of study drug 
must also be entered in eCRF.
6.3.4.
Weight, Height, Body Mass Index
Height will be recorded in meters (to the nearest cm) at Screening. Weight (kg) will be measured 
at Screening and during the study as indicated in the Schedule of Events (Table 1). Body mass 
index (BMI) at Screening will be calculated as follows: Body weight (kg) / [Height (m)]2. All 
results should be recorded in the eCRF.


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6.3.5.
Pregnancy Test
Urine pregnancy test is required for women of childbearing potential (see Section 6.2). 
Pregnancy test will be done at Screening and during the study as indicated in the Schedule of 
Events (Table 1). Test strips will be used. The results will be documented in the eCRF.
6.3.6.
Drug Screening
Urine test strips will be used to detect traces of methadone, benzodiazines, cocaine, amphetamines, 
cannabinoids, opiates, barbiturates, tricyclic antidepressant. The list of prohibited drugs may 
vary based on country-specific regulations. The result will be documented in the eCRF.
6.3.7.
Breath Alcohol Test
Alcohol levels in exhaled oxygen will be measured at Screening and Randomization/Baseline 
visit. Electronic breathalyzer will be used. The result will be documented in the eCRF.
6.3.8.
Abdominal Ultrasound
Abdominal ultrasound will be done at Screening. Special attention must be paid to liver 
structure. All abnormalities must be recorded of the eCRF.
6.3.9.
Serum Alpha-fetoprotein
Serum alpha-fetoprotein will be measured for all participants at Screening. The alpha-fetoprotein 
test is intended to rule out hepatocellular carcinoma.
Samples to be sent to the central laboratory.
6.3.10.
Serology, HDV RNA, HCV RNA and HBeAg Test at Screening
The below listed laboratory tests will be done at central laboratory at Screening: 

HIV antibodies

HCV antibodies

HDV antibodies

HBeAg and HBeAg antibodies

HBV DNA (for participants not receiving the treatment with nucleoside/nucleotide analogue 
for chronic HBV infection)
Note: In case of positive HCV antibodies test, HCV RNA (qualitative) test must be done. If the 
result for HCV RNA test is negative, the participant can be enrolled into the study.
The below listed laboratory test will be done at central virology laboratory at Screening:
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6.4.
Efficacy Procedures
If, in the case of external unavoidable circumstances, including COVID-19 pandemic spread in 
the world, it is not possible for participant to visit the site, upon consent of the participants and 
by the decision of investigator, the blood sampling may be performed out of the site: at 
participant’s home or laboratory medical office.
6.4.1.
Virology Tests
A list of virology tests is given below. These tests will be done by central virology laboratory 
from frozen samples. Schedule of blood sampling is given in Table 1:

HDV RNA by quantitative PCR

HBV DNA by quantitative PCR

HBsAg levels by quantitative immunoassay

HBeAg and HBeAg antibodies, only if participant is HBeAg positive at Screening

HBsAg antibodies
Note: Blood sampling for HBsAg antibodies should be done as indicated in Table 1. Testing 
will be done only if HBsAg becomes undetectable.
Instruction for blood sample collection, processing and transport will be given in Laboratory 
manual.
6.4.2.
ALT
The biochemistry sample will be used to obtain ALT results for efficacy assessment as described 
in Section 6.5.4.
6.4.3.
HBV/HDV genotyping
HBV/HDV genotyping will be done in central virology laboratory once during the study. HDV 
genotyping will be done at Randomization/Baseline visit, using sequencing technique. HBV 
genotyping is performed at first occasion of positive result for HBV DNA in a blood sample 
collected for HBV DNA quantitative PCR assay starting from Baseline visit.
Frozen samples to be sent to the central laboratory for analysis. Instruction for blood sample 
collection, processing and transport will be given in Laboratory manual.
6.4.4.
NTCP Polymorphism and Resistance Tests
Blood samples for determination of NTCP polymorphism are collected at Day 1 for all the 
participants. NTCP polymorphism will be performed in central laboratory for participant who are 
either non-responders or have viral breakthrough defined as below. Details on collection, storage 
and transportation of samples are provided in laboratory manual.


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Sodium-taurocholate cotransporting polypeptide (NTCP) polymorphism will be assessed by 
partial sequencing of the human genome with the focus on all 5 NTCP exons to determine NTCP 
polymorphism (SNP Ser267 and others). Single nucleotide polymorphism (SNP) analysis will be 
performed to compare participant´s NTCP polymorphisms and the respective consensus NTCP 
sequence.
Blood samples for phenotypic assay are collected at Day 1 for all the participants. Baseline 
phenotypic assay will be performed in at least 10% of Day 1 samples, in order to determine an 
EC50 threshold at baseline. The five first participants from each bulevirtide treatment arm (Arms 
B, C and D) and three first participants from Arm A after randomization will be included into the 
analysis based on their baseline HDV RNA titer which is supposed to be not less than 
1000 IU/mL.
For other resistance tests (e.g. HBV genome sequencing, and HDV genome sequencing) and 
phenotypic assay at the other timepoints back-up virology samples are used. Resistance testing is 
performed in central laboratory. Details on collection, storage and transportation of samples are 
provided in laboratory manual.
Full resistance testing will be performed in participants for whom results of HDV RNA testing in 
central laboratory indicate lack of response (non-responders) or viral breakthrough using the 
following definitions:
Definition for Viral Breakthrough
A) Two consecutive HDV RNA values ≥ LoD (target detected) if the HDV RNA value was 
previously < LLoD (target not detected) at least at two consecutive time points.
or
B) A confirmed increase of ≥ 1 log10 IU/mL HDV RNA from the nadir on two consecutive visits 
under treatment and/or until the end of treatment, assuming the nadir was previously at least 
1 log10 IU/mL below the HDV RNA baseline value at two consecutive visits.
Definition for Non-Responder
A) No decline in HDV RNA values at any time point during treatment
or
B) A less than 1 log10 IU/mL decline in HDV RNA after 6 months (24 weeks) of treatment.
The decision tree for selection of participants for resistance testing is provided below.


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HBV genome sequencing
Partial sequencing of HBV genome will be performed with the focus on the HBV envelope open 
reading frame (ORF) for the L, M, S genes. Baseline isolates are compared with isolates of 
virological failure or timepoints were no response to the study drug was observed.
Phenotypic assay
An in vitro infectivity assay will be performed to determine the EC50 of bulevirtide at baseline 
and at the time of the virological failure. The following results will be obtained:

EC50 value of baseline sample

EC50 values determination of at least 10% of all BL samples in order to define resistance 
threshold.

EC50 value of reference strain (lab virus stock)

EC50 value of sample at the time of virological failure

Fold resistance change calculation = EC50 value at the time of failure / EC50 of reference 
strain

Fold resistance change calculation = EC50 value at the time of failure / EC50 of baseline
Responder: 
,----+ 
Defined as patients with continuous HDV RNA 
decline of at least >1 log10 IU/ml throughout 
the whole treatment period 
~ 
HDV RNA decline I-
of >1 log10 IU/ml 
Viral breakthrough A: 
Defined as two consecutive HDV RNA 
,----+ 
values ~ LlDD (target 
detected} if HDV RNA value was previously 
< LlDD (target not detected} 
,-
I 
Patients treated with 
~ 
at least at two consecutive timepoints. 
Bulevirtide within dinical trials 
Analysis of viral resistance: 
1} Genotypic data on HBV 
Viral breakthrough B: 
Two consecutive visits with ~1 log10 IU/ml 
envelope proteins. 
HDV RNA increase from the nadir, assuming ,-
2) Genotypic data on NTCP, 
~ 
the nadir was previously at least 1 log10 IU/ml 
NTCP polymorphism, 
below the baseline value at two consecutive 
visits. 
sequencing of all 5 NTCP exons 
1----t 
H 
I 
3} Phenotypic serum infectivity 
NoHDVRNA 
Non-responder A: 
assay and determination of 
dedine 
I 
Defined as no decline in HDV RNA values at ,-
ICSO of the study drug. 
any time point during treatment. 
4} HDV RNA sequencing where 
reduced susceptibility to 
Non-responder B: 
Bulevirtide in the phenotypic 
Y 
HDV RNA decline ~ 
Defined as patients with HDV RNA dedine of 
assay was confirmed. 
,-
of <1 log10 IU/ml 
<1 log10 IU/ml after 6 months (24 weeks} of 
treatment. 


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HDV genome sequencing
Whole genome sequencing for HDV genome is performed in cases where a reduced 
susceptibility to bulevirtide in the phenotypic assay was confirmed. Baseline isolates are 
compared with isolates of virological failure or timepoints were no response to the study drug 
was observed.
Blood samples collected within the study can be analyzed for other parameters for further 
investigational purposes.
6.4.5.
Serum Alpha-2-Macroglobulin
Test for serum fibrosis marker, alpha-2-macroglobulin, will be done at Randomization/Baseline 
visit and during the study as indicated in Schedule of Events (Table 1). Enzyme immunoassay 
analysis will be used.
Samples to be sent to the central laboratory for analysis. Instruction for blood sample collection, 
processing and transport will be given in Laboratory manual.
6.4.6.
Liver Biopsy
It is not necessary to perform liver biopsy at the study site. If agreed with Medical Monitor and 
Project Manager, liver biopsy can be performed in other institution or any other study site.
Liver biopsy samples should be collected if feasible at Screening and week 72 (Arm A) and 
week 120 (Arms B, C, and D) as indicated in Table 1. If baseline liver biopsy samples are not 
available (were not provided to central laboratory or were considered as non-evaluable by central 
laboratory) subsequent liver biopsy should not be performed. 
Participants with medical contraindication for liver biopsy are exempt from liver biopsy 
requirements in this study.
Note: At Screening liver biopsy is performed after confirmation of eligibility. Should the 
Investigator have any doubts regarding participant eligibility, he should contact Medical Monitor 
prior to biopsy. If liver biopsy was performed within 1 year prior to Screening, and a participant 
can provide biopsy records and appropriate biopsy specimens, the available specimens can be 
used for the baseline evaluation and biopsy at Screening is not required. 
Part of the biopsy sample will be used for determination of intrahepatic parameters. Frozen and 
ambient samples to be sent to the central laboratory for analysis. Instruction for biopsy sample 
collection, processing and transport will be given in Laboratory manual.
6.4.7.
Transient Elastometry
Transient elastometry (Fibroscan) is done at Screening and during the study as indicated in 
Schedule of Events (Table 1) to assess liver fibrosis staging. The result should be presented in 
kPa and documented in the eCRF.
It is not necessary to perform the procedure at the study site. If agreed with Medical Monitor and 
Project Manager, Fibroscan can be performed in other institution or any other study site.


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6.5.
Safety Procedures
If, in the case of external unavoidable circumstances, including COVID-19 pandemic spread in 
the world, it is not possible to collect the blood and urine samples for safety analysis at the site, it 
can be recommended by the investigator to perform such analysis an any local laboratory for 
safety control, i.e. adverse events monitoring.
6.5.1.
Physical Examination
A complete physical examination is performed at Screening, Randomization (V1), week 24, 
week 48, week 96, and week 144. A complete physical examination includes evaluation of 
general appearance, skin, head, eyes, ears, nose and throat, lymph nodes, respiratory, 
cardiovascular, gastrointestinal including hepatobiliary assessment, musculoskeletal, endocrine 
system, nervous systems, and urogenital system. At all other visits (Table 1), a symptom directed 
physical examination is performed.
Any finding present at the screening visit should be reported in the CRF as medical history and 
its importance for including the participant into the study must be considered. Any clinically 
significant worsening of conditions which were present at baseline (last assessment before study 
drug administration) or clinically significant worsening as a result of study procedure must be 
reported as adverse event in the eCRF. 
Complete Eye Examination
Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein 
thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, papilledema and serous 
retinal detachment are induced or aggravated by treatment with alpha interferons. All 
participants should receive an eye examination at Screening. Participants with pre-existing 
ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic 
ophthalmologic exams during interferon alpha treatment. Any participant who develops ocular 
symptoms should receive a prompt and complete eye examination. Interferon alpha treatment 
should be discontinued in participants who develop new or worsening ophthalmologic disorders.
Ophthalmologic exams can be performed at any institution by any qualified specialist, i.e. it is 
not necessary to perform the procedure at the study site. 
Assessment of Local Reactions at the Injection Sites
The investigator will evaluate the injection sites as indicated in Table 1.
In case of any observed clinical abnormalities at the injection sites the investigator should:

assess the clinical significance according to the local reaction to injectable product toxicity 
grading criteria from Table A for “Clinical Abnormalities of the Guidance for Industry 
Toxicity Grading Scale for Healthy Adult and Adolescent Participants Enrolled in Preventive 
Vaccine Clinical Trials” (Table 3).


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
in case of clinical significance (abnormality corresponds to any of the below grade), register 
it as an Adverse Event and record in the source documents and in eCRF the Grade according 
to the local reaction to injectable product toxicity grading criteria from Table A for “Clinical 
Abnormalities of the Guidance for Industry Toxicity Grading Scale for Healthy Adult and 
Adolescent Participants Enrolled in Preventive Vaccine Clinical Trials” and the Grade 
according to NCI-CTCAE (version 5.0)
In case of Grade 3 according to the local reaction to injectable product toxicity grading criteria 
from Table A for “Clinical Abnormalities of the Guidance for Industry Toxicity Grading Scale 
for Healthy Adult and Adolescent Participants Enrolled in Preventive Vaccine Clinical Trials” or 
above the photo should be taken by the investigator. The photo should be uploaded into eCRF.


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Table 3.
Tables for Clinical Abnormalities
Reaction to
Injectable Product
Mild (Grade 1)
Moderate 
(Grade 2)
Severe (Grade 
3)
Potentially 
Life
Threatening
(Grade 4)
Pain 
Does 
not 
interfere 
with activity 
Repeated use of 
non-narcotic 
pain reliever > 
24 
hours 
or 
interferes 
with 
activity 
Any 
use 
of 
narcotic 
pain 
reliever 
or 
prevents daily 
activity 
Emergency 
room 
(ER) visit or 
hospitalization 
Tenderness 
Mild discomfort 
to touch 
Discomfort with 
movement 
Significant 
discomfort 
at 
rest 
ER visit or 
hospitalization 
Erythema/Redness 
* 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling 
** 
2.5 – 5 cm and 
does 
not 
interfere 
with activity 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a 
continuous variable. 
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement.
6.5.2.
Vital Signs
Blood pressure, heart rate, and body temperature should be measured at Screening and during the 
study as indicated in Table 1. Vital signs are assessed before study drug administration and at 
additional times if clinically indicated.
Any finding present at the screening visit should be reported in the eCRF as medical history and 
its importance for including the participant into the study must be considered. Investigator should 
assess all results of vital signs assessment that deviate of normal range and investigator should 
decide whether these deviations qualify as adverse event or not. See Section 7 for definition and 
reporting requirements for results of vital signs assessment that qualify as adverse events
Blood pressure and heart rate will be measured after 5 minutes of rest in the supine/sitting 
position. Systolic and diastolic blood pressure will be measured (mmHg). All recordings should 
be made using the same blood pressure recording instrument on the same arm. Heart rate is 
defined as radial pulse counted for 30 seconds in the supine/sitting position (beats/minute). 
Respiratory rate is defined as number of breaths counted for 15 seconds in the supine/sitting 
position (breaths/minute). 
Vital signs are entered into eCRF.


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6.5.3.
Electrocardiogram
A 12-lead electrocardiogram (ECG) will be recorded at Screening and further during the study as 
indicated in Table 1. Additional assessments could be performed as clinically indicated. 
The following parameters will be noted in the eCRF: heart rate, QRS, RR, PQ, QT and QTc 
intervals. All values should be entered in the eCRF together with a general assessment on 
whether normal or abnormal and a description of the nature of the abnormality. 
Clinically significant deteriorations of ECG parameters compared to Screening should be 
reported as adverse events.
If, in the case of external unavoidable circumstances, including COVID-19 pandemic spread in 
the world, it is not possible for participant to visit the site, upon consent of the participants and if 
agreed with Medical Monitor and Project Manager, ECG can be performed in other institution or 
any other study site.
6.5.4.
Hematology, Biochemistry, Coagulogram, Vitamin D and TSH
Hematology, biochemistry and coagulogram will be analyzed by central laboratory using 
standard methods. Schedule of blood sampling is given in Table 1. Additional samples can be 
taken if samples were considered to be not suitable for analysis at central laboratory or for 
monitoring of clinically significant abnormalities (e.g. Grade 3 or Grade 4 abnormalities 
according to CTCAE). Additional samples should be also sent to central laboratory. 
Instruction for blood sample collection, processing and transport will be given in Laboratory 
manual.
Any abnormalities that are discovered at Screening should be further investigated where 
clinically indicated, in order to ensure that participants are fit to be included in the study and to 
receive study treatment. Investigator should assess all results of laboratory tests that deviate of 
normal range and investigator should decide whether these deviations qualify as adverse event or 
not. See Section 7 for definition and reporting requirements for results of laboratory tests that 
qualify as adverse events. 
Hematology will include:

Hematocrit

Hemoglobin

Platelets

Reticulocytes

Red blood cell (RBC) count

White blood cell (WBC) count


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
WBC differential (percentage): neutrophils, eosinophils, basophils, monocytes, lymphocytes

WBC differential (absolute counts): neutrophils, eosinophils, basophils, monocytes, 
lymphocytes
Coagulogram will include:

Prothrombin time

Activated partial thromboplastin time

INR
Biochemistry (full panel) will include:

Total protein

Albumin

ALT

AST

GGT

P-amylase

Alkaline phosphatase

Lipase

Total bilirubin

Direct bilirubin

Total cholesterol 

Creatinine

Urea

Glucose

Potassium

Sodium

Chloride


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
Phosphorus

C-reactive protein (CRP)
Biochemistry (abbreviated panel) will include:

Albumin

ALT

AST

GGT

Total bilirubin

Direct bilirubin

Creatinine

P-amylase

Lipase

CRP
Additionally, levels of Vitamin D and TSH (only for Arms A, B, C) are assessed.
6.5.5.
Total Blood Bile Salts
Total bile salts will be analyzed by central laboratory. Analysis to be performed at all visits 
except Screening visit.
Instruction for blood sample collection, processing and transport will be given in Laboratory 
manual.
6.5.6.
Urinalysis
Urinalysis will be analyzed by central laboratory using standard methods. Schedule of urine 
sampling is given in Table 1.
The following parameters will be measured:

pH

Specific gravity

Protein


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
Glucose

Bilirubin

Urobilinogen

Ketones

Erythrocytes

Leukocytes

Nitrites
Instruction for urine sample collection, processing and transport will be given in Laboratory 
manual.
Any abnormalities that are discovered at Screening should be further investigated where 
clinically indicated, in order to ensure that participants are fit to be included in the study and to 
receive study treatment. Investigator should assess all results of laboratory tests that deviate of 
normal range and investigator should decide whether these deviations qualify as adverse event or 
not. See Section 7 for definition and reporting requirements for results of laboratory tests that 
qualify as adverse events.
6.5.7.
Adverse Events
See Section 7.
6.6.
Other Procedures
6.6.1.
Immunogenicity
Bulevirtide antibodies will be determined at central laboratory for B, C and D Arms only. 
Schedule of blood sampling is given in Table 1. Samples for immunogenicity assessment should 
be taken before administration of the study drug. ELISA method will be used for analysis.
Instruction for blood sample collection, processing and transport will be given in Laboratory 
manual.
6.6.2.
Pharmacokinetics
Bulevirtide concentration will be measured throughout the study to investigate the possible 
bulevirtide accumulation. Analysis will be done by central laboratory. Pharmacokinetics samples 
are taken only for Arms B, C and D. 
Blood samples will be collected at Randomization/Baseline visit and all Treatment visits after 
the start of bulevirtide therapy as indicated in Table 1. Sampling should be done 1 hour ± 15 min 
post bulevirtide injection. 


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Frozen samples to be sent to the central laboratory for analysis. Instruction for blood sample 
collection, processing and transport will be given in Laboratory manual.
6.7.
Participant Diary
All participants will be given a Participant Diary to register the following information over the 
course of the treatment:

Date and time of each bulevirtide and/ or Peginterferon alfa-2a dosing

Adverse events experienced by a participant
Paper Participant Diary includes detachable sections for each visit. At each visit to the study site 
as indicated in Table 1, completed Participant Diary parts will be teared of and collected. 
6.8.
The Quality of Life Questionnaires
The quality of life questionnaires will be completed by the participants as indicated in Table 1. 
The following questionnaires will be given to participants:

EuroQol 5-Dimentions (EQ-5D)

Fatigue Severity Scale (FSS)

The Hepatitis Quality of Life Questionnaire™ (HQLQ™)
6.9.
Liver Related Clinical Events
Investigators should closely monitor the following liver related clinical events starting from the 
randomization, including, but not limited to: cirrhosis development; development or worsening 
jaundice, coagulopathy, ascites, hepatic encephalopathy; bleeding from esophageal varices; 
hepatocellular carcinoma development; liver transplantation; liver related hospitalization: 
amount of hospitalizations and duration of each period of hospitalization; liver related death. In 
case of such event onset it will be recorded in eCRF and registered as AE/ SAE. See Section 
7.1.3.


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7.
ADVERSE EVENTS
7.1.
Definitions
7.1.1.
Adverse event (AE)
Any untoward medical occurrence in a participant or clinical investigation participant 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E2А).
NOTE: Conditions that existed before study drug administration (e.g. ALT elevation before 
study drug administration) should not be reported as adverse event unless a notable deterioration 
has occurred or SAE has occurred after signature of informed consent.
7.1.2.
Serious Adverse Event (SAE)
An SAE is any untoward medical occurrence that at any dose:

Results in death,

Is life-threatening,
NOTE:
The term “life-threatening” refers to an event in which the participant is at immediate risk of 
death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it were more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization,
NOTE:
An event that leads to hospitalization under the following circumstances should not be reported 
as an adverse event or a serious adverse event:

Hospitalization for respite care,

Planned hospitalization required by the protocol (e.g. planned hospitalization for conducting 
liver biopsy),

Hospitalization for a preexisting condition, provided that all of the following criteria are met:


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The hospitalization was planned prior to the study or was scheduled during the study 
when elective surgery became necessary because of the expected normal progression of 
the disease,
The participant has not experienced an adverse event,
An event that leads to hospitalization under the following circumstances is not considered to be a 
serious adverse but should be reported as an adverse event instead:

Hospitalization that was necessary because of participant requirement for outpatient care 
outside of normal outpatient clinic operating hours.

Results in persistent or significant disability/incapacity, or

Is a congenital anomaly/birth defect.
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require intervention to prevent one of the other outcomes listed in the definition above.
These should also usually be considered serious. Examples of such events are intensive treatment 
in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse.
When an SAE occurs, the investigator is required to follow the procedures described in Section 
7.3.3.
7.1.3.
Adverse Event of Special Interest (AESI)
An AESI is a noteworthy event for the study drug that should be monitored closely. It could be 
either serious or non-serious.
7.1.3.1.
Local Reactions at the Injection Sites
Local reactions at the injection sites belong to adverse event of special interest that will be 
actively monitored during the study.
Refer to the Section 6.5.1 for requirements on assessment and registration of local reactions at 
the injections site.
7.1.3.2.
Liver Related Adverse Events
Investigators should closely monitor the following liver related clinical events starting from the 
randomization including, but not limited to: cirrhosis development; development or worsening 
jaundice, coagulopathy, ascites, hepatic encephalopathy; bleeding from esophageal varices; 
hepatocellular carcinoma development; liver transplantation; liver related hospitalization: 
amount of hospitalizations and duration of each period of hospitalization; liver related death. In 


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case of such event onset it will be recorded in eCRF and registered as AE/ SAE. Ascertaining 
whether an AE is considered liver-related should be as per the Investigator opinion.
7.1.4.
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result must be 
reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms,

Results in a change in study treatment (e.g., dosage modification, treatment interruption, or 
treatment discontinuation),

Results in a medical intervention (e.g., potassium supplementation for hypokalemia), a 
change in concomitant therapy or close medical monitoring,

Is clinically significant in the investigator’s judgment.
NOTE: Bulevirtide increases total bile salts level and this effect is related to the primary 
mechanism of action of bulevirtide. If isolated increase of total bile salts level above the upper 
limit of normal is both asymptomatic and judged by investigator to be clinically insignificant it 
should not be reported as adverse event.
It is the investigator’s responsibility to review all laboratory findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5  ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event form in the eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the Adverse Event eCRF. If the laboratory abnormality 
can be characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.
7.1.5.
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event. A vital sign result must be 
reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms,

Results in a change in study treatment (e.g., dosage modification, treatment interruption, or 
treatment discontinuation),

Results in a medical intervention, change in concomitant therapy or close medical 
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
Is clinically significant in the investigator’s judgment. 
It is the investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should be 
classified as an adverse event.
7.1.6.
Adverse drug reaction (ADR)
In the pre-approval clinical experience with a new medicinal product or its new usages, 
particularly as the therapeutic dose(s) may not be established: all noxious and unintended 
responses to a medicinal product related to any dose should be considered adverse drug 
reactions. The phrase responses to a medicinal product means that a causal relationship between 
a medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationship 
cannot be ruled out.
7.1.7.
Unexpected adverse drug reaction 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g., Investigator's Brochure for an unapproved investigational product or package 
insert/summary of product characteristics for an approved product) (ICH E6).
Suspected Unexpected Serious Adverse Reaction (SUSAR): 
Serious ADR that is classified as unexpected, i.e. a serious adverse reaction, the nature and 
severity of which is not consistent with the applicable product information (Investigator's 
Brochure for an unapproved investigational product or package insert/summary of product 
characteristics for an approved product).
7.2.
Classification of an Adverse Event
7.2.1.
Severity of Event
The severity of the adverse event should follow the NCI-CTCAE (version 5.0), and the highest 
level of severity that the adverse event reached should be entered in the eCRF.
A copy of the CTCAE version 5.0 can be downloaded from the following web site
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
If a CTCAE term cannot be found, grade must be assigned as follows:
Grade
Severity
Definition
Grade 1
Mild
Discomfort noticed but no disruption of normal 
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Grade
Severity
Definition
Grade 2
Moderate
Discomfort sufficient to reduce or affect daily 
activity; no treatment or medical intervention is 
indicated although this could improve the overall 
well-being or symptoms of the participant.
Grade 3
Severe
Inability to work or perform normal daily activity; 
treatment or medical intervention is indicated in 
order to improve the overall well-being or 
symptoms; delaying the onset of treatment is not 
putting the survival of the participant at direct risk.
Grade 4
Life-threatening/
disabling
An immediate threat to life or leading to a 
permanent mental or physical conditions that 
prevents work or performing normal daily activities; 
treatment or medical intervention is required in 
order to maintain survival.
Grade 5
Death
AE resulting in death.
If severity of AE changed during the course of development of the event, the maximum severity 
is reported. 
Refer to the Section 6.5.1 for requirements on severity assessment of local reactions at the 
injections site.
7.2.2.
Relationship to Study Medication
For all collected AEs, the investigator who examines and evaluates the participant will evaluate 
whether there is a reasonable causal relationship between the occurrence of the AE and the 
exposure to the study drug(s) and/or clinical trial protocol procedure(s). Medical judgment 
should be used to determine the relationship, considering all relevant factors including the 
pattern of reaction, temporal relationships, positive dechallenge or rechallenge, relevant medical 
history, and confounding factors such as co-medication or concurrent diseases.
The expression “reasonable causal relationship” is meant to convey in general that there are 
factor arguments to suggest a causal relationship (ICH E2A, Section IIIA 1).
The relationship assessment for an AE is to be completed using the following definitions as a 
guideline for all AEs occurring during this clinical trial.
Reasonable possibility:
According to the reporting investigator, there is a reasonable possibility (i.e. suggestive evidence 
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
Between the study drug and the AE, and/or

Between the clinical trial protocol procedure and the AE
No Reasonable Possibility:
No suggestive evidence or arguments can be identified regarding a causal relationship between 
the study drug or the clinical trial protocol procedure and the AE.
7.2.3.
Adverse Event Outcome
The outcome is the information on recovery and any sequelae.
Outcome
Definition
Not recovered/not resolved:
The AE still persists.
Recovered/resolved:
The AE is resolved.
Recovered/
resolved with sequelae:
The participant is stabilized, but with sequelae from this AE
Recovering/resolving:
The participant is recovering from this AE/this AE is 
resolving.
Fatal:
The participant died as a result of this AE.
Unknown:
The outcome of this AE is not known.
7.2.4.
Adverse Event Assessment and Follow-up
Information to be collected includes event description, date and time of onset, clinician’s 
assessment of severity, seriousness, relationship to study product, study procedures, other 
therapy and underlying disease, action taken and date of resolution/stabilization of the event with 
AE outcome. Adverse Events assessed as related to the study drug and/or procedure will be 
monitored until they have resolved or reached a stable condition, with or without sequelae. Other 
AEs will be monitored until the last visit if they have not resolved or reached a stable condition. 
AEs will be characterized as intermittent if interval between the events with the same term does 
not exceed two days. For such AEs documentation of first episode onset and the last episode end 
date is required.
7.3.
Reporting procedure
7.3.1.
Adverse Event Reporting Period
Investigators will seek information on adverse events at each participant contact. All adverse 
events, whether reported by the participant or noted by study personnel, will be recorded in the 
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Reporting period for SAEs starts after informed consent has been obtained and ends at the End of 
Study visit. These SAEs include events caused by a protocol-mandated intervention (e.g., 
invasive procedures such as biopsies, discontinuation of medications). If SAE is considered to be 
related to the study drug or study procedures it must be reported to the sponsor regardless of the 
reporting period. For information on reporting of SAEs to sponsor see Section 7.3.3. 
Reporting period for non-serious AEs starts with the initiation of study treatment and ends at the 
End of Study visit. Non-serious AEs at Screening period which are in the Investigator’s opinion 
related to study procedures (e.g. biopsy) also should be reported. 
7.3.2.
Adverse Event Reporting
A consistent methodology of non-directive questioning should be adopted for eliciting adverse 
event information. Example of non-directive question:
"How have you felt since your last clinic visit?"
Any AE occurring during the AE reporting period, whether or not related to the study drug 
and/or study procedure, will be recorded immediately in the source document, and described on 
the AE form of the eCRF along with the date and time of onset, seriousness, severity, 
relationship to the study drug(s) and/or study procedure and/or other therapy and/or underlying 
disease, action taken, and outcome with the date of resolution/stabilization of the event, if 
applicable, and outcome, without omitting any requested and known information.
AEs assessed as related to the study drug and/or procedure will be monitored until they have 
resolved or reached a stable condition, with or without sequalae. Other AEs will be monitored 
until the last visit if they have not resolved or reached a stable condition.
Reporting procedures for SAEs (see Section 7.3.3), AESIs (see Section 7.4), and pregnancies 
(see Section 7.5) must be followed.
7.3.3.
Serious Adverse Event Reporting
For any SAE occurring during the clinical trial, regardless of whether or not related to the study 
drug and/or procedure, the investigator must:
1. Take prompt and appropriate medical action, if necessary. 
2. Ensure that the event is evaluated as an SAE. 
3. Immediately complete the paper SAE form, compile any relevant information or anonymized 
medical records (e.g. laboratory test results) and send it via email or by fax within 24 hours of 
receipt of this relevant information to: 
Contact information for Investigator’s notification in case of SAEs
Gilead Global Patient Safety
Email: 
or
PPD
PPD


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NOTE: Before sending the SAE report, please inform Clinical research associate (CRA) by telephone.
4. Complete the AE form in the eCRF. As soon as the event is saved as serious, an email alert will 
be sent to predefined recipients to highlight that an SAE has occurred.
All SAEs will be followed until satisfactory resolution or until the site investigator deems the 
event to be chronic or reached a stable condition. For all additional follow-up evaluations, the 
paper SAE form must be completed and sent via email or by fax to Gilead Global Patient Safety 
within 24 hours of receipt of the updated information. Other supporting documentation of the 
event may be requested by the study sponsor and should be provided as soon as possible, within 
24 hours of receipt of the updated information. As soon as it is possible to do so, any SAE 
reported via paper must be transcribed onto the Adverse Event eCRF. Whenever an SAE is 
updated in eCRF, a new email alert will be sent. 
When the outcome of the event is known, an updated SAE form must be completed and sent via 
email or fax to Gilead Global Patient Safety.
The study sponsor will be responsible for reporting to the competent authorities in all the 
Member States concerned of any unexpected fatal or life-threatening suspected adverse reaction 
as soon as possible (without delay) but in no case later than 7 calendar days after the sponsor's 
initial receipt of the information, and no later than 15 days for other suspected unexpected 
serious adverse reaction. The Sponsor will inform all the investigators of the occurrence of any 
SUSAR during the clinical conduct of the study.
The study sponsor will be responsible for notifying the manufacturer of Peginterferon alfa-2a of 
any serious adverse reaction related to Peginterferon alfa-2a.
7.4.
Events of Special Interest
See Section 7.1.3.
7.5.
Hepatic Safety Adjudication Committee
A Hepatic Safety Adjudication Committee (HSAC) will be implemented to assess all severe and 
serious adverse events related to Hepatobiliary system and other significant safety issues as 
considered necessary by Sponsor.
7.6.
Reporting of Pregnancy
Any pregnancy occurring during clinical trials, must be monitored until its outcome in order to 
ensure the complete collection of safety data.
If a participant becomes pregnant, the investigator must:
-
Withdraw the participant from the clinical trial.
-
Complete as fully as possible Paper Pregnancy Report form and/or Pregnancy 
Outcome Report form (as applicable). 
-
Send the paper form via email or by fax within 24 hours of receipt of the 
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Gilead Global Patient Safety
Email: 
or
Fax: 
-
Complete the Pregnancy Report form in eCRF. Email alert will be sent to 
predefined recipients to highlight that a pregnancy has occurred.
If the pregnancy leads to an abortion (spontaneous abortion or therapeutic abortion), in utero 
death or congenital anomaly, follow the procedure for declaration of an SAE (see Section 7.3.3). 
Other cases, such as reports of induced termination of pregnancy without information on 
congenital malformation, reports of pregnancy exposure without outcome data, or reports which 
have a normal outcome should not be submitted as SAE.
If a female partner of a male participant receiving/ received bulevirtide becomes pregnant, the 
investigator should propose signing of the Information Sheet for pregnant partner and Informed 
Consent Form to the provision of information about pregnancy and its outcome.
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8. STATISTICAL CONSIDERATIONS
8.1.
Analysis Populations
Enrolled set: All participants screened and enrolled (signed Informed Consent) into this study.
Randomized set: All enrolled and randomized participants.
Full analysis set (FAS): All participants randomized who received study medication (pegylated 
interferon and/or bulevirtide) at least once after randomization.
Per-protocol (PP) set: All participants of the FAS for whom no protocol deviations are judged to 
have an impact on the analysis of the primary efficacy endpoint of SVR 24. Details will be 
specified in the statistical analysis plan and final decision on exclusion from PP set will be made 
in a data review meeting before database lock.
Safety population: All participants who had been exposed to study mediation (pegylated 
interferon and/or bulevirtide)
Analyses based on the randomized set and the FAS will use the randomized treatment. Analyses 
based on the PP population and the Safety population will use the actual treatment received.
8.2.
Description of Statistical Methods
8.2.1.
Demographic and Baseline Measurements
All demographic and background characteristic variables will be summarized by treatment group 
and overall to describe the study population.
The data will be presented for all participants in the FAS and the PP population. Presentation for 
Safety, and Randomized set (if applicable) will be done if the corresponding set size differs from 
the FAS set size by more than 10%.  
8.2.2.
Analysis of Efficacy
Continuous variables will be summarized in terms of descriptive statistics including number of 
observations, mean, standard deviation, minimum, maximum and quartiles. Categorical variables 
will be summarized in terms of frequencies and percentages. Where data are collected over time, 
both the observed data and the change from baseline will be summarized by treatment group at 
each visit.
Primary Analysis
The primary efficacy analysis of this study is the estimation of the difference in rates between the 
combination of pegylated interferon + bulevirtide 10 mg (Arm C) and bulevirtide 10 mg 
monotherapy (Arm D) of sustained virological response (SVR 24) defined as undetectable HDV 
RNA at FU-24 after the scheduled end of treatment. A 95%-confidence interval with exact 


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unconditional confidence limits using the score statistic will be presented for the rate differences. 
Clopper-Pearson 95%-confidence intervals will be calculated for the single rates. The p-value of 
a two-sided Fisher test will be calculated. 
Paiiicipants with missing FU-24 assessment in HDV RNA will be handled as non-responders 
unless it is related to COVID-19 in which case missing values will be imputed using the next 
observation can ied backwai·d (NOCB) approach. 
The primaiy analysis will be based on the FAS. The analysis will be repeated for the PP set and 
in case of differences between the FAS and the randomized set also for the randomized set to 
assess consistency and robustness of results. 
The influence of covai·iables e.g. presence of cinhosis and region will be investigated using 
logistic models. 
8.2.3. 
Analysis of Safety 
Adverse Events 
Adverse events (AE) will be coded using MedDRA and will be presented by primaiy SOC and 
Prefen ed Te1m (PT). The analysis will focus on the treatment-emergent AEs (TEAE), i.e., AEs 
which staited or worsened after strut of treatment and no later than 30 days after pe1manent 
discontinuation of treatment. The frequency of TEAEs will be summai·ized by incidences. In 
these sUffilnai·ies, each paiiicipant will be counted only once within each prefen ed tenn and 
soc. 
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Frequencies of TEAEs will also be presented by relationship to study treatment and by maximum 
severity. Additional analyses will be performed for SAE, TESAE and AEs leading to dose 
reduction and AE leading to discontinuation.
Vital Signs 
Vital signs will be described by summary statistics for measured values and changes from 
baseline by visit.
Laboratory Parameters
Laboratory parameters will be described by summary statistics for measured values and changes 
from baseline by visit.
The clinical assessment of laboratory variables (abnormal high/ clinically relevant, abnormal 
high/not clinically relevant, within normal limits, abnormal low/not clinically relevant, abnormal 
low/clinically relevant) will be tabulated by visit for each clinical laboratory analyte in frequency 
tables. Additionally, for each laboratory parameter shifts in assessments from baseline to week 
48 and week 96 visit will be presented (shift tables).
ECG
The ECG assessment summary categories will be tabulated by visit. Additionally, shifts in 
assessments from baseline to visits will be presented (shift tables).
Descriptive summaries of actual values and changes from baseline will be presented for ECG 
measures of PR interval, QRS interval, QT interval, QT-interval corrected for heart rate (QTc, 
Bazett), and heart rate by visit.
Also, the number and percent of participants in each treatment group with QTc values 451 - 480 
ms, 481 - 500 ms or >500 ms and the number and percent of participants in each treatment group 
who experienced a change vs. baseline >30 ms or a change >60 ms will be presented by visit.
Immunogenicity
The production of bulevirtide antibodies will be presented by visit.
Pharmacokinetics 
Plasma concentration of bulevirtide will be described by descriptive statistics.
Other Safety Assessments
Other safety variable will be described by appropriate descriptive statistics. 
8.2.4.
Determination of Sample Size
The primary efficacy analysis of this study is the estimation of the difference in rates between the 
combination of pegylated interferon + bulevirtide 10 mg (Arm C) and bulevirtide 10 mg 


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monotherapy (Alm D) of sustained virological response (SVR 24) defined as undetectable HDV 
RNA at week 24 after the scheduled end of treatment i.e. at study week 120. With 48 paiiicipants 
per treatment group a two-sided continuity coITected 95%-confidence interval for the difference 
of the SVR 24 rates will extend less than 22.5% from the observed difference. The sample size 
will be slightly increased to 50 paiiicipants per treatment group to account for a few potential 
early withdrawals before exposme. 
The ti·eatment group with the combination of pegylated interferon + bulevirtide 2 mg will be of 
the same size. The ti·eatment group with the pegylated interferon will include 25 participants. 
Hence 175 paiiicipants will be randomized. 
8.2.5. 
Interim, Follow-up and Final Analyses 
Analyses of data ai·e planned to be perfo1med at following times: 
2) When all paiiicipants complete the FU-24 visit or discontinue the study (FU-24 main primaiy 
analysis). 
3) When all paiiicipants complete the final follow-up visit at 48 weeks after the scheduled end 
of ti·eatment (FU-48) or discontinue the study (FU-48 final analysis: analysis of all collected 
data from the study). 
Any deviation( s) from the original statistical plan will be described and justified in protocol 
and/or in the final repo1i, as appropriate. 
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9.
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction and evaluation of the study. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, participant evaluation 
checklists, recorded data from automated instruments, participant files and records kept at the 
pharmacy, at the laboratories, and medico-technical departments involved in the clinical study. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The investigator may need to request 
previous medical records or transfer records, depending on the study. Also, current medical 
records must be available. The eCRF is essentially considered a data entry form and should not 
constitute the original (or source) medical records unless otherwise specified. 
The investigator is responsible for maintaining source documents.
Direct access to source data and documents must be provided to the Study Medical Monitor, 
sponsor’s CRA and authorized representatives (contract research organization, CRO), 
Sponsor’s/CRO’s auditor, regulatory inspectors, members of ethics committees and 
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10.
QUALITY ASSURANCE AND QUALITY CONTROL
10.1.
Periodic Monitoring
Monitoring will be done by the CRAs according to standard operation procedures and 
Monitoring Plan. At the beginning of the trial the responsible CRA will perform an Initiation 
visit at the investigational site (prior to the inclusion of the first study participant). During regular 
On-site visits the CRA will review the entries into the eCRFs on the basis of applicable source 
documents. The investigators must allow the CRA to verify all essential documents and must 
provide support to the CRA at any time. Frequency of monitoring will be defined in the 
Monitoring Plan. By frequent communications (letters, telephone, fax), the CRA will ensure that 
the study is conducted according to the protocol and regulatory requirements.
If, in the case of external unavoidable circumstances, including COVID-19 pandemic spread in 
the world, On-site visit is impossible, remote monitoring will be performed, given that all 
regulatory and essential data protection requirements are met and appropriate arrangements to 
ensure participants’ personal data protection and confidentiality are taken. Such remote 
monitoring can be performed, for example, using telephone contacts or video conferences, 
provided that source documents or records with personal data of the study participants may not 
leave the study site, not even as a copy, and therefore no permanent storage outside the study site 
may take place.
10.2.
Audit and Inspection
Competent and local authorities and an auditor authorized by the Sponsor may request access to 
all source documents, eCRF, and other trial documentation. Direct access to these documents 
must be guaranteed by the investigators who must provide support at all times for these 
activities. In case inspections will be announced to the Principal Investigator, the Sponsor and 
the CRA should be informed in time.


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11.
ETHICS / PROTECTION OF HUMAN SUBJECTS
11.1.
Ethical Standard
The investigator will ensure that this study is conducted in full conformity with Declaration of 
Helsinki and the ICH E6 (GCP).
11.2.
Independent Ethics Committee (IEC) and/or Institutional Review Board 
(IRB)
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IEC/IRB for review and approval. Approval of both the protocol and the 
consent form must be obtained before any participant is enrolled. Any substantial amendment to 
the protocol will require review and approval by the IEC/IRB before the changes are 
implemented to the study. Any amendment to the protocol deemed by the sponsor as 
“substantial” will be submitted to the regulatory authority for notification and approval. All 
changes to the consent form will be IEC/IRB approved; a determination will be made regarding 
whether previously consented participants need to be re-consented.
11.3.
Informed Consent Process
Consent forms describing in detail the study medications, study procedures, and risks are given 
to the participant and written documentation of informed consent is required prior to starting any 
study procedures.
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of participation will be provided to the participants. Consent forms 
will be IEC/IRB-approved and the participant will be asked to read and review the document. 
The investigator will explain the research study to the participant and answer any questions that 
may arise. All participants will receive a verbal explanation in terms suited to their 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
research participants. Participants will have the opportunity to carefully review the written 
consent form and ask questions prior to signing. The participants should have the opportunity to 
discuss the study with their surrogates or think about it prior to agreeing to participate. The 
participant will sign the informed consent document prior to any procedures being done 
specifically for the study. The participants may withdraw consent at any time throughout the 
course of the trial. A copy of the informed consent document will be given to the participants for 
their records. The rights and welfare of the participants will be protected by emphasizing to them 
that the quality of their medical care will not be adversely affected if they decline to participate 
in this study.
If, in the case of external unavoidable circumstances, including COVID-19 pandemic spread in 
the world, it is not possible for participant to visit the site, however, any urgent measures need to 
be implemented in the interest of participant’s safety, informed consent can be received receive 
the participant’s oral consent by phone supplemented with an email confirmation (if it is 


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possible) before the respective action. Updated participant information sheet and consent form 
should be signed at the subsequent visit, where applicable. Any consent obtained this way should 
be documented clearly.
11.4.
Participant and Data Confidentiality
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
and the sponsor and their agents. This confidentiality is extended to cover testing of biological 
samples in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.
The CRA, other authorized representatives of the sponsor, representatives of the IEC/IRB or 
pharmaceutical company supplying study product may inspect all documents and records 
required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records.
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by local regulations.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the authorized CRO/Data Management company. 
This will not include the participant’s contact or identifying information. Rather, individual 
participants and their research data will be identified by a unique study identification number. 
The study data entry and study management systems used by clinical sites and by authorized 
CRO/Data Management company will be secured and password protected. 


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12.
DATA HANDLING AND RECORD KEEPING
12.1.
The Entering of Data Into the eCRF 
All data must be entered in English. The eCRFs should always reflect the latest observations on 
the participants participating in the study. Therefore, the eCRFs should be completed as soon as 
possible during or after the participant’s visit. To avoid inter-observer variability, every effort 
should be made to ensure that the same individual who made the initial baseline determinations 
completes all corresponding follow-up evaluations. The investigator must verify that all data 
entries in the eCRFs are accurate and correct. If some assessments are not done, or if certain 
information is not available, not applicable or unknown, this should be indicated in the eCRF. 
The investigator will be required to electronically sign off the clinical data.
12.2.
The Query Process
The monitor will review the eCRFs and evaluate them for completeness and consistency. Each 
eCRF will be compared with the respective source documents to ensure that there are no 
discrepancies between critical data. All entries, corrections, and alterations are to be made by the 
investigator or designee. The monitor cannot enter data in the eCRFs. Once clinical data have 
been submitted to the central server via the eCRF, corrections to the data fields will be audit 
trailed, meaning that the reason for change, the name of the person who made the change, 
together with time and date will be logged. Roles and rights of the site personnel responsible for 
entering clinical data into the eCRF will be determined in advance. If additional corrections are 
needed, the responsible monitor or Data Manager will raise a query in the electronic data capture 
application. The appropriate study personnel will answer the queries in the eCRF. This will be 
audit trailed by the electronic data capture application meaning that the name of study personnel, 
time, and date are logged.
12.3.
Data Collection and Management Responsibilities
Data collection is the responsibility of the clinical study staff at the site under the supervision of 
the site PI. The investigator is responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. When making changes or corrections, cross out the original entry with a 
single line, and initial and date the change. Do not erase, overwrite, or use correction fluid or 
tape on the original.
Data reported in the eCRF derived from source documents should be consistent with the source 
documents.
The data system includes password protection and internal quality checks, such as automatic 
range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data 
will be entered directly from the source documents.


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12.3.1.
User ID
eCRF records will be automatically appended with the identification of the creator, by means of 
their unique User ID. Specified records will be electronically signed by the investigator to 
document his/her review of the data and acknowledgement that the data are accurate. This will 
be facilitated by means of the investigator’s unique User ID and password; date and time stamps 
will be added automatically at time of electronic signature. If an entry in an eCRF requires 
change, the correction should be made in accordance with the relevant software procedures. 
12.3.2.
Audit Trail
All changes in the eCRF will be fully recorded in a protected audit trail, and a reason for the 
change will be required.
12.4.
Study Records Retention
Study documents should be retained until at least 15 years have elapsed since the study 
completion. These documents should be retained for a shorter or longer period, however, if 
required by local regulations. No records will be destroyed without the written consent of the 
sponsor, if applicable. 
12.5.
Protocol Deviations
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or manual of 
procedures requirements (if applicable). The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions 
are to be developed by the site and implemented promptly.
These practices are consistent with ICH E6: 

4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 

5.1 Quality Assurance and Quality Control, section 5.1.1 

5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
It is the responsibility of the site to use continuous vigilance to identify and report deviations. 
Protocol deviations must be sent to the local IEC/IRB per their guidelines. The site PI/study staff 
is responsible for knowing and adhering to their IEC/IRB requirements. 
All protocol deviations related to COVID-19 should be classified as “COVID-19 related” and 
described in the clinical study report.
12.6.
Publication and Data Sharing Policy
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 


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The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.


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13.
FINANCING AND INSURANCE
13.1.
Financing
The sponsor financially supports the study. The company will deliver the study drugs free of 
charge as well as paying the investigator/ investigational sites a fee for the participants enrolled 
to cover trial costs. 
13.2.
Insurance
According to applicable national laws and EU regulations, an insurance policy has to be 
subscribed covering in its terms and provisions the 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.


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14.
LITERATURE REFERENCES
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г.;78(5):2537–2544. 
2. Niro GA, Smedile A. Current concept in the pathophysiology of hepatitis delta infection. 
Current infectious disease reports. 2012 г.;14(1):9–14. 
3. Niro GA, Smedile A, Ippolito AM, Ciancio A, Fontana R, Olivero A, и др. Outcome of 
chronic delta hepatitis in Italy: a long-term cohort study. Journal of hepatology. 2010 
г.;53(5):834–840. 
4. Cole SM, Gowans EJ, Macnaughton TB, De La M. Hall P, Burrell CJ. Direct evidence for 
cytotoxicity associated with expression of hepatitis delta virus antigen. Hepatology. 1991 
г.;13(5):845–851. 
5. Lacombe K, Boyd A, Desvarieux M, Serfaty L, Bonnord P, Gozlan J, и др. Impact of 
chronic hepatitis C and/or D on liver fibrosis severity in patients co-infected with HIV and 
hepatitis B virus. Aids. 2007 г.;21(18):2546–2549. 
6. Zachou K, Yurdaydin C, Drebber U, Dalekos GN, Erhardt A, Cakaloglu Y, и др. 
Quantitative HBsAg and HDV-RNA levels in chronic delta hepatitis. Liver International. 
2010 г.;30(3):430–437. 
7. Verme G, Amoroso P, Lettieri G, Pierri P, David E, Sessa F, и др. A histological study of 
hepatitis delta virus liver disease. Hepatology. декабрь 1986 г.;6(6):1303–7. 
8. Yurdaydın C, Idilman R, Bozkaya H, Bozdayi AM. Natural history and treatment of chronic 
delta hepatitis. Journal of viral hepatitis. 2010 г.;17(11):749–756. 
9. Wedemeyer H. Re-emerging interest in hepatitis delta: new insights into the dynamic 
interplay between HBV and HDV. Journal of hepatology. 2010 г.;52(5):627–629. 
10. Rizzetto M. Hepatitis D: thirty years after. Journal of hepatology. 2009 г.;50(5):1043–1050. 
11. Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: 
update and challenges ahead. Nature Reviews Gastroenterology and Hepatology. 2010 
г.;7(1):31. 
12. Robert A, Sprey RP, Niesters HG, Heijtink RA, Zondervan PE, Hop W, и др. Survival and 
complications in a cohort of patients with anti-delta positive liver disease presenting in a 
tertiary referral clinic. Journal of hepatology. 1995 г.;23(6):662–667. 
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Chronic hepatitis D: a vanishing Disease? An Italian multicenter study. Hepatology. 2000 
г.;32(4):824–827. 
14. Manesis EK, Vourli G, Dalekos G, Vasiliadis T, Manolaki N, Hounta A, и др. Prevalence 
and clinical course of hepatitis delta infection in Greece: a 13-year prospective study. Journal 
of hepatology. 2013 г.;59(5):949–956. 
15. Romeo R, Del Ninno E, Rumi M, Russo A, Sangiovanni A, De Franchis R, и др. A 28-year 
study of the course of hepatitis Δ infection: a risk factor for cirrhosis and hepatocellular 
carcinoma. Gastroenterology. 2009 г.;136(5):1629–1638. 


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16. Buti M, Homs M, Rodriguez-Frias F, Funalleras G, Jardi R, Sauleda S, и др. Clinical 
outcome of acute and chronic hepatitis delta over time: a long-term follow-up study. Journal 
of viral hepatitis. 2011 г.;18(6):434–442. 
17. Heidrich B, Manns MP, Wedemeyer H. Treatment options for hepatitis delta virus infection. 
Current infectious disease reports. 2013 г.;15(1):31–38. 
18. Cornberg M, Protzer U, Dollinger MM, Petersen J, Wedemeyer H, Berg T, и др. 
Prophylaxis, diagnosis and therapy of hepatitis B virus (HBV) infection: the German 
guidelines for the management of HBV infection. Zeitschrift für Gastroenterologie. 2007 
г.;45(12):1281–1328. 
19. Gish RG, Yi DH, Kane S, Clark M, Mangahas M, Baqai S, и др. Coinfection with hepatitis B 
and D: Epidemiology, prevalence and disease in patients in N orthern C alifornia. Journal of 
gastroenterology and hepatology. 2013 г.;28(9):1521–1525. 
20. Kucirka LM, Farzadegan H, Feld JJ, Mehta SH, Winters M, Glenn JS, и др. Prevalence, 
correlates, and viral dynamics of hepatitis delta among injection drug users. The Journal of 
infectious diseases. 2010 г.;202(6):845–852. 
21. Wedemeyer H, Yurdaydìn C, Dalekos GN, Erhardt A, Çakaloğlu Y, Değertekin H, и др. 
Peginterferon plus adefovir versus either drug alone for hepatitis delta. New England Journal 
of Medicine. 2011 г.;364(4):322–331. 
22. Heidrich B, Yurdaydın C, Kabaçam G, Ratsch BA, Zachou K, Bremer B, и др. Late HDV 
RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta. Hepatology. 
2014 г.;60(1):87–97. 
23. Gheorghe L, Iacob S, Simionov I, Vadan R, Constantinescu I, Caruntu F, и др. Weight-based 
dosing regimen of peg-interferon α-2b for chronic hepatitis delta: a multicenter Romanian 
trial. Journal of Gastrointestinal & Liver Diseases. 2011 г.;20(4). 
24. Trauner M, Boyer JL. Bile salt transporters: molecular characterization, function, and 
regulation. Physiological reviews. 2003 г.;83(2):633–671. 
25. Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, и др. Sodium taurocholate cotransporting 
polypeptide is a functional receptor for human hepatitis B and D virus. elife. 2012 
г.;1:e00049. 
26. Liu R, Chen C, Xia X, Liao Q, Wang Q, Newcombe PJ, и др. Homozygous p. Ser267Phe in 
SLC10A1 is associated with a new type of hypercholanemia and implications for 
personalized medicine. Scientific Reports. 2017 г.;7(1):9214. 
27. Hagenbuch B, Meier PJ. Molecular cloning, chromosomal localization, and functional 
characterization of a human liver Na+/bile acid cotransporter. The Journal of clinical 
investigation. 1994 г.;93(3):1326–1331. 
28. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, и др. 
Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial 
treatment of chronic hepatitis C: a randomised trial. The Lancet. 2001 г.;358(9286):958–965. 
29. Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, и др. 
Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive 
chronic hepatitis B: a randomised trial. The Lancet. 2005 г.;365(9454):123–129. 
30. Castelnau C, Le Gal F, Ripault M-P, Gordien E, Martinot-Peignoux M, Boyer N, и др. 
Efficacy of peginterferon alpha-2b in chronic hepatitis delta: relevance of quantitative RT-
PCR for follow-up. Hepatology. 2006 г.;44(3):728–735. 


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31. Niro GA, Ciancio A, Gaeta GB, Smedile A, Marrone A, Olivero A, и др. Pegylated 
interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis 
delta. Hepatology. 2006 г.;44(3):713–720. 
32. MYR202, Interim Clinical Study Report, Version 1.0 dated 10 May 2018.
33. Terrault N, Lok A, McMahon B, et al. Update on prevention, diagnosis, and treatment of 
chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018 
Apr;67(4):1560-1599.
34. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on 
the management of hepatitis B virus infection. J Hepatol. 2017 Aug;67(2):370-398.
35. http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractio
nslabeling/ucm093664.htm#classInhibit (Table 5.1).
36. Nakanishi T, Tamai I. Genetic polymorphisms of OATP transporters and their impact on 
intestinal absorption and hepatic disposition of drugs. Drug Metab Pharmacokinet 
2012;27:106-21. 
37. Smith NF, Figg WD, Sparreboom A. Role of the liver-specific transporters OATP1B1 and 
OATP1B3 in governing drug elimination. Expert Opin Drug Metab Toxicol 2005;1:429-45.
38. Talavera Pons S, Boyer A, Lamblin G, Chennell P, Châtenet FT, Nicolas C, Sautou V, 
Abergel A. Managing drug-drug interactions with new direct-acting antiviral agents in 
chronic hepatitis C. Br J Clin Pharmacol 2017;83:269-293. 


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APPENDIX 1. CONFIRMATION OF PARTICIPANTS’ ELIGIBILITY
Inclusion Criteria
Confirmation
1
Provision of signed and dated informed consent form
Signed and dated informed consent 
form and documented medical 
record 
2
Male or female, aged 18-65 years (inclusive)
Documented by Investigator in 
medical record
3
Positive serum HDV antibody results or PCR results for 
serum/ plasma HDV RNA for at least 6 months before 
Screening
Copy of lab test report or copy of 
discharge
4
Positive PCR results for serum/ plasma HDV RNA at 
Screening
Central Lab test report
5
Alanine transaminase level >1  ULN, but less than 
10  ULN
Central Lab test report
6
Serum albumin >28 g/L
Central Lab test report
7
Thyroid stimulating hormone (TSH) within normal ranges 
(including on medication for control of thyroid function)
Central Lab test report
8
Negative urine pregnancy test for females of childbearing 
potential
Urine pregnancy test result at site 
documented in medical records
Female participant: Postmenopausal for at least 2 years
Female participant: Surgically sterile (total hysterectomy 
or bilateral oophorectomy, bilateral tubal ligation, staples, 
or another type of sterilization)
Female participant: Abstinence from heterosexual 
intercourse throughout the treatment period
9
Female participant: Willingness to use highly effective 
contraception (double barrier method or barrier 
contraception in combination with hormonal or 
intrauterine contraceptive) throughout the treatment 
period and for 6 months after the last dose of the study 
medication
Assessed and documented by 
Investigator in medical record
10
Male participants must agree to use a highly effective 
contraception (double barrier method or barrier 
contraception in combination with hormonal or 
intrauterine contraceptive used by female partners) and 
not to donate sperm throughout the treatment period and 
for 6 months after the last dose of the study medication
Assessed and documented by 
Investigator in medical record 


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Exclusion Criteria
Confirmation
1
Child-Pugh hepatic insufficiency score of B-C or over 
6 points. NOTE: Child-Pugh hepatic insufficiency 
score of 6 points is allowed. Only participants with 
compensated cirrhosis are allowed. Uncomplicated 
oesophageal varices allowed; Participants with 
current bleeding or ligation, or history of bleeding or 
ligation within the last 2 years are excluded.
Assessed and documented by 
Investigator in medical record 
2
HCV or HIV co-infection. Participants with HCV 
antibodies can be enrolled, if screening HCV RNA 
test is negative
Central Lab test report
3
Creatinine clearance < 60 mL/min as estimated using 
Cockcroft-Gault formula
Calculated and documented by 
Investigator in medical record 
based on Central Lab test report
4
Total bilirubin ≥ 34.2 µmol/L. [Participants with 
higher total bilirubin values may be included after the 
consultation with the Study Medical Monitor, if such 
elevation can be clearly attributed to Gilbert’s 
syndrome associated with low-grade 
hyperbilirubinemia.]
Central Lab test report;
Evidence of Gilbert’s syndrome: 
anamnestic data (discharge) or 
assessed and documented by 
Investigator in medical record
5
Evidence of an active or suspected malignancy or an 
untreated pre-malignancy disorder, or a history of 
malignancy within the last 5 years (with the exception 
of successfully treated carcinoma of the cervix in situ 
and successfully treated basal cell carcinoma and 
squamous cell carcinoma not less than 1 year prior to 
screening [and no more than 3 excised skin cancer 
within the last 5 years prior to screening]) or history 
of hepatic carcinoma.
Assessed and documented by 
Investigator in medical record
6
Systemic connective tissue disorders
Assessed and documented by 
Investigator in medical record
7
NYHA (New York Heart Association) class III-IV 
congestive heart failure
Assessed and documented by 
Investigator in medical record
8
Participants with uncontrolled arterial hypertension: 
systolic blood pressure > 150 mm Hg and/ or diastolic 
blood pressure > 100 mm Hg at Screening.
Assessed and documented by 
Investigator in medical record
9
Previous or unstable concurrent diseases or conditions 
that prevent participant’s enrolment into the study
Assessed and documented by 
Investigator in medical record


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Exclusion Criteria
Confirmation
10
Participants with mental disorders or social 
circumstances that preclude them from following 
protocol requirements
Assessed and documented by 
Investigator in medical record
11
Current or previous decompensated liver disease, 
including coagulopathy, hepatic encephalopathy and 
esophageal varices hemorrhage
Assessed and documented by 
Investigator in medical record
12
One or more additional known primary or secondary 
causes of liver disease, other than hepatitis B (e.g., 
alcoholism, autoimmune hepatitis, malignancy with 
hepatic involvement, hemochromatosis, alpha-1 
antitrypsin deficiency, Wilson’s Disease, other 
congenital or metabolic conditions affecting the liver, 
congestive heart failure or other severe 
cardiopulmonary disease, etc). Gilbert’s syndrome, a 
benign disorder associated with low-grade 
hyperbilirubinemia, will not exclude participants from 
participation in this trial. Autoimmune hepatitis 
stigmata attributed to HDV infection in the opinion of 
the investigator are allowed.
Assessed and documented by 
Investigator in medical record
13
White blood cells (WBC) count < 3000 cells/mm3 
(<1500 if African participants)
Central Lab test report
14
Absolute neutrophil count < 1500 cells/mm3 (<1000 
if African participants)
Central Lab test report
15
Platelet count < 90,000 cells/mm3
Central Lab test report
16
Hemoglobin < 12 g/ dL
Central Lab test report
17
Use of prohibited psychotropic agents at Screening
Urine drug screening test result 
at site documented in medical 
record;
Assessed and documented by 
Investigator in medical record
17
Use of interferons within 6 months before Screening
Assessed and documented by 
Investigator in medical record
19
History of solid organ transplantation
Assessed and documented by 
Investigator in medical record
20
Current alcohol abuse or alcohol abuse within 6 
months prior to enrolment in this study; current drug 
addict or history of drug use within 2 years prior to 
Screening
Alco-test result at site 
documented in medical record;
Assessed and documented by 
Investigator in medical record


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Exclusion Criteria
Confirmation
21
History of disease requiring regular use of systemic 
glucocorticosteroids (inhalative glucocorticosteroids 
are allowed) or other immunosuppressants
Assessed and documented by 
Investigator in medical record
22
Pregnant or breast-feeding females
Pregnancy urine test result at site 
documented in medical record;
Assessed and documented by 
Investigator in medical record
23
Participation in another clinical study with 
investigational study drug within 30 days prior to 
randomization
Assessed and documented by 
Investigator in medical record
24
Receipt of bulevirtide previously, e.g. in clinical trials
Assessed and documented by 
Investigator in medical record
25
Inability to follow protocol requirements and undergo 
all protocol procedures. NOTE: Participants with 
medical contraindication for liver biopsy are allowed 
to participate in this study. Such participants will 
exempt from liver biopsy requirements in this study.
Participants 
receiving 
prohibited 
treatment 
at 
Screening cannot be included into the study unless this 
treatment is withdrawn prior to randomization.
Assessed and documented by 
Investigator in medical record
26
Contraindications, intolerance or hypersensitivity to 
interferons alfa, genetically engineered E.coli 
medications, polyethylene glycol or other components 
of peginterferon alfa.
Assessed and documented by 
Investigator in medical record
27
Presence or history of severe retinopathy, significant 
diabetic or hypertensive retinopathy.
Copy of ophthalmologic 
examination’s results performed 
during Screening period
Assessed and documented by 
Investigator in medical record
28
Uncontrolled diabetes mellitus.
Assessed and documented by 
Investigator in medical record
29
Uncontrolled cardiovascular disorders within 6 
months before screening.
Assessed and documented by 
Investigator in medical record
30
History of autoimmune disorder (e.g. myositis, 
hepatitis, thrombotic thrombocytopenic purpura, 
idiopathic thrombocytopenic purpura, severe 
psoriasis, rheumatoid arthritis, interstitial nephritis, 
thyroiditis, and systemic lupus erythematosus)
Assessed and documented by 
Investigator in medical record


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Exclusion Criteria
Confirmation
31
Presence or history of significant psychiatric disorder 
(e.g. severe depression, suicide attempt, severe 
neurosis or cognitive disorder).
Assessed and documented by 
Investigator in medical record
32
Presence or history of chronic lung disease with 
respiratory malfunction.
Assessed and documented by 
Investigator in medical record


protocol MYR204 Amendment 4
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Research eSigned
CCI
PPD

SAP_001.pdf: 
  
STATISTICAL ANALYSIS PLAN
Study Title:
A Multicenter, Open-label, Randomized Phase 2b Clinical 
Study to Assess Efficacy and Safety of Bulevirtide in 
Combination with Pegylated Interferon alfa-2a in Patients with 
Chronic Hepatitis Delta
Name of Test Drug:
Bulevirtide (BLV)
Study Number:
MYR204
Protocol Version (Date):
Version 5.0: 08 February 2022
Analysis Type:
Final Analysis
Analysis Plan Version:
Version 3.0
Analysis Plan Date:
13 November 2023
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD-


Bulevirtide (BLV)
MYR204
Statistical Analysis Plan – Final Analysis
Version 3.0
13 November 2023                                 GILEAD CONFIDENTIAL INFORMATION                          Page 2 of 49
TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................2
LIST OF IN-TEXT TABLES .........................................................................................................................................4
LIST OF ABBREVIATIONS.........................................................................................................................................5
1.
INTRODUCTION..................................................................................................................................................7
1.1.
Study Objectives........................................................................................................................................7
1.2.
Study Design .............................................................................................................................................7
1.3.
Sample Size and Power .............................................................................................................................8
2.
TYPE OF PLANNED ANALYSIS........................................................................................................................9
2.1.
Week 24 Analysis......................................................................................................................................9
2.2.
Follow-up Week 24 Analysis (Primary Analysis).....................................................................................9
2.3.
Final Analysis............................................................................................................................................9
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.............................................................................10
3.1.
Analysis Sets ...........................................................................................................................................10
3.1.1.
All Randomized Analysis Set................................................................................................10
3.1.2.
All Enrolled Analysis Set ......................................................................................................10
3.1.3.
Full Analysis Set....................................................................................................................10
3.1.4.
Per-Protocol Analysis Set......................................................................................................11
3.1.5.
Safety Analysis Set................................................................................................................11
3.1.6.
Anti-drug Antibody Analysis Set ..........................................................................................11
3.2.
Participant Grouping ...............................................................................................................................11
3.3.
Strata and Covariates...............................................................................................................................11
3.4.
Examination of Participant Subgroups....................................................................................................12
3.5.
Multiple Comparisons .............................................................................................................................12
3.6.
Missing Data and Outliers.......................................................................................................................12
3.6.1.
Missing Data..........................................................................................................................12
3.6.2.
Outliers ..................................................................................................................................12
3.7.
Data Handling Conventions and Transformations ..................................................................................12
3.8.
Analysis Visit Windows..........................................................................................................................13
3.8.1.
Definition of Study Day ........................................................................................................13
3.8.2.
Analysis Visit Windows........................................................................................................14
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window .................................................................................................................................14
4.
PARTICIPANT DISPOSITION ..........................................................................................................................16
4.1.
Participant Enrollment and Disposition...................................................................................................16
4.2.
Extent of Study Drug Exposure and Compliance....................................................................................17
4.2.1.
Study Drug Exposure ............................................................................................................17
4.2.2.
Study Drug Compliance ........................................................................................................17
4.2.3.
Summaries of Study Drug Exposure and Compliance..........................................................18
4.3.
Protocol Deviations .................................................................................................................................18
4.4.
Assessment of COVID-19 Impact...........................................................................................................18
4.4.1.
Protocol Deviations Due to COVID-19 ................................................................................19
5.
BASELINE CHARACTERISTICS .....................................................................................................................20
5.1.
Demographics and Baseline Characteristics ...........................................................................................20
5.2.
Other Baseline Characteristics ................................................................................................................20
5.3.
Substance Use..........................................................................................................................................22
5.4.
Medical History.......................................................................................................................................22


Bulevirtide (BL V) 
MYR204 
Statistical Analysis Plan - Final Analysis 
Version 3.0 
6. 
EFFICACY ANALYSES ..................................................................................................................................... 23 
6.1. 
General Considerations ........................................................................................................................... 23 
6.2. 
Pri1nruy Efficacy Endpoint ...................................................................................................................... 23 
6.2.1. 
Primruy Analysis of the Prima1y Efficacy Endpoint ............................................................. 23 
6.2.2. 
Sensitivity Analysis of the Primruy Efficacy Endpoint ......................................................... 24 
6.2.3. 
Logistic Regression of the Prima1y Efficacy Endpoint.. ....................................................... 24 
6.2.4. 
Per-protocol Analysis of the Prima1y Efficacy Endpoint ...................................................... 24 
6.2.5. 
Subgroup Analysis of the Prima1y Efficacy Endpoint .......................................................... 24 
6.2.6. 
Other Analyses of the Primruy Efficacy Endpoint ................................................................ 24 
6.3. 
Secondruy Efficacy Endpoints ................................................................................................................ 24 
6.3.1. 
Anal sis of Secondai Efficac End oints ........................................................................... 25 
Necroinflammation and Fibrosis Assessed at liver biopsy .............................. 27 
HBsAg Loss with/without Seroconversion ..................................................... 27 
Liver Related Clinical Events .......................................................................... 28 
Ew-oQol 5-Dimentions 3-Levels (EQ-5D-3L) ................................................. 29 
Fatigue Severity Scale (FSS) ........................................................................... 29 
He atitis uali ofLife uestionnaire 
L 
............................................ 29 
-
6.5. 
Additional Efficacy Endpoint .................................................................................................................. 30 
7. 
SAFETY ANALYSES ......................................................................................................................................... 32 
7.1. 
Adverse Events and Deaths ..................................................................................................................... 32 
7.1. 1. 
Adverse Event Dictiona1y ..................................................................................................... 32 
7.1.2. 
Adverse Event Severity ......................................................................................................... 32 
7.1.3. 
Relationship of Adverse Events to Study Dmg ..................................................................... 32 
7.1.4. 
Serious Adverse Events ......................................................................................................... 32 
7.1.5. 
Treatinent-Emergent Adverse Events .................................................................................... 32 
7.1.5.1. 
Definition of Treatinent-Emergent Adverse Events ........................................ 32 
7 .1.5.2. 
Inco1nplete Dates ............................................................................................. 33 
7.1.6. 
SW'lllllaries of Adverse Events and Deaths ............................................................................ 33 
7 .1.6.1. 
SW'lllnaries of AE incidence ............................................................................ 34 
7.1.7. 
Additional Analysis of Adverse Events ................................................................................ 35 
7 .1.7 .1. 
Hepatic Adverse Events ................................................................................... 35 
7.1.7.2. 
Subgroup Analyses of Adverse Events ............................................................ 35 
7 .2. 
Laborato1y Evaluations ........................................................................................................................... 36 
7.2.1. 
SW'll1lla1ies ofNume1ic Laborat01y Results .......................................................................... 36 
7.2.2. 
SW'll1lla1ies of Qualitative Laborat01y Results ...................................................................... 38 
7.2.3. 
Graded Laborato1y Values .................................................................................................... 38 
7 .2.3.1. 
Treatinent-Emergent Laborat01y Abnonnalities ............................................. 39 
7.2.3.2. 
SW'lllnaries of Laborat01y Abnonnalities ........................................................ 39 
7.2.4. 
Liver-related Laborat01y Evaluations .................................................................................... 39 
7.2.4.1. 
Potential Drng Induced Liver Injwy (DILi) .................................................... 39 
7.2.5. 
Shifts Relative to the Baseline Value .................................................................................... 39 
7.3. 
Body Weight and Vital Signs ................................................................................................................. .40 
7 .4. 
Physical Exrunination ............................................................................................................................. .40 
7.5. 
Ptior and Concolllitant Medications ....................................................................................................... .40 
7 .5.1. 
Ptior and Concolllitant Medications ..................................................................................... .40 
7.5.2. 
HBV Medications ................................................................................................................. .41 
7.6. 
Electrocru·diogra1n Results ...................................................................................................................... .42 
7.6.1. 
Investigator Electi·ocardiogram Assessment ........................................................................ .42 
7 .6.2. 
Other Electi·ocardiogram Assessment .................................................................................. .42 
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7.7.
Other Safety Measures ............................................................................................................................42
8.
IMMUNOGENICITY ANALYSES ....................................................................................................................43
8.1.
ADA Incidence and Prevalence...............................................................................................................43
9.
PHARMACOKINETIC (PK) ANALYSES.........................................................................................................44
9.1.
PK Sample Collection .............................................................................................................................44
9.2.
PK Analyses ............................................................................................................................................44
10.
OTHER EVALUATIONS....................................................................................................................................45
10.1.
HBeAg.....................................................................................................................................................45
10.2.
Liver Biopsy - Molecular Analysis and Gene Expression ......................................................................45
11.
SOFTWARE.........................................................................................................................................................47
12.
SAP REVISION...................................................................................................................................................48
13.
APPENDICES......................................................................................................................................................49
LIST OF IN-TEXT TABLES
Table 3-1.
Virology LLOQ and LOD .......................................................................................................13
Table 3-2.
Analysis Visit Windows for by Visit Assessments .................................................................14
Table 6-1.
Definition of Potential Liver Related Clinical Events.............................................................28
Table 7-1.
Impute Partial AE Dates (year and month available but day missing)....................................33
Table 7-2.
Impute Partial AE Dates (year available but month and day missing)....................................33
Table 7-3.
Impute Completely Missing AE Onset Date ...........................................................................33
Table 7-4.
Impute Completely Missing AE End Date..............................................................................33
Table 7-5.
Impute Partial Medication Dates .............................................................................................41
Table 8-1.
Definition of ADA Incidence ..................................................................................................43


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LIST OF ABBREVIATIONS
ADA
anti-drug antibody 
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BLV
bulevirtide 
BMI
body mass index
CHD
chronic hepatitis delta
CI
confidence interval
CRF
case report form
CRP
c-reactive protein
CS
clinically significant
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DILI
drug-induced liver injury
ECG
electrocardiogram
EOT
end of treatment
EQ-5D-3L
EuroQol 5-dimentions 3-levels 
ET
early termination
FAS
full analysis set
FSS
fatigue severity scale 
GGT
gamma glutamyl transferase
HBeAg
hepatitis B e antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HQLQ
hepatitis quality of life questionnaire 
HLT
high-level term
INR
International Normalized Ratio
LLOQ
lower limit of quantification
LOD
limit of detection
MedDRA
Medical Dictionary for Regulatory Activities
MEF
missing equals failure 
NCS
not clinically significant
NOCB
next observation carried backward 
OC
observed case
PEG-IFNα
pegylated interferon alfa-2a
PP
per-protocol


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PT
preferred term
Q1, Q3
first quartile, third quartile
QRS
electrocardiographic deflection between the beginning of the Q wave and termination of the 
S wave representing time for ventricular depolarization
QT
electrocardiographic interval between the beginning of the Q wave and termination of the 
T wave representing the time for both ventricular depolarization and repolarization to occur
QTc
QT interval corrected for heart rate
RR
electrocardiographic interval representing the time measurement between the R wave of one 
heartbeat and the R wave of the preceding heartbeat
SAP
statistical analysis plan
SD
standard deviation
SOC
system organ class
SVR24
sustained virological response at follow-up Week 24
SVR48
sustained virological response at follow-up Week 48
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
TSH
thyroid stimulating hormone
ULN
upper limit of normal
ULOQ
upper limit of quantification 
VAS
visual analogue scale
WHO
World Health Organization


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentation to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study MYR204. This SAP is based on the study protocol dated 08 February 2022 and the 
electronic case report form (eCRF). The SAP will be finalized before database finalization. Any 
changes made after the finalization of the SAP will be documented in the CSR.
1.1.
Study Objectives
The primary objective of this study is to evaluate the efficacy of bulevirtide (BLV) administered 
subcutaneously at a dose of 2 mg/day or 10 mg/day in combination with pegylated interferon 
alfa-2a (PEG-IFNα) once weekly relative to 10 mg/day BLV monotherapy in participants with 
chronic hepatitis delta (CHD).
The secondary objective of this study is to assess the safety of BLV.
1.2.
Study Design
This is a randomized, open-label, active controlled, parallel group multicenter Phase 2b study 
investigating the efficacy and safety of BLV given alone or with PEG-IFNα in participants with 
CHD with or without compensated cirrhosis.
A total of 175 participants were randomized, with stratification by presence of liver cirrhosis to 
4 treatment groups in the ratio of 1:2:2:2, of whom 174 participants were treated as follows:
•
Arm A (n=24): PEG-IFNα for 48 weeks with additional 48 weeks follow-up
•
Arm B (n=50): BLV 2 mg/day + PEG-IFNα for 48 weeks followed by BLV 2 mg/day for 
48 weeks with an additional 48 weeks follow-up
•
Arm C (n=50): BLV 10 mg/day + PEG-IFNα for 48 weeks followed by BLV 10 mg/day for 
48 weeks with an additional 48 weeks follow-up
•
Arm D (n=50): BLV 10 mg/day for 96 weeks with an additional 48 weeks follow-up
CCI
I 
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1.3.
Sample Size and Power
The primary efficacy endpoint analysis is the difference in rates of sustained virological response 
at follow-up Week 24 (SVR24) between Arm C and Arm D, where SVR24 is defined as 
undetectable HDV RNA at follow-up Week 24. With 48 participants per treatment group, a two 
sided continuity corrected 95% confidence interval for the difference in the SVR24 rates 
between Arms D and C would extend less than 22.5% from the observed difference. The sample 
size was slightly increased to 50 participants per treatment group to account for a few potential 
early withdrawals. Arm B would be of the same size, and Arm A would include 25 participants; 
hence a total of 175 participants would be randomized.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Week 24 Analysis
The analysis was conducted when all participants completed visit at Week 24 or discontinued the 
study. The details of the analysis methods were specified in the separate SAP.
2.2.
Follow-up Week 24 Analysis (Primary Analysis)
The analysis was conducted when all participants completed visit at follow-up Week 24 or 
discontinued the study. The details of the analysis methods were specified in the separate SAP.
2.3.
Final Analysis
The final analysis will be performed after all participants have completed the study, outstanding 
data queries have been resolved or adjudicated as unresolvable, and the data have been cleaned 
and finalized.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of participants in each category will be presented; for continuous 
variables, the number of participants (n), mean, standard deviation (SD) or standard error (SE), 
median, first quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
All statistical tests will be 2-sided and performed at the 5% significance level unless otherwise 
specified.
By-participant listings will be presented for all participants in the All Randomized Analysis Set 
and sorted by participant identification number, visit date, and time (if applicable). Data 
collected on log forms, such as AEs, will be presented in chronological order for each 
participant. The treatment group to which participants were randomized will be used in the 
listings. Age, sex at birth, and race will be included in the listings, as space permits.
3.1.
Analysis Sets
Analysis sets define the participants to be included in an analysis. Analysis sets and their 
definitions are provided in this section. The analysis set will be identified and included as a 
subtitle for each table, figure, and listing.
For each analysis set, the number and percentage of participants eligible for inclusion will be 
summarized by treatment. In addition, the number and percentage of participants who were 
excluded from the Per-Protocol (PP) Analysis Set and the reasons for their exclusion will be 
presented, and the corresponding listing will be provided.
3.1.1.
All Randomized Analysis Set
All Randomized Analysis Set includes all participants who were enrolled (informed consent 
signed) and randomized in the study. This is the primary analysis set for listings.
3.1.2.
All Enrolled Analysis Set
All Enrolled Analysis Set includes all participants who were screened and enrolled in the study. 
The All Enrolled Analysis Set will be used for listings if it differs from the All Randomized 
Analysis Set.
3.1.3.
Full Analysis Set
The Full Analysis Set (FAS) includes all randomized participants who took at least 1 dose of 
study drug. This is the primary analysis set for efficacy analyses.


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3.1.4.
Per-Protocol Analysis Set
The Per-Protocol (PP) Analysis set includes participants in the FAS for whom no protocol 
deviations are judged to have an impact on the analysis of the primary efficacy endpoint of 
SVR24. The PP Analysis Set is the secondary analysis set for efficacy analyses.
The decision of whether a particular protocol deviation is considered as reason for exclusion 
from the PP Analysis Set should be made at the follow-up Week 24 data review meeting and 
documented in the data review meeting report.
3.1.5.
Safety Analysis Set
The Safety Analysis Set includes all participants who took at least 1 dose of study drug. This is 
the primary analysis set for safety analyses.
3.1.6.
Anti-drug Antibody Analysis Set
The Anti-drug antibody (ADA) Analysis Set includes all participants who took at least 1 dose of 
BLV (alone or with PEG-IFNα) and had at least 1 nonmissing ADA data. This is the primary 
analysis set for the immunogenicity analyses.
3.1.7.
Pharmacokinetic Analysis Set
The Pharmacokinetic (PK) Analysis Set will include all randomized participants who took at 
least 1 dose of BLV (alone or with PEG-IFNα) and had at least 1 nonmissing BLV concentration 
value reported by the PK laboratory. This is the primary analysis set for the PK analyses.
3.2.
Participant Grouping
For analyses based on the FAS, participants will be grouped according to the treatment to which 
they were randomized. For analyses based on the PP Analysis Set, Safety Analysis Set, PK 
Analysis Set and ADA Analysis Set, participants will be grouped according to the actual 
treatment received. The actual treatment received will differ from the randomized treatment only 
when their actual treatment differs from randomized treatment for the entire treatment duration.
3.3.
Strata and Covariates
Participants eligible for the study will be randomly assigned to treatment groups via the 
electronic randomization system in a 1:2:2:2 ratio using a stratified randomization schedule. 
Stratification will be based on the following variable:
•
Cirrhosis status at randomization (presence vs. absence)
For efficacy endpoints, the stratification factor and region (France; Moldova/Romania; Russia) 
will be included as covariates in the efficacy analysis model as specified in Section 6.


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3.4.
Examination of Participant Subgroups
The efficacy endpoints will be examined using the following subgroups. Details will be specified 
in the corresponding sections.
•
Cirrhosis status at randomization (presence vs. absence)
•
Prior PEG-IFNα use (yes vs. no)
•
Concomitant HBV medication (yes vs. no)
The safety endpoints will be examined using the following subgroups. Details will be specified 
in the corresponding sections.
•
ADA incidence at Week 96 (positive vs. negative)
•
ADA incidence at Week 48 (positive vs. negative)
3.5.
Multiple Comparisons
All endpoint tests will be conducted at the significant level of 0.05 with no multiplicity 
adjustment in this Phase 2b study.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified.
The handling of missing or incomplete dates for AE is described in Section 7.1.5.2, and for prior 
and concomitant medications in Section 7.5. Imputation rules adopted in the efficacy analyses 
are specified in Section 6.
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis.
3.7.
Data Handling Conventions and Transformations
In general, age in years at the time when informed consent was signed will be used for analyses 
and presented in listings.
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•
Values below the lower limit of quantification (< LLOQ) with specification of target not 
detected will be imputed as 0.
•
Values < LLOQ without specification of target not detected will be imputed as half of the 
LLOQ value, if LLOQ does not equal the limit of detection (LOD).
•
Values < LLOQ will be imputed as 0, if LLOQ equals LOD (ie, HBV DNA by MLM).
•
Values above the upper limit of quantification (ULOQ) will be imputed as the ULOQ.
•
Non-measurable data will be considered as missing data.
For log10 transformed data, the following rules will be applied:
•
Untransformable value of 0 will be imputed as 0 if LOD > 1.
•
Untransformable value of 0 will be imputed as log10(LOD/2) if LOD < 1.
The LLOQ and LOD for virology parameters are specified in the Table 3-1.
Table 3-1.
Virology LLOQ and LOD
Parameter
Lab Institute
LLOQ
LOD
HDV RNA
Frankfurt (transfered through MLM)
50 IU/mL
6 IU/mL
HBV DNA
Frankfurt (transfered through MLM)
10 IU/mL
10 IU/mL
HBV DNA 
Invitro 
100 IU/mL
20 IU/mL
HBsAg
Frankfurt (transfered through MLM)
not applicable
0.05 IU/mL
Safety laboratory data that are continuous in nature but less than the LLOQ or above the ULOQ 
(reported in the form of “< xx.xx” or “> xx.xx”) will be imputed as one half of LLOQ, or as the 
same as ULOQ to calculate summary statistics.
3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day will be calculated from the first dose date of study drug and derived as follows:
1) For postdose study days: Assessment Date – First Dose Date + 1
2) For days prior to the first dose: Assessment Date – First Dose Date 
Therefore, Study Day 1 is the day of first dose of study drug administration.


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3.8.2.
Analysis Visit Windows
The nominal visit as recorded on the CRF will be used when data are summarized by visit. 
However, when the nominal visit was made outside the analysis visit window (Table 3-2), the 
value will not be used in the analyses.
Table 3-2.
Analysis Visit Windows for by Visit Assessments
Visit Window Study Day
Analysis Visit
Target Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 4
29
2
59
Week X
X×7+1
X×7+1-30
X×7+1+30
Follow-up Week X (Arm A)
(48+X)×7+1
(48+X)×7+1-30
(48+X)×7+1+30
Follow-up Week X (Arm B/C/D)
(96+X)×7+1
(96+X)×7+1-30
(96+X)×7+1+30
The measurement at end of treatment (EOT) are defined as records collected at the visit within 
(last dose date of bulevirtide ± 7 days) for Arms B, C and D, and (last dose of PEG-IFN + 6 days 
± 7 days) for Arm A.
The data collected at unscheduled visits (including early termination [ET] visits) will be used in 
the following ways:
•
An unscheduled visit on or prior to the first dose of study drug may be included in the 
calculation of the baseline value, if applicable.
•
Unscheduled visits after the first dose of study drug will be included in determining the 
maximum postbaseline toxicity grade.
•
Unscheduled visits after the first dose of study drug will be included in determination of the 
value at EOT.
•
Record from unscheduled visit will be assigned to a visit when there is no available data in 
the corresponding analysis visit window. If multiple measurements from unscheduled visits 
exist, the selection rule specified in Section 3.8.3 will be followed.
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window.
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If multiple valid, nonmissing measurements from unscheduled visits exist in an analysis window, 
records will be chosen based on the following rules if a single value is needed:
•
For baseline, the last nonmissing value on or prior to the first dose of study drug will be 
selected, unless specified differently.
•
For postbaseline, record from ET visit will be selected. If there is no available ET record, the 
data from unscheduled visits will be selected as below.
The record closest to the target day for that visit will be selected.
If there are 2 records that are equidistant from the target day, the later record will be 
selected.


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4.
PARTICIPANT DISPOSITION
4.1.
Participant Enrollment and Disposition
A summary of participant enrollment will be provided by treatment group for each region. The 
summary will present the number and percentage of participants enrolled. For each column, the 
denominator for the percentage calculation will be the total number of participants analyzed for 
that column.
A similar enrollment table will be provided by randomization stratum. The denominator for the 
percentage of participants in the stratum will be the total number of enrolled participants.
A summary of participant disposition will be provided by treatment group. This summary will 
present the number of participants screened, the number of participants who met all eligibility 
criteria but were not randomized with reasons participants not randomized, the number of 
participants enrolled, the number of participants randomized, the number of participants 
randomized but not dosed, and the number of participants in each of the categories listed below:
•
Safety Analysis Set
•
Full Analysis Set
•
Per-Protocol Analysis Set
•
Completed Week 48
•
Completed Week 96
•
Completed Follow-up Week 24
•
Completed study (ie, complete follow-up Week 48)
•
Did not complete the study with reasons for premature discontinuation of study
For the status of study completion and reasons for premature discontinuation, the number and 
percentage of participants in each category will be provided. The denominator for the percentage 
calculation will be the total number of participants in the Safety Analysis Set corresponding to 
that column.
The following by-participant listings will be provided by participant identification (ID) number 
in ascending order to support the above summary tables:
•
Reasons for premature study discontinuation
•
Reasons for screen failure (will be provided by screening ID number in ascending order)


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4.2.
Extent of Study Drug Exposure and Compliance
The sponsor will capture, clean, and validate the missing doses that are not documented in the 
participant diary (hereafter referred to as “sponsor-identified missed doses”) in an excel file 
(included in the clean file report as an appendix).
4.2.1.
Study Drug Exposure
The total duration of BLV exposure in weeks will be computed as (last dose date of BLV – first 
dose date of BLV + 1)/7 regardless of any temporary interruptions and will keep 2 decimal 
places (ie, 4.56 weeks). Total duration of PEG-IFNα exposure in weeks will be computed as (last 
dose of PEG-IFNα + 6 – first dose date of PEG-IFNα + 1)/7 regardless of any temporary 
interruptions and will keep 2 decimal places.
The total dose (in mg or μg) administered will be computed as the sum of all doses administered 
(as reported in the participant diary, which takes participant reported missed doses into 
consideration) minus sponsor identified missed doses (the number of days without dosing times 
the planned daily dose for BLV).
The dose intensity (in mg/week or μg/week) will be computed as the total dose administered 
divided by the total duration of exposure.
4.2.2.
Study Drug Compliance
The compliance rate of the full regimen will be computed as the ratio of the total dose 
administered to the expected full regimen dose and expressed as a percentage. The expected full 
regimen dose for BLV is defined as 96 weeks of planned daily dosage (2 mg or 10 mg) for 
participants in Arms B, C and D, and the expected full regimen dose for PEG-IFNα is defined as 
48 weeks of physician-prescribed dosage for participants in Arms A, B, and C.
The total number of missed doses will be computed as the expected total number of doses minus 
the number of doses administered (as reported in the participant diary), plus the number of 
sponsor-identified missed doses. If this results in a negative number, the total number of missed 
doses will be set to the number of sponsor-identified missed doses, or zero if there were no 
sponsor identified missed doses.
The expected total number of BLV doses will be defined as (last on-treatment visit date [or ET 
date, whichever comes first] – first dose date + 1). The expected total number of PEG-IFNα 
doses will be defined as (last on-treatment visit date [or ET date, whichever comes first] – first 
dose date + 1)/7 and rounded to the least integer greater than or equal to the quotient using the 
ceiling function. If this results in expected total number of doses greater than 48 for PEG-IFNα, 
it will be set to 48.
The proportion of missed doses will be computed as the ratio of the total number of missed doses 
to the expected total number of doses and expressed as a percentage.


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4.2.3.
Summaries of Study Drug Exposure and Compliance
Descriptive statistics for following parameters will be presented by treatment group for BLV by 
Weeks 48 and 96, and for PEG-IFNα by Week 48.
•
Total duration of exposure
•
Total dose administered
•
Dose intensity
•
Compliance rate
•
Participants with ≥ 1 missed dose
•
Total number of missed doses
•
Proportion of missed doses
In addition, the by-participant listings of study drug administration and accountability will be 
provided. No formal statistical testing is planned.
4.3.
Protocol Deviations
Participants who did not meet the eligibility criteria for study entry but enrolled in the study, will 
be summarized regardless of whether they were exempted by the sponsor or not. The summary 
will present the number and percentage of participants who did not meet at least 1 eligibility 
criterion and the number of participants who did not meet specific criteria by treatment group 
based on the All Randomized Analysis Set. A by-participant listing will be provided for those 
participants who did not meet at least 1 eligibility (inclusion or exclusion) criterion. The listing 
will present the eligibility criterion (or criteria if more than 1 deviation) that participants did not 
meet and related comments, if collected.
Protocol deviations occurring after participants entered the study are documented during routine 
monitoring. The number and percentage of participants with important protocol deviations by 
deviation reason will be summarized by treatment group for the All Randomized Analysis Set. A 
by-participant listing will be provided for those participants with important protocol deviation.
4.4.
Assessment of COVID-19 Impact
This study was ongoing during the novel coronavirus (COVID-19) pandemic which has an 
impact on the study conduct. This section describes how special situations due to COVID-19 will 
be handled in the analysis.


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4.4.1.
Protocol Deviations Due to COVID-19
A summary of important protocol deviations due to COVID-19 will be provided, similar to the 
summary described in the protocol deviations section (Section 4.3).
The number and percentage of participants with non-important protocol deviations related to 
COVID-19 by deviation reason will be summarized by treatment group.
A by-participant listing will be provided for participants with important protocol deviations 
related to COVID-19 if applicable. A separate listing will be provided for participants with non-
important protocol deviations related to COVID-19 if applicable.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
Participant demographic and baseline characteristics variables will be summarized by treatment 
group and overall using descriptive statistics for continuous variables, and number and 
percentage of participants for categorical variables. The summary of demographic and baseline 
characteristics data will be provided for the FAS and PP Analysis Sets for the following:
•
Age (years)
•
Sex (male, female)
•
Race (Asian, Black or African American, White, other)
•
Height (cm)
•
Body weight (kg)
•
Body mass index (BMI, kg/m2)
•
BMI categories (<30 kg/m², ≥30 kg/m²)
If Safety Analysis Set differs from Full Analysis Set, or there are participants whose actual 
treatment differs from randomized treatment for the whole treatment period, this summary will 
be provided for Safety Analysis Set as well.
A by-participant demographic and baseline characteristics listing, including the informed consent 
date, will be provided. No formal statistical testing is planned.
5.2.
Other Baseline Characteristics
Participant’s other baseline characteristics variables will be summarized by treatment group and 
overall using descriptive statistics for continuous variables, and number and percentage of 
participants for categorical variables. The summary of other baseline characteristics data will be 
provided for the FAS and PP Analysis Sets for the following:
•
Cirrhosis status at randomization (presence, absence)
•
Baseline Child–Pugh score for cirrhotic participants
•
Baseline Child–Pugh class for cirrhotic participants
•
Abdominal ultrasound (abnormal clinically significant [CS], abnormal not clinically 
significant [NCS], normal)


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•
Baseline serum alpha-fetoprotein (AFP; IU/mL)
•
Baseline alanine aminotransferase (ALT; U/L)
•
Baseline ALT (≤ upper limit of normal [ULN], > ULN to ≤ 1.5×ULN, > 1.5×ULN)
•
Baseline creatinine clearance (mL/min)
•
Baseline creatinine clearance (≥ 60 to < 90 mL/min vs. ≥ 90 mL/min)
•
Baseline liver stiffness (kpa)
•
Baseline liver stiffness (< 12 kPa, 12 to 20 kPa, > 20 kPa)
•
Prior PEG-IFNα use (Prior medication preferred name contains the word ‘interferon’) (yes, 
no)
•
HIV antibody (positive, negative, missing)
•
HCV antibody (positive, negative, missing)
•
HDV antibody (positive, negative, missing)
•
HBeAg (positive, negative, missing)
•
HBeAg antibody (positive, negative, missing)
•
Qualitative HBV DNA at screening (positive, negative, missing)
•
HDV genotype
•
HBV genotype
•
Baseline HDV RNA (log10 IU/mL)
•
Baseline HBV DNA (log10 IU/mL)
•
Baseline HBV DNA (< LLOQ target not detected, < LLOQ target detected, ≥ LLOQ )
•
Baseline HBsAg (log10 IU/mL)
•
Baseline aspartate aminotransferase (AST) (U/L)
•
Baseline alkaline phosphatase (ALP) (U/L)
•
Baseline gamma glutamyl transferase (GGT) (U/L)


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•
Baseline platelet count (×10^9/L)
•
Baseline total bilirubin (μmol/L)
•
Baseline total bile salts (μmol/L)
•
Concomitant oral HBV medication (yes, no)
If the Safety Analysis Set differs from the Full Analysis Set, or there are participants whose 
actual treatment differs from randomized treatment for the whole treatment duration, this 
summary will be provided for Safety Analysis Set as well.
A by-participant listing of other baseline characteristics will be provided. No formal statistical 
testing is planned.
5.3.
Substance Use
Participant substance use will be summarized by treatment group and overall using number and 
percentage of participants. The summary will be provided for the FAS and PP Analysis Sets for 
the following:
•
Smoking status (current, former, never)
•
Alcohol consumption status (current, former, never)
•
Alcohol breath test at screening (positive, negative)
•
Alcohol breath test at baseline (positive, negative)
•
Urine drug test at screening (positive, negative)
•
Drug abuse status (current, former, never)
5.4.
Medical History
Medical history collected at screening will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) 26.0.
Medical history will be summarized for Safety Analysis Set by system organ class (SOC), 
preferred term (PT), treatment group, and overall. Participants who report 2 or more medical 
history items that are coded to the same SOC and/or PT will be counted only once by the unique 
coded term in the summary. No formal statistical testing is planned. A by-participant listing of 
medical history will be provided.


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EFFICACY ANALYSES 
6.1. 
General Considerations 
Version 3.0 
The prirmuy analysis set for efficacy analyses will be the FAS, defined in Section 3. 1.3. 
Derivation of Multi-component Endpoints 
For the derivation of multi-component endpoints including combined response, virological 
response, and composite endpoint we will use the following steps unless othe1w ise specified: 
• 
Step 1: assign individual components to analysis visit windows specified in Section 3.8.2 
• 
Step 2: impute missing data for individual components 
• 
Step 3: derive the compound endpoint with the con esponding imputed individual 
components 
Missing Data Imputation 
Below are the descriptions for the imputation methods that will be used in the efficacy analyses: 
• 
Missing Equals Failure (MEF): For bina1y response endpoints, missing value will be imputed 
as nomesponder. For all analyses of the primai end oint usin FAS MEF will be adopted 
when missin was not related to COVID-19. 
• 
Next Observation Can ied Backward (NOCB): Missing value will be imputed using the next 
observation (including observation from unscheduled visit). For all analyses ( except the 
sensitivity analysis) of the primaiy efficacy endpoint using FAS, NOCB will be used when 
missing was related to COVID-19. 
• 
Observed Case (OC): Missing values remain missing. The OC will be used for analyses of 
continuous endpoints, analyses using PP Analysis Set, and analyses for completers. 
6.2. 
Primary Efficacy Endpoint 
The primaiy efficacy endpoint is SVR24 defined as undetectable HDV RNA (HDV RNA value 
< LLOQ with target not detected) at follow-up Week 24. 
6.2.1. 
Primary Analysis of the Primary Efficacy Endpoint 
The prima1y analysis of SVR24 is the estimated rate difference between Alms C and D with 95% 
exact unconditional confidence interval (CI) based on the score statistic. The p-value from 
two-sided Fisher's exact test will also be provided. For each aim the response rate with 
Clopper-Peai·son 95% Cls will be presented. 
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6.2.2.
Sensitivity Analysis of the Primary Efficacy Endpoint
The same analysis as specified in Section 6.2.1 will be repeated using the data for which missing 
values were imputed as failure regardless of whether it was related to COVID-19 (Section 6.1).
6.2.3.
Logistic Regression of the Primary Efficacy Endpoint
To evaluate the impact of covariates on the primary efficacy endpoint, the SVR24 response in 
Arms C and D will be analyzed using the logistic regression of the same data as the primary 
analysis. The covariates to be included are stratification factor and region. The treatment odds 
ratio with 95% CI and p-value will be presented. The p-value for each covariate will also be 
provided.
6.2.4.
Per-protocol Analysis of the Primary Efficacy Endpoint
The same analysis as specified in Section 6.2.1 will be repeated using the PP Analysis Set.
6.2.5.
Subgroup Analysis of the Primary Efficacy Endpoint
Descriptive statistics for SVR24 will be provided by treatment and subgroups for efficacy 
endpoints as defined in Section 3.4 using FAS and PP Analysis Set, respectively. The Clopper-
Pearson 95% CIs of response rate in each arm will also be presented.
6.2.6.
Other Analyses of the Primary Efficacy Endpoint
For SVR24 response in Arms A and B, and remaining pairwise comparisons of SVR24 (Arm B 
vs Arm A; Arm C vs Arm A; Arm D vs Arm A; Arm C vs. Arm B; Arm D vs. Arm B), the same 
analyses as described in Section 6.2.1, 6.2.2, 6.2.3, 6.2.4 and 6.2.5, respectively, will be 
performed. The logistic regression will include data from all arms instead of constructing 
separate models for each pair of arms.
6.3.
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
•
Undetectable HDV RNA at Weeks 48 and 96
•
Combined response at follow-up Week 24 and 48, defined as the fulfilment of both 
conditions below:
Undetectable HDV RNA or HDV RNA decrease ≥ 2 log10 IU/mL from baseline
ALT normalization
•
Sustained virological response 48 (SVR48), defined as undetectable HDV RNA at follow-up 
Week 48
•
Change from baseline in liver stiffness as measured by elastography at Week 48 and 96, and 
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6.3.1.
Analysis of Secondary Efficacy Endpoints
Undetectable HDV RNA at Weeks 48 and 96
Descriptive statistics will be provided by treatment group for undetectable HDV RNA at Week 
48 and 96 using FAS, and the Clopper-Pearson 95% CIs of response rate in each arm will also be 
presented. The same summary will be repeated by subgroups for efficacy endpoints as defined in 
Section 3.4.
Combined Response at Follow-up Week 24 and 48
Descriptive statistics will be provided by treatment group for combined response at follow-up 
Week 24 and 48 using FAS, and the Clopper-Pearson 95% CIs of response rate in each arm will 
also be presented. The estimated rate differences between each pair of arms with 95% exact 
unconditional CI, and the p-value from Fisher’s exact test will also be provided.
Descriptive statistics for combined response at follow-up Week 24 and 48 will be provided by 
treatment and subgroups for efficacy endpoints as defined in Section 3.4 using FAS. The 
Clopper-Pearson 95% CIs of response rate in each arm will also be presented.
Sustained Virological Response 48 (SVR48)
Descriptive statistics will be provided by treatment group for SVR48, and the Clopper-Pearson 
95% CIs of response rate in each arm will also be presented. The estimated rate differences 
between each pair of arms with 95% exact unconditional CI, and the p-value from Fisher’s exact 
test will also be provided.
The same analyses as described above will be repeated for completers (participants with 
observed case).
To evaluate the impact of covariates, SVR48 will be analyzed using the logistic regression. The 
logistic regression will include data from all arms, and the covariates to be included are 
stratification factor and region. The odds ratio of each pair of arms with 95% CI and p-value will 
be presented. The p-value for each covariate will also be provided.
Descriptive statistics for SVR48 will be provided by treatment and subgroups for efficacy 
endpoints as defined in Section 3.4 using FAS and for completers, respectively. The Clopper-
Pearson 95% CIs of response rate in each arm will also be presented.
Change from Baseline in Liver Stiffness at Week 48 and 96, and Follow-up Week 48
The mixed-effects models for repeated measurements (MMRM) model will be used to evaluate 
treatment effect on change from baseline in liver stiffness using FAS with treatment, region, 
presence of cirrhosis, visit and treatment by visit interaction included as fixed effects, and 
baseline value as covariable. An unstructured variance-covariance matrix will be used. The 
Kenward-Roger method will be used to estimate the degrees of freedom. Restricted maximum 
likelihoods (REML) will be used to fit the model. Missing change values will not be otherwise 


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imputed using MMRM. For each treatment group at each postbaseline visit, the least squares 
(LS) mean with 95% CI will be presented. For each pair of anns at each postbaseline visit, the 
difference in LS means with 95% CI and the p-value will be provided. 
Since the study schedule differs between Alm A and Alms B, C, D, 2 different models will be 
fitted: 
• 
The first model will be used for paiiwise comparisons among Anns B, C and D, and data 
from Alms B, C and D will be included. 
• 
The second model will be used for comparisons between Alm A and each of the rest of the 
aims, and data from all aims at the Alm A scheduled visits will be included. 
Descriptive statistics of liver stiffness at each visit as well as the change from baseline will be 
provided by ti·eatment group. The summaiy will be repeated by subgroups for efficacy endpoints 
defined in Section 3 .4 using FAS. The plots of mean ± SD of change from baseline in liver 
stiffness over tiine, as well as by subgroup of ciIThosis status, will be presented. 
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6.5.
Additional Efficacy Endpoint
The composite endpoint is defined as the fulfilment of both conditions below:
•
Undetectable HDV RNA
CCI


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ALT nonnalization 
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The composite endpoint at follow-up Week 24 will be analyzed in the same way as SVR24. The 
composite endpoint at follow-up Week 48 will be analyzed in the same way as SVR48. 
In addition, a by-paiiicipant listing will be provided for SVR24, SVR48, and composite endpoint 
at follow-up Week 24 and 48. This listing will also present HDV RNA (log10 IU/mL) and change 
from baseline, ALT n01malization, ALT and change from baseline, HBV DNA (log10 IU/mL), 
HBsAg (log10 IU/mL) and liver stiffness at all visits. The same listing will be repeated for non-
responders of SVR24, SVR48, or composite endpoint at follow-up Week 24 or 48. 
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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the MedDRA 26.0. System 
organ class (SOC), high-level group term (HLGT), high-level term (HLT), preferred term (PT), 
and lower-level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
The severity of adverse events will be graded as Grade 1, 2, 3, 4, or 5 according to the Common 
Terminology Criteria for Adverse Events (CTCAE, Version 5.0), and the highest observed 
severity grade for each event will be reported. Events for which a CTCAE term cannot be found 
will be assigned a severity grade according to the classification of AEs specified in study 
protocol. The severity grade of events for which the investigator did not record severity will be 
categorized as “missing” for tabular summaries and data listings. The missing category will be 
listed last in summary presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
The related AEs for each study drug are those for which the investigator selected “Reasonable 
possibility” on the AE CRF to the question of causality. Relatedness will always default to the 
investigator’s choice, not that of the medical monitor. Events for which the investigator did not 
record relationship to study drug will be considered related to study drug for summary purposes. 
However, by-participant data listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met the 
definitions of SAEs that were specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with the SAEs captured and stored in the Gilead global safety 
database before data finalization.
For SAEs with multiple reports (initial reports and one or more follow-up reports), only the last 
report will be included in the summary tables and listings.
7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as 1 or both of the following:
•
Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug


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•
Any AEs leading to premature discontinuation of study drug
7.1.5.2.
Incomplete Dates
If the onset or end date of an AE is fully or partially unknown, the incomplete date will be 
imputed before analysis according to the rules in the Table 7-1, Table 7-2, Table 7-3 and 
Table 7-4.
Table 7-1.
Impute Partial AE Dates (year and month available but day missing)
Scenario 
Imputed Onset Date
Imputed End Date
AE year/month same as first dose year/month
First dose date or AE end date 
whichever comes first
Last day of the month
AE year/month before first dose year/month
First day of the month
Last day of the month
AE year/month after first dose year/month
First day of the month
Last day of the month
Table 7-2.
Impute Partial AE Dates (year available but month and day missing)
Scenario
Imputed Onset Date
Imputed End Date
AE year same as first dose year
First dose date or AE end date, 
whichever comes first
31 December
AE year before first dose year
01 January
31 December
AE year after first dose year
01 January
31 December
Table 7-3.
Impute Completely Missing AE Onset Date
Scenario
Imputed Onset Date
Imputed End Date
AE end date before first dose date
AE end date
NA
AE end date after first dose date
First dose date
NA
Table 7-4.
Impute Completely Missing AE End Date
Scenario
Imputed Onset Date
Imputed End Date
All
NA
Last visit date or AE onset date, whichever comes last
7.1.6.
Summaries of Adverse Events and Deaths
Summaries of AEs will be provided for the Safety Analysis Set.


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7.1.6.1.
Summaries of AE incidence
A brief, high-level summary of the number and percentage of participants who experienced at 
least 1 TEAE in the categories described below will be provided by treatment group. All deaths 
observed in the study will also be included in this summary.
For the AE categories described below, summaries will be provided by SOC, PT, and treatment 
group.
•
TEAEs
•
TEAEs with Grade 3 or higher
•
TEAEs with Grade 2 or higher
•
TEAEs related to BLV
•
TEAEs related to PEG-IFNα
•
TEAEs related to BLV with Grade 3 or higher
•
TEAEs related to PEG-IFNα with Grade 3 or higher
•
TEAEs related to BLV with Grade 2 or higher
•
TEAEs related to PEG-IFNα with Grade 2 or higher
•
TE SAEs
•
TE SAEs related to BLV
•
TE SAEs related to PEG-IFNα
•
TEAEs leading to premature discontinuation of BLV
•
TEAEs leading to premature discontinuation of PEG-IFNα
•
TEAEs leading to dose reduction of PEG-IFNα
•
TEAEs leading to death (ie, outcome of death)
Multiple events will be counted only once per participant in each summary. Adverse events will 
be summarized and listed first in alphabetical order of SOC, and then by PT in descending order 
of total frequency within each SOC. For summaries by severity grade, the most severe grade will 
be used for those AEs that occurred more than once in an individual participant during the study.
In addition to the above summary tables, all TEAEs, TEAEs with Grade 3 or higher, TEAEs 
occurred in ≥ 10% participants of any arm, TE SAEs, TEAEs related to BLV, TEAEs related to 
PEG-IFNα, TE SAEs related to BLV, TE SAEs related to PEG-IFNα, TEAEs leading to 
premature discontinuation of BLV, and TEAEs leading to premature discontinuation of PEG-
IFNα will be summarized by PT only, in descending order of total frequency.


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The TEAEs summaries described above will also be provided for period by Week 48. In 
addition, the TEAEs during treatment and AEs in post-treatment period will be summarized by 
PT and treatment group, respectively.
In addition, data listings will be provided for the following:
•
All AEs, indicating whether the event is treatment emergent
•
All SAEs
•
All Deaths
•
All AEs with severity of Grade 3 or higher
•
All AEs with severity of Grade 2 or higher
•
All SAEs related to BLV
•
All SAEs related to PEG-IFNα
•
All AEs leading to premature discontinuation of BLV
•
All AEs leading to premature discontinuation of PEG-IFNα
•
All AEs leading to dose reduction of PEG-IFNα
7.1.7.
Additional Analysis of Adverse Events
7.1.7.1.
Hepatic Adverse Events
The hepatic AEs will be identified using MedDRA search terms. The number and percentage of 
participants who experienced any TE hepatic AE will be summarized by PT and treatment group. 
In addition, the hepatic AEs will be summarized for on-treatment period up to Week 48, on-
treatment period up to Week 96 and follow-up period, respectively. The by-participant listing of 
hepatic AEs will also be provided.
7.1.7.2.
Subgroup Analyses of Adverse Events
The following subgroup analyses will be provided by PT and treatment group:
•
TEAEs by ADA incidence at Week 96
•
TEAEs by Week 48 by ADA incidence at Week 48


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7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. When values are below the LOQ, they will be listed as 
such, and the imputed value will be used for the purpose of calculating summary statistics as 
specified in Section 3.7.
A by-participant listing for laboratory test results will be provided for hematology, coagulogram, 
serum chemistry, total bile salts, and urinalysis separately. Values falling outside of the relevant 
reference range and/or having a severity grade of 1 or higher on the CTCAE severity grade will 
be flagged in the data listings, as appropriate. No formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics of baseline values, values at each postbaseline visit, change and percentage 
change from baseline at each postbaseline visit will be provided by treatment group for the 
following laboratory tests. White blood cell differential results from manual assay will not be 
included as they are not considered valid.
•
Hematology
Haematocrit (%)
Haemoglobin (g/dL)
Platelet Count (×10^9/L)
Reticulocytes (‰)
Red Blood Cells (×10^12/L)
White Blood Cells (×10^9/L)
Absolute Neutrophils (×10^9/L)
Relative Neutrophils (%)
Absolute Eosinophils (×10^9/L)
Relative Eosinophils (%)
Absolute Basophils (×10^9/L)
Relative Basophils (%)
Absolute Monocytes (×10^9/L)


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Relative Monocytes (%)
Absolute Lymphocytes (×10^9/L)
Relative Lymphocytes (%)
•
Total Bile Salts (μmol/L)
•
Coagulogram
Prothrombin Time (%)
Activated Partial Thromboplastin Time (aPTT) (sec)
International Normalized Ratio (INR)
•
Chemistry
Total Protein (g/L)
Albumin (g/L)  
AST (U/L)
GGT (U/L)
Total Amylase (U/L)
Pancreatic Amylase (U/L)
ALP (U/L)
Lipase (U/L)
Total Bilirubin (μmol/L)
Direct Bilirubin (μmol/L)
Total Cholesterol (mmol/L)
Creatinine (μmol/L) 
Urea (mmol/L)
Glucose (mmol/L)


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Potassium (mmol/L)
Sodium (mmol/L)
Chloride (mmol/L)
Phosphorus (mmol/L)
C-Reactive Protein (CRP) (mg/L)
Vitamin D (ng/mL)
Thyroid stimulating hormone (TSH; mU/L)
•
Urinalysis
pH
Specific Gravity (g/L)
The change and percentage change from EOT at each visit will be provided by treatment group 
for AST, total bilirubin and direct bilirubin.
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
first dose of study drug. Change from baseline to a postbaseline visit will be defined as the visit 
value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum values will 
be displayed to the reported number of digits; SD values will be displayed to the reported 
number of digits plus 1.
Median (Q1, Q3) of the observed values for these laboratory tests will be plotted using a line plot 
by treatment group and visit.
7.2.2.
Summaries of Qualitative Laboratory Results
The summary of clinical assessment of laboratory variables (abnormal high CS, abnormal high 
NCS, normal, abnormal low NCS, abnormal low CS) will be presented by visit and treatment 
group for laboratory tests listed in Section 7.2.1 as well as for urinalysis of protein, glucose, 
bilirubin, urobilinogen, ketones, erythrocytes, leukocytes, and nitrites.
7.2.3.
Graded Laboratory Values
The CTCAE Version 5.0 will be used to assign toxicity grades (0 to 4) to laboratory results for 
analysis. Grade 0 includes all values that do not meet the criteria for an abnormality of at least 
Grade 1. For laboratory tests with criteria for both increased and decreased levels, analyses for 
each direction (ie, increased, decreased) will be presented separately.


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7.2.3.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of study drug plus 30 days. If the relevant baseline laboratory value is missing, any 
abnormality of at least Grade 1 observed within the time frame specified above will be 
considered treatment emergent.
7.2.3.2.
Summaries of Laboratory Abnormalities
The following summaries (number and percentage of participants) for treatment-emergent 
laboratory abnormalities will be provided by lab test and treatment group. Participants will be 
categorized according to the most severe postbaseline abnormality grade for a given lab test:
•
Graded laboratory abnormalities
•
Grade 3 or 4 laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of participants 
with nonmissing postbaseline values up to 30 days after last dosing date. The summaries will be 
repeated for period by Week 48.
A by-participant listing of treatment-emergent laboratory abnormalities will be provided. This 
listing will include all test results that were collected throughout the study for the lab test of 
interest, with all applicable severity grades or abnormal flags displayed. In addition, the listing of 
treatment-emergent Grade 3 or 4 laboratory abnormalities will also be provided.
7.2.4.
Liver-related Laboratory Evaluations
7.2.4.1.
Potential Drug Induced Liver Injury (DILI)
The participants with potential drug induced liver injury (DILI) will be summarized for period up 
to Week 48 and Week 96 by treatment, and the corresponding listing will be provided. The 
potential DILI is defined as participants meeting any of the following criteria at on-treatment 
visits:
•
Criteria 1: ALT and/or AST > 3×ULN and Total Bilirubin > 2×ULN
•
Criteria 2: ALT > 5×ULN
•
Criteria 3: Total Bilirubin > 2×ULN
7.2.5.
Shifts Relative to the Baseline Value
Shift tables will be presented by showing changes in results from baseline value (abnormal high 
CS, abnormal high NCS, normal, abnormal low NCS, abnormal low CS) to Week 48 and 96 for 
laboratory tests listed in Section 7.2.1 and 7.2.2. The number and percentage of participants in 
each cross-classification group of the shift table will be presented. Participants with a missing 
value at baseline or postbaseline will not be included in the denominator for percentage 
calculation.


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7.3.
Body Weight and Vital Signs
Descriptive statistics will be provided by treatment group for body weight and vital signs 
(systolic and diastolic blood pressures [mmHg], respiratory rate [breaths/min] and body 
temperature [C]) as follows:
•
Baseline value
•
Values at each postbaseline visit
•
Change from baseline at each postbaseline visit
A baseline value will be defined as the last available value collected on or prior to the first dose 
of study drug. Change from baseline to a postbaseline visit will be defined as the postbaseline 
value minus the baseline value.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No formal statistical testing is planned.
A by-participant listing of vital signs will be provided. Body weight will be included in the vital 
signs listing if space permits. If not, they will be provided separately.
7.4.
Physical Examination
For each type of local reaction at injection site, the number and percentage of participants with at 
least one instance reported will be summarized by severity and treatment, and the maximum 
severity grade of the reaction type will be presented. In addition, a by-participant listing will be 
provided for local reaction at injection site.
7.5.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the World Health 
Organization (WHO) Drug dictionary.
7.5.1.
Prior and Concomitant Medications
Prior medications are defined as medications stopped prior to the first dose date of study drug. 
Concomitant medications are defined as ongoing medications or medications stopped on or after 
the first dose date of study drug, excluding medications started after the last dose date of study 
drug. Post-treatment medications are defined as medications started after the last dose date of 
study drug. If the medication start or stop date is partially unknown, the incomplete date will be 
imputed according to the rules in the Table 7-5. If a medication cannot be classified using the 
reported and/or imputed start and end dates, it will be considered as concomitant medication. The 
original reported dates will be presented in data listings.


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Table 7-5.
Impute Partial Medication Dates
Scenario
Imputed Start Date
Imputed End Date
Unknown year
Missing
Missing
Unknown month
01 January
31 December
Unknown day
First day of month
Last day of month
Prior medications, concomitant medications and post-treatment medications will be summarized 
separately by preferred name and treatment group. A participant reporting the same medication 
more than once will be counted only once when calculating the number and percentage of 
participants who received that medication. The summary will be ordered by preferred term in 
order of descending overall frequency. For drugs with the same frequency, sorting will be done 
alphabetically.
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned. In 
addition, by-participant listings will be provided.
7.5.2.
HBV Medications
HBV medications are defined as oral medications with preferred names containing any of the 
following terms: tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, tenofovir 
disoproxil, entecavir, adefovir, lamivudine, telbivudine, adefovir dipivoxil.
The following HBV medications summaries will be provided by preferred name and treatment 
group, and the corresponding listings as well as the listing of participants with all HBV 
medication started after last dose date of study drug will be generated.
•
Participants with concomitant HBV medications
•
Participants with HBV medications started before baseline and ongoing during treatment: 
participants with any HBV medication started before the first dose date of study drug, and 
any concomitant HBV medication (same as or different from the previous one[s]) ongoing 
on/after the first dose date of study drug
•
Participants with prior HBV medications (stopped before baseline): participants with all 
HBV medications stopped before the first dose date of study drug
•
Participants with HBV medications started on-treatment: participants with all HBV 
medications started on/after the first dose date of study drug and on/before the last dose date 
of study drug
•
Participants with HBV medications started post-treatment: participants with all HBV 
medications started after the last dose date of study drug
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.


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7.6.
Electrocardiogram Results
7.6.1.
Investigator Electrocardiogram Assessment
The investigators’ assessment of electrocardiogram (ECG) results (normal, abnormal NCS, 
abnormal CS, or missing) will be tabulated at each visit by treatment group.  In addition, a shift 
table of the ECG assessment at each visit compared with baseline values will be presented by 
treatment group. The number and percentage of participants in each cross-classification group of 
the shift table will be presented. Participants with a missing value at baseline or postbaseline will 
not be included in the denominator for percentage calculation.
A by-participant listing for ECG assessment results will be provided. No formal statistical testing 
is planned.
7.6.2.
Other Electrocardiogram Assessment
Descriptive statistics will be provided by visit and treatment group for ECG measurements and 
change from baseline including RR interval (msec), PQ interval (msec), QRS interval (msec), 
QT interval (msec), QT interval corrected for heart rate (QTc, Bazett) (msec), and heart 
rate(beats/min).
In addition, the number and percentage of participants with QTc values in each category below 
will be summarized by visit and treatment group:
•
< 451 msec
•
451 to 480 msec
•
481 to 500 msec
•
> 500 msec 
The number and percentage of participants with QTc change from baseline values in each 
category below will be summarized by visit and treatment group:
•
> 30 msec
•
> 60 msec
In addition, a by-participant listing for ECG measurements will be provided. No formal 
statistical testing is planned.
7.7.
Other Safety Measures
A data listing will be provided for participants who become pregnant during the study.


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8.
IMMUNOGENICITY ANALYSES
8.1.
ADA Incidence and Prevalence 
The evaluable population for ADA prevalence is participants with at least one nonmissing ADA 
data at any visit, including the baseline. The evaluable population for ADA incidence is 
participants with at least one nonmissing ADA data at postbaseline visits.
•
ADA prevalence: participants with positive ADA at any visit including the baseline will be 
considered as ADA positive. Otherwise, participants will be considered as ADA negative.
•
ADA incidence is defined in the Table 8-1
Table 8-1.
Definition of ADA Incidence
Baseline ADA
Postbaseline ADA
ADA Incidence
Negative/Missing
Positive (any visit)
Positive
Positive/Negative/Missing 
Negative (all visits)
Negative
Positive
Positive (any visit)
Negative
The number and percentage of ADA prevalence and incidence at Week 48 and Week 96 will be 
summarized by treatment group. The corresponding listing will be provided.


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9.
PHARMACOKINETIC (PK) ANALYSES
9.1.
PK Sample Collection
For participants in Arms B, C and D, blood samples for analysis of BLV concentration will be 
collected at all treatment visits. Sampling will be done 60 ±15 minutes after BLV injection.
9.2.
PK Analyses
Descriptive statistics (including geometric mean, arithmetic coefficients of variation [%CV], and 
geometric %CV) of BLV plasma concentrations will be presented by treatment group and visit. 
In addition, the geometric mean of BLV plasma concentration will be plotted by treatment group 
and visit using a line plot. The by-participant listing of PK sampling details and PK 
concentrations will be provided.


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10.
OTHER EVALUATIONS
The analyses of variables from other evaluation will be conducted using the FAS.
10.1.
HBeAg
HBeAg status and HBeAg antibody status will be summarized by visit and treatment group for 
participants who are positive for HBeAg at screening.
10.2.
Liver Biopsy - Molecular Analysis and Gene Expression
Descriptive statistics will be presented by visit and treatment group on log10 transformed data for 
the following parameters (including the change from baseline). In addition, the by-participant 
listings will be provided.
Molecular analysis:
•
Relative expression level of HDV RNA
•
Relative expression level HBV RNA (S region)
•
Relative expression level of total HBV RNA (X region)
•
Relative expression level of pregenomic HBV RNA
•
HBV DNA (S region; copies/cell)
•
Total HBV DNA (X region; copies/cell)
•
HBsAg
Molecular analysis using immunofluorescence staining:
•
HDAg, % of positive hepatocytes
Gene expression:
•
Relative expression level of NTCP mRNA
•
Relative expression level of CYP7A1 mRNA
•
Relative expression level of CXCL10 mRNA
•
Relative expression level of ISG15 mRNA
•
Relative expression level of MX1 mRNA


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•
Relative expression level of OAS mRNA
•
Relative expression level of HLA-E mRNA
•
Relative expression level of TAP1 mRNA
•
Relative expression level of USP18 mRNA
•
Relative expression level of CXCL11 mRNA
•
Relative expression level of CXCL9 mRNA
•
Relative expression level of CXCR3 mRNA
•
Relative expression level of CCL5 mRNA
•
Relative expression level of CXCL8 mRNA
•
Relative expression level of IL18 mRNA
•
Relative expression level of TGFB1 mRNA
For the following parameters only the by-participant listings will be provided:
•
Molecular analysis: DNA content (ng/μL), RNA content (ng/μL), Beta globin (copies), 
cccDNA (copies/cell).
•
Gene expression: GAPDH CT, RPL30CT, SERPINA1 mRNA CT


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11.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.


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12.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision
13 NOV 2023
Sections 6.4.2 and 10.2
Analysis methods of 
liver biopsy data were 
added in Sections 6.4.2 
and 10.2. 
The liver biopsy data became 
available, so the analysis methods 
were added.
16 NOV 2023
Cover page
Administrative change to 
correct a typo on the 
cover page.
The analysis plan date on the cover 
page should be 13 November 2023 
instead of 13 December 2023.


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13.
APPENDICES
Appendix 1.
Sample SAS Code
The following statement will be used to construct the confidence interval for the binomial 
proportions described in Section 6:
proc freq data=final;
 
table trtp*aval/riskdiff(cl=exact) fisher;
 
exact riskdiff;
where trtp = "Arm X" | trtp = "Arm Y";
run;
proc freq data=final;
by trtp;
 
table aval/bnomial;
 
exact binomial;
run;
The following statement will be used to construct logistic regression described in Section 6:
proc logistic data=final;
class region strata trtp (ref=”Arm X” param=ref);
 
model aval(event=’1’)=trtp region strata; 
run;
The following statement will be used to construct MMRM model described in Section 6:
proc mixed data=final;
class usubjid trtp avisit region strata;
 
model chg=base region strata trtp avisit trtp*avisit/ddfm=kr;
repeated avisit/subject=usubjid type=un;
lsmeans trtp*avisit/diff cl;
run;


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