A Multicenter, Open-label, Randomized Phase 3 Clinical Study to Assess Efficacy and Safety of Bulevirtide in Patients With Chronic Hepatitis Delta
Phase: PHASE3
Conditions: Chronic Hepatitis Delta
Sponsor: Gilead Sciences

CLINICAL STUDY PROTOCOL
Study Title:
A Multicenter, Open-label, Randomized Phase 3 Clinical 
Study to Assess Efficacy and Safety of Bulevirtide in 
Patients With Chronic Hepatitis Delta
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
Protocol Identification:
MYR301
Version Number and 
Date:
EudraCT Number: 
ClinicalTrials.gov
Identifier:
Version 7.0 dated 25 January 2023
2019-001213-17 
NCT03852719
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The information contained in this document, particularly unpublished data, is the property 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........................................................................................................................................4
SIGNATURE PAGE 1 (SPONSOR)..............................................................................................................................5
SIGNATURE PAGE 2 (PRINCIPAL INVESTIGATOR).............................................................................................6
CONTACT INFORMATION.........................................................................................................................................7
LIST OF ABBREVIATIONS.........................................................................................................................................8
SYNOPSIS....................................................................................................................................................................11
1.
INTRODUCTION................................................................................................................................................25
1.1.
Hepatitis Delta.........................................................................................................................................25
1.2.
Treatment Options for Hepatitis Delta ....................................................................................................26
1.3.
Background on Bulevirtide......................................................................................................................27
1.3.1.
Description of the Study Drug...............................................................................................27
1.3.2.
Summary of Clinical Data.....................................................................................................27
1.4.
Study Rationale .......................................................................................................................................36
1.4.1.
Rationale for Patient Population............................................................................................37
1.4.2.
Rationale for Selection of the Dose of the Study Drug.........................................................37
1.5.
Benefit/Risk Assessment.........................................................................................................................38
2.
STUDY OBJECTIVES ........................................................................................................................................39
2.1.
Objectives................................................................................................................................................39
2.2.
Endpoints.................................................................................................................................................39
3.
OVERALL STUDY DESIGN .............................................................................................................................42
3.1.
Randomization.........................................................................................................................................43
3.2.
Blinding ...................................................................................................................................................43
4.
SELECTION OF STUDY POPULATION..........................................................................................................44
4.1.
Inclusion Criteria.....................................................................................................................................44
4.2.
Exclusion Criteria....................................................................................................................................45
4.3.
Withdrawal Criteria.................................................................................................................................47
4.4.
Replacement of Participants....................................................................................................................47
4.5.
Premature Termination of Study .............................................................................................................48
5.
TREATMENTS....................................................................................................................................................49
5.1.
Treatments Administered ........................................................................................................................49
5.1.1.
Bulevirtide .............................................................................................................................49
5.2.
Labelling of Bulevirtide ..........................................................................................................................50
5.3.
Dosing and Administration......................................................................................................................50
5.3.1.
Supplying Patients With Bulevirtide.....................................................................................50
5.3.2.
Administration of Bulevirtide................................................................................................51
5.4.
Dose Adjustments/Modifications/Delays................................................................................................51
5.5.
Accountability Procedures.......................................................................................................................52
5.6.
Treatment Compliance ............................................................................................................................52
5.7.
Concomitant Therapy ..............................................................................................................................52
5.7.1.
Treatment With Nucleoside/Nucleotide Analogues..............................................................53
5.7.2.
Prohibited Treatments ...........................................................................................................53
6.
STUDY PROCEDURES......................................................................................................................................55

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6.1.
Early Discontinuation Visit .....................................................................................................................55
6.2.
Restrictions During the Study .................................................................................................................55
6.3.
Demographic and Other Baseline Characteristics...................................................................................57
6.3.1.
Demographics........................................................................................................................57
6.3.2.
Medical History.....................................................................................................................57
6.3.3.
Prior and Concomitant Therapy ............................................................................................57
6.3.4.
Weight, Height, Body Mass Index ........................................................................................57
6.3.5.
Pregnancy Test ......................................................................................................................58
6.3.6.
Drug Screening......................................................................................................................58
6.3.7.
Breath Alcohol Test...............................................................................................................58
6.3.8.
Abdominal Ultrasound ..........................................................................................................58
6.3.9.
Serum Alpha-fetoprotein.......................................................................................................58
6.3.10.
Serology, HDV RNA, HCV RNA, and HBeAg Test at Screening.......................................58
6.4.
Efficacy Procedures.................................................................................................................................59
6.4.1.
Virology Tests .......................................................................................................................59
6.4.2.
Alanine Aminotransferase.....................................................................................................59
6.4.4.
NTCP Polymorphism and Resistance Tests..........................................................................60
6.4.5.
Serum Alpha-2-Macroglobulin .............................................................................................62
6.4.6.
Liver Biopsy ..........................................................................................................................62
6.4.7.
Transient Elastometry............................................................................................................63
6.5.
Safety Procedures ....................................................................................................................................63
6.5.1.
Physical Examination ............................................................................................................63
6.5.2.
Vital Signs .............................................................................................................................64
6.5.3.
Electrocardiogram .................................................................................................................65
6.5.4.
Hematology, Biochemistry, Coagulogram, Vitamin D.........................................................65
6.5.5.
Total Blood Bile Salts ...........................................................................................................67
6.5.6.
Urinalysis...............................................................................................................................67
6.5.7.
Adverse Events......................................................................................................................68
6.6.
Other Procedures .....................................................................................................................................68
6.6.2.
Pharmacokinetics...................................................................................................................69
6.7.
Patient Diary............................................................................................................................................69
6.9.
Liver-related Clinical Events...................................................................................................................69
7.
ADVERSE EVENTS ...........................................................................................................................................70
7.1.
Definitions ...............................................................................................................................................70
7.1.1.
Adverse Event (AE) ..............................................................................................................70
7.1.2.
Serious Adverse Event ..........................................................................................................70
7.1.3.
Adverse Event of Special Interest (AESI).............................................................................71
7.1.4.
Liver-related Adverse Events................................................................................................73
7.1.5.
Abnormal Laboratory Values................................................................................................73
7.1.6.
Abnormal Vital Sign Values .................................................................................................74
7.1.7.
Adverse Drug Reaction (ADR) .............................................................................................74
7.1.8.
Unexpected Adverse Drug Reaction .....................................................................................74
7.1.9.
Suspected Unexpected Serious Adverse Reaction (SUSAR)................................................74
7.2.
Classification of an Adverse Event .........................................................................................................74
7.2.1.
Severity of Event ...................................................................................................................74
7.2.2.
Relationship to Study Medication .........................................................................................75
7.2.3.
Adverse Event Outcome........................................................................................................76
7.2.4.
Adverse Event Assessment and Follow-up ...........................................................................76
7.3.
Reporting Procedure................................................................................................................................76
7.3.1.
Adverse Event Reporting Period...........................................................................................76
7.3.2.
Adverse Event Reporting ......................................................................................................77
7.3.3.
Serious Adverse Event Reporting .........................................................................................77
CCI
CCI
CCI

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7.4.
Events of Special Interest ........................................................................................................................78
7.5.
Hepatic Safety Adjudication Committee.................................................................................................78
7.6.
Reporting of Pregnancy...........................................................................................................................78
8.
STATISTICAL CONSIDERATIONS.................................................................................................................80
8.1.
Analysis Populations ...............................................................................................................................80
8.2.
Description of Statistical Methods ..........................................................................................................80
8.2.1.
Demographic and Baseline Measurements ...........................................................................80
8.2.2.
Analysis of Efficacy ..............................................................................................................80
8.2.3.
Analysis of Safety..................................................................................................................82
8.2.4.
Determination of Sample Size...............................................................................................83
8.2.5.
Interim and Final Analyses....................................................................................................84
9.
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .............................................85
10.
QUALITY ASSURANCE AND QUALITY CONTROL ...................................................................................86
10.1.
Periodic Monitoring.................................................................................................................................86
10.2.
Audit and Inspection................................................................................................................................86
11.
ETHICS/PROTECTION OF HUMAN SUBJECTS............................................................................................87
11.1.
Ethical Standard.......................................................................................................................................87
11.2.
Independent Ethics Committee and/or Institutional Review Board........................................................87
11.3.
Informed Consent Process.......................................................................................................................87
11.4.
Participant and Data Confidentiality .......................................................................................................88
12.
DATA HANDLING AND RECORD KEEPING................................................................................................89
12.1.
The Entering of Data into the eCRF........................................................................................................89
12.2.
The Query Process...................................................................................................................................89
12.3.
Data Collection and Management Responsibilities.................................................................................89
12.3.1.
User ID ..................................................................................................................................90
12.3.2.
Audit Trail .............................................................................................................................90
12.4.
Study Records Retention .........................................................................................................................90
12.5.
Protocol Deviations .................................................................................................................................90
12.6.
Publication and Data Sharing Policy.......................................................................................................91
13.
FINANCING AND INSURANCE.......................................................................................................................92
13.1.
Financing .................................................................................................................................................92
13.2.
Insurance..................................................................................................................................................92
14.
LITERATURE REFERENCES ...........................................................................................................................93
15.
APPENDICES......................................................................................................................................................96
LIST OF IN-TEXT TABLES
Table 1.
Schedule of Events ..................................................................................................................20
Table 2.
Patients With HDV RNA Response and Combined Response at Week 24 (MYR202 
Study, Modified Intention-to-Treat Population)......................................................................33
Table 3.
Tables for Clinical Abnormalities ...........................................................................................64
LIST OF IN-TEXT FIGURES
Figure 1.
Study Plan................................................................................................................................42

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SIGNATURE PAGE 1 (SPONSOR)
Protocol Title: A Multicenter, Open-label, Randomized Phase 3 Clinical Study to Assess 
Efficacy and Safety of Bulevirtide 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.
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 3 Clinical Study to Assess 
Efficacy and Safety of Bulevirtide 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
ADR
adverse drug reaction
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BMI 
body mass index
CD
cluster determinant
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
CRO
contract research organization
CRP
C-reactive protein
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450 enzyme
DNA
deoxyribonucleic acid
EASL
European Association for the Study of the Liver
EC50
half-maximal effective concentration
ECG
electrocardiogram
eCRF
electronic case report form
ELISA
enzyme-linked immunosorbent assay
EOS
end of study
EOT
end of treatment
EQ-5D
EuroQol (5 dimensions)
EU
European Union 
FAS
Full Analysis Set
FSS
Fatigue Severity Scale
FU
follow up
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HBeAg
hepatitis B e antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HDAg
hepatitis delta antigen

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HDV
hepatitis delta virus
HIV
human immunodeficiency virus
HQLQ™
The Hepatitis Quality of Life Questionnaire™
HSAC
Hepatic Safety Adjudication Committee
ICF
informed consent form
ICH
International Council for Harmonisation (of Technical Requirements for 
Pharmaceuticals for Human Use)
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
LLOQ
lower limit of quantification
LOCF
last observation carried forward
LOD
limit of detection
MAH
marketing authorization holder
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-effects model for repeated measures
NCI
National Cancer Institute
NTCP
sodium-taurocholate cotransporting polypeptide
OATP
organic anion transporting polypeptide 
PCR
polymerase chain reaction
Peg-IFNα
pegylated interferon alpha
PI
principal investigator
PP
per protocol
PR (interval)
electrocardiographic interval occurring between the onset of the P wave and the QRS 
complex representing time for atrial and ventricular depolarization, respectively
PT
preferred term
QRS
electrocardiographic deflection between the beginning of the Q wave and termination of 
the S wave, representing time for ventricular depolarization
QT (interval)
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
RBC
red blood cell
RNA
ribonucleic acid
REML
restricted maximum likelihood 
RR (interval)
electrocardiographic interval representing the time measurement between the R wave of 
one heartbeat and the R wave of the preceding heartbeat
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous(ly)
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction 
SVR
sustained virological response

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TDF
tenofovir disoproxil fumarate
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 3 Clinical Study to 
Assess Efficacy and Safety of Bulevirtide in Patients With Chronic 
Hepatitis Delta
Protocol 
Identification:
MYR301
Study Sites:
Approximately 24 study sites in approximately 6 countries globally 
which may include Germany, Russia, Italy, Georgia, United States 
(US), and Sweden 
Phase of 
Development:
Phase 3
Objectives:
Primary:
The primary objective of this study is to evaluate the efficacy of 
bulevirtide administered subcutaneously (SC) for 48 weeks at a dose 
of 2 mg or 10 mg once daily for treatment of chronic hepatitis delta in 
comparison to delayed treatment.
Secondary:

To evaluate optimal treatment duration

To assess the safety of bulevirtide
Methodology:
This is a randomized, open-label, parallel-group multicenter 
Phase 3 study. Randomization is stratified by the presence of liver 
cirrhosis (no/yes).
Diagnosis and Main 
Criteria for 
Inclusion:
Adult male and female with chronic HDV infection and elevated 
alanine aminotransferase (ALT) at Screening.
CCI

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Treatments:
Arm A 
(comparator):
Observation for 48 weeks followed by bulevirtide 10 mg/day for 
96 weeks and further follow-up period for 96 weeks.
Arm B:
Bulevirtide 2 mg/day for 144 weeks with a further follow-up period 
of 96 weeks
Arm C:
Bulevirtide 10 mg/day for 144 weeks with a further follow-up period 
of 96 weeks
Mode of 
Administration:
The study is open-label.
Bulevirtide 10 mg: two injections of bulevirtide each 5 mg. 
Two injections are performed one after another without time lag 
between injections. These injections are performed daily, every 24 ± 
1 hour.
Bulevirtide 2 mg: one injection of 2 mg bulevirtide. Injection is 
performed daily, every 24 ± 1 hour.
Concomitant 
Medication:
Nucleoside/nucleotide analogue indicated for the treatment of chronic 
HBV infection should be given during screening, treatment, and/or 
follow-up period if required for control of the underlying chronic 
HBV infection, according to the current clinical guidelines (European 
Association for the Study of the Liver [EASL] and American 
Association for the Study of Liver Diseases [AASLD]).
The sponsor will be providing tenofovir (tablets) if the drug cannot be 
made available for patients through routine medical care. In patient in 
whom tenofovir is contraindicated, entecavir (tablets) will be 
provided.
Criteria for 
Evaluation:
Primary Efficacy Endpoint
Combined response at Week 48. Combined response is defined as 
fulfilment of two conditions simultaneously:
Undetectable (< lower limit of quantification [LLOQ], target 
not detected) HDV RNA or decrease by ≥ 2 log10 IU/mL from 
baseline
ALT normalization
Secondary Efficacy Endpoints

Undetectable HDV RNA at Week 48

ALT normalization at Week 48 

Undetectable HDV RNA 24 weeks after scheduled end of 
treatment (sustained virological response [SVR24])

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Statistical Methods:
Sample size
The primary analysis of the study is the separate comparisons of 
bulevirtide 2 mg and bulevirtide 10 mg treatment with delayed 
treatment after a period of 48 weeks. The primary endpoint is defined 
as the response rate at Week 48 measured by undetectable HDV RNA 
or a decrease by ≥ 2 log10 IU/mL from baseline combined with normal 
ALT values within the reference range. The overall significance level 
will be 0.05. An interim analysis will be performed on the response 
rates at Week 24. To account for the repeated analysis of response the 
nominal two-sided significance level will be split among the time 
points with 0.01 for 24 weeks leaving 0.04 for 48 weeks. At each time 
point the bulevirtide doses will be compared with delayed treatment 
in terms of a hierarchical testing procedure starting with the higher 
dose at the respective adjusted two-sided significance levels.
The expected response rates at 48 weeks for the bulevirtide 2 mg and 
10 mg doses are 45% or greater. The conservative expectation for the 
delayed treatment response rates are 8% or less. These assumptions 
are based on results from preceding Phase 2 study (MYR202).
With a sample size of 47 patients per treatment group a Fisher's exact 
test with a 0.04 two-sided significance level will have 97.8% power to 
detect this difference between the bulevirtide 10 mg and the delayed 
treatment proportions and between the bulevirtide 2 mg and the 
delayed treatment proportions. The power to reject both null 
hypotheses simultaneously will be 95.6%.
This sample size will be slightly increased to 50 patients per treatment 
group to account for a few potential early withdrawals before 
exposure.
Hence 150 patients will be randomized.
Analysis populations

All Enrolled Analysis Set: All patients screened and enrolled 
into this study.

All Randomized Analysis Set: All enrolled and randomized 
patients.

Full Analysis Set (FAS): All patients randomized to delayed 
treatment arm or randomized to bulevirtide and received 
bulevirtide at least once after randomization.

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Statistical Methods 
(continued):

Per Protocol (PP) Analysis Set: All patients of the FAS for 
whom no protocol deviations are judged to have an impact on 
the analysis of the primary efficacy endpoint of combined 
response (or on secondary efficacy endpoint of sustained 
virological response [SVR48] at follow-up Week 48 [FU 4], 
ie, study Week 192). Details will be specified in the statistical 
analysis plan (SAP) and final decision on exclusion from PP 
Analysis Set will be made in a data review meeting before 
data base lock.

Safety Population: All patients randomized to delayed 
treatment arm or randomized to bulevirtide and received 
bulevirtide at least once after randomization.
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 patients in the FAS. 
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 time point.
Primary analysis:
The primary endpoint of this study is the response rates at Week 48 
where response is defined as undetectable HDV RNA or decrease by 
≥ 2 log10 IU/mL from baseline combined with ALT level within 
reference range. Two two-sided Fisher tests at an overall significance 
level of 0.05 will be performed to sequentially test the hypotheses 
H01: pO = pM10mg vs. H11: pO ≠ pM10mg 
H02: pO = pM2mg vs. H12: pO ≠ pM2mg 
At each time point where pO, pM2mg, and pM10mg are the expected 
response rate for delayed treatment group, bulevirtide 2 mg and 
bulevirtide 10 mg, respectively. Patients with missing assessment at 
48 weeks in the primary endpoint will be handled as nonresponder 
unless it is related to COVID-19 in which case missing values will be 
imputed using the last observation carried forward (LOCF) approach. 
In terms of a hierarchical testing procedure, the second null 
hypothesis will not be rejected if the first null hypothesis could not be 
rejected. CIs with confidence probability adjusted to the respective 

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Statistical Methods 
(continued):
significance levels using exact unconditional confidence limits based 
on the score statistic will be presented for the rate differences. 
Clopper-Pearson 95%-CIs will be calculated for the single rates. 
An interim analysis will be performed on the response rates at 
Week 24. To account for the repeated analysis of response the 
nominal two-sided significance level will be split among the time 
points with 0.01 for 24 weeks and 0.04 for 48 weeks.
The primary analysis will be based on the FAS. The analysis will be 
repeated for the PP Analysis 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.
Due to the expected low number of responders in delayed treatment 
group the analysis will not be stratified by covariables. The effect of 
region and the presence of liver cirrhosis will be analyzed 
descriptively.
Key secondary analysis
The proportion of patients with undetectable HDV RNA at Week 48 
is the key secondary endpoint and will be used to test differences 
between the bulevirtide doses and hence evaluate the dose response 
relationship. Patients with missing assessment at 48 weeks in 
undetectable HDV RNA will be handled in the same way as the 
primary efficacy endpoint described above.
A two-sided Fisher tests will be performed to test the hypotheses 
H03: rM2mg = rM10mg vs. H13: rM2mg ≠ rM10mg
where rM2mg, rM10mg are the expected rates of patients with 
undetectable HDV RNA for bulevirtide 2 mg and bulevirtide 10 mg, 
respectively.
Continuing the hierarchical testing procedure used for the primary 
endpoint this test will only be performed if both primary null 
hypotheses have been rejected. Otherwise, null hypothesis H03 will 
not be rejected. To maintain control of the family-wise error rate the 
same nominal levels of significance will be employed that was used 
for the primary analyses.
CIs with confidence probability adjusted to the respective significance 
levels using exact unconditional confidence limits based on the score 
statistic will be presented for the rate differences. Clopper-Pearson 
95%-CIs will be calculated for the single rates.
The same methods will be applied at the interim analysis on response 
at Week 24.

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Other secondary analyses
All other efficacy data will be analyzed descriptively.
Rates of patients with ALT normalization at Week 48, undetectable 
HDV RNA at 24 and 48 weeks after scheduled end of treatment 
(sustained virological responseSVR24 and SVR48) will be analyzed 
analogously to the primary endpoint in the framework of explorative 
analysis without adjusting for multiple testing.
Change from baseline in liver stiffness as measured by elastography 
will be analyzed in a mixed-effects model for repeated measures 
(MMRM) with fixed-effect factors treatment, region, presence of 
cirrhosis, visit, and treatment-by-visit interaction and the baseline 
values as covariable. CIs will be based on estimated means (least 
square means) and corresponding t-statistics. Restricted maximum 
likelihood (REML) will be employed to fit the model for primary 
analysis. Within- patient variation will be modeled as random effect 
with unstructured covariance structure. The Kenward-Roger 
approximation will be used to estimate the denominator degrees of 
freedom. If the model still fails to converge, the model will be fit 
using covariance matrices of the following order specified by a 
decreasing number of covariance parameters until convergence is 
met: heterogeneous Toeplitz, heterogeneous autoregressive, Toeplitz, 
and autoregressive.
Analysis of safety
Adverse events
Adverse events will be coded using MedDRA and will be presented 
by primary system organ class (SOC) and preferred term (PT). The 
analysis will focus on the treatment-emergent AEs (TEAE), ie, AEs 
which started or worsened after randomization (delayed treatment 
group) or after start of treatment (bulevirtide groups) and no later than 
30 days after permanent discontinuation of treatment. The frequency 
of TEAEs will be summarized by incidences. In these summaries, 
each patient will be counted only once within each PT.
Frequencies of TEAEs will also be presented by relationship to study 
treatment and by maximum severity. Additional analyses will be 
performed for serious AEs (SAEs), treatment-emergent SAEs, and 
AEs leading to discontinuation.
Vital signs 
Vital signs will be described by summary statistics for measured 
values and changes from baseline by visit.
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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).
Electrocardiogram
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 patients in each treatment group with 
QTc values 451-480 ms, 481-500 ms or > 500 ms and the number and 
percentage of patients in each treatment group who experienced a 
change versus baseline > 30 ms or a change > 60 ms will be presented 
by visit.
Other safety assessments
The number and percentages of patients with normal/abnormal 
findings in physical examinations as well as with production of 
bulevirtide antibodies will be presented by visit.

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Table 1.
Schedule of Events
Screening
144-week Treatment Phase (app. 3 years)*
96-week Follow-up Phase
SCR
V1
V2–V7
V8
V9–V18
V19
FU 1
FU 2-5
FU 6/EOS
Study Phase
V (Visit)/
W (Week)/
D (Day)
Procedures1
D-28 to D-1 
**
W0/D1
± 2 days:
W4, W8, 
W16, W24, 
W32, W40
± 2 days: 
W48
± 2 days: 
W52, W56, W64, 
W72, W80, W88, 
W96, W108, 
W120, W132
± 2 days: 
W144
± 3 days: 
W148 
±7 days:
W156 (FU 2), 
W168 (FU 3), 
W180 (FU 3.1), 
W192 (FU 4), 
W216 (FU 5)
±7 days
W240
CLINICAL AND INSTRUMENTAL EVALUATIONS
Informed consent 2
X
Demographics 3
X
Medical history, prior therapy 4
X
Weight, height, BMI
(height and BMI at SCR only)
X
X
X
X
X
X
X
X
X
Physical examination 5
X
X 6
X
X
X
X
X
X
X
Assessment of local reactions at the 
bulevirtide injection site7
X
X
X
X
X
X
Vital signs 8
X
X
X
X
X
X
X
X
X
12-lead electrocardiogram (ECG)
X
X (W8, 
W24 only)
X
X (W72, W96, 
W120 only)
X
X (W192 only)
X
Abdominal ultrasound
X
Transient elastometry (FibroScan)
X
X
X (W96 only)
X
X (W192 only)
X
Breath alcohol test
X
X
Inclusion/Exclusion criteria
X
X
Adverse events (including liver-
related clinical events starting from 
randomization)
X (SAE 
only)
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
Randomization 9 
X

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Screening
144-week Treatment Phase (app. 3 years)*
96-week Follow-up Phase
SCR
V1
V2–V7
V8
V9–V18
V19
FU 1
FU 2-5
FU 6/EOS
Study Phase
V (Visit)/
W (Week)/
D (Day)
Procedures1
D-28 to D-1 
**
W0/D1
± 2 days:
W4, W8, 
W16, W24, 
W32, W40
± 2 days: 
W48
± 2 days: 
W52, W56, W64, 
W72, W80, W88, 
W96, W108, 
W120, W132
± 2 days: 
W144
± 3 days: 
W148 
±7 days:
W156 (FU 2), 
W168 (FU 3), 
W180 (FU 3.1), 
W192 (FU 4), 
W216 (FU 5)
±7 days
W240
TREATMENT DISPENSING/RETURN
Bulevirtide 10
X 7, 10
X 7, 10
X 10
X 10
X 10
Treatment compliance assessment
X7
X
X
X
Patient Diary 
Dispensing/Review/Collection 
X7
X7
X
X
X
LOCAL LABORATORY/STUDY SITE
Urine pregnancy test 11
X
X
X
X
X
X
X
X
X
Urine drug screening test
X
ANALYSES PERFORMED IN CENTRAL LABORATORY/SAMPLES TO BE SENT TO CENTRAL LABORATORY AT ONCE
Serology (anti-HIV, 
anti-HCV, anti-HDV)
X
HCV RNA (if anti-HCV positive at 
SCR)
X
HBeAg and HBeAg antibodies
X
Urinalysis
X
X 6
X 12
X
X 12
X
X 12
X
Hematology 13
X
X 6
X
X
X
X
X
X
X
Biochemistry (full panel) 14
X
X 6
X (W24 
only)
X
X (W72, W96, 
W120 only)
X
X
Biochemistry (abbreviated panel) 15
X (W4, W8, 
W16, W32, 
W40 only)
X (W52, W56, 
W64, W80, W88, 
W108, W132 
only)
X
X
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Screening
144-week Treatment Phase (app. 3 years)*
96-week Follow-up Phase
SCR
V1
V2–V7
V8
V9–V18
V19
FU 1
FU 2-5
FU 6/EOS
Study Phase
V (Visit)/
W (Week)/
D (Day)
Procedures1
D-28 to D-1 
**
W0/D1
± 2 days:
W4, W8, 
W16, W24, 
W32, W40
± 2 days: 
W48
± 2 days: 
W52, W56, W64, 
W72, W80, W88, 
W96, W108, 
W120, W132
± 2 days: 
W144
± 3 days: 
W148 
±7 days:
W156 (FU 2), 
W168 (FU 3), 
W180 (FU 3.1), 
W192 (FU 4), 
W216 (FU 5)
±7 days
W240
ANALYSIS PERFORMED IN CENTRAL LABORATORY/SAMPLES TO BE STORED AT SITE
NTCP polymorphism20
X
Resistance test 21 (HBV genome 
sequencing, phenotypic assay, and 
HDV genome sequencing)
X
X
X
X
X
X
X
X
Pharmacokinetics 
X 22
X 22
X 22
X 22
X 22
Liver biopsy
X23
X24
X 24, 25 (W192 or 
W216)
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; CRP = C-reactive protein; DNA = deoxyribonucleic acid; EOS = end of study; EQ-
5D = EuroQol (5 dimensions); FSS = Fatigue Severity Scale; FU = follow-up; GGT = gamma-glutamyl transferase; HBeAg = hepatitis B e antigen; HBsAb = hepatitis B surface 
antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HDV = hepatitis delta virus; HIV = human immunodeficiency virus; 
HQLQ = Hepatitis Quality of Life Questionnaire; NTCP = sodium-taurocholate cotransporting polypeptide; RBC = red blood cell; RNA = ribonucleic acid; SCR = screening; 
ULN = upper limit of normal; WBC = white blood cell
*Visits at W0-W8 and W48-W56 are performed every 28 ± 2 days; at W8-W48 and W56-W96: every 56 ± 2 days; at W96-W144: every 84 ± 2 days
**Screening can be shorter than 28 days as soon as eligibility of patient 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 include: 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 patient 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.
Arm A: starting from W48. 
8.
Vital signs include body temperature, heart rate, and blood pressure. Vital signs are measured as indicated in Table 1 and when clinically indicated.
 
 
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1.
INTRODUCTION
1.1.
Hepatitis Delta
Hepatitis delta is liver inflammation caused by infection with hepatitis delta virus (HDV), which 
requires the presence of the hepatitis B surface antigen (HBsAg) for its complete replication and 
transmission. HDV is a hepatotropic virus with a small RNA genome also containing the 
hepatitis delta antigen (HDAg). HDV is necessarily associated with hepatitis B virus (HBV) 
infection, as HDV ribonucleoprotein buds through the HBsAg secretory pathway. The HDV 
genome is a single-stranded RNA of 1,680 bases; it has historical homology with viroids or plant 
virus satellite RNA [1]. The HDAg consists of 2 isoforms, the small 24 kD protein which is 
required for the replication, and the larger 27 kD protein which is needed for virion formation 
[2]. There are 8 genotypes of HDV, while virus of genotype 1 is the most common in the world 
and in Europe [3].
In general, HDV is a highly pathogenic virus causing acute and chronic liver disease. Although 
benign course of the disease has been described [4], patients with chronic hepatitis delta (CHD) 
usually have progressive liver disease leading to compensated or decompensated cirrhosis. 
Evidence was reported in the literature, that unlike HBV, HDV can be associated with direct 
cytotoxicity which may hasten the fibrosis process [5, 6]. However, the immune system plays the 
major role in the clearance of the infected hepatocytes; levels of HDV viremia are not directly 
associated with histological changes [7]. There is no histological feature distinctive of hepatitis 
delta from other types of viral hepatitis. Biopsy specimens of patients with CHD exhibit portal 
and periportal inflammation, fragmentary necrosis, often accompanied by fibrosis and cirrhosis. 
Marked intraglobular infiltration by mononuclear cells and degenerative changes in hepatocytes 
[8] is seen. Clinically, HDV may cause acute or fulminant hepatitis, chronic infection may lead 
to asymptomatic carrier state or evolve to rapidly progressive chronic liver disease.
Chronic hepatitis delta develops in 70-90% of patients with HDV superinfection. The liver 
disease associated with HDV runs a more progressive course than chronic hepatitis B (CHB) and 
may lead to cirrhosis within 2 years in 10-15% of patients [9]. Hepatitis delta is considered the 
most severe form of viral hepatitis in humans [10], and is associated with progression of liver 
disease, development of cirrhosis and decompensation [11, 12].
A study conducted with a patient cohort observed for a long time showed a clear trend towards a 
decreased survivability of hepatitis B e antigen (HBeAg)-negative patients with HDV, compared 
to patients with HBV monoinfection [13]. In endemic populations with HDV infection, liver 
disease is a serious medical problem. In the study performed in Italy in 1987, anti-HDV 
antibodies were detected in 40% of patients with hepatic cirrhosis. Despite the fact that in 
2000 the percent was reduced to 11% [14], HDV infection continues to be a huge burden for 
health care services. A longitudinal study has shown that 20% of CHD patients develop a 
liver-related first-time event during the median follow-up time of 4 years, versus only 8.5% of 
HBV monoinfected patients [15]. At baseline, 19.8% of the patients of this cohort had cirrhosis, 
compared to 7.3% of CHB patients. HDV was a cause of death for 60% of patients in a 28-year 
study from Italy [16]. HDV coinfection is associated with faster progression to fibrosis and 
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Liver cirrhosis and cancer occur 10-15 years earlier in HBV/HDV co-infection and the 5-year 
mortality of co-infected individuals is twice that of HBV monoinfection [20]. Chronic HDV 
infection causes cirrhosis and hepatocellular carcinoma (HCC) with annual rates of 4% and 
2.8%, respectively [16].
On average, 5 to 10% of HBsAg-positive patients admitted to tertiary centers in Europe test 
positive for HDV. The calculation of total number of people affected by CHD in the European 
Union (EU) has yielded the estimate of 145,000 persons. Accounting for EU population of 
505,665,700 (2013), the expected prevalence of HDV among EU citizens, under these 
assumptions, is 2.9 in 10,000, where best- and worst-case assumptions (the limits of the 95 per 
cent credibility interval) are 1.6 and 4.7 in 10,000, respectively. The worst-case scenario is below 
the Orphan Drug designation threshold of 5 in 10,000 people affected by this condition.
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 [21]. 11% of injection drug users were tested positive for HDV in Baltimore; in 
those with chronic HBV infection, 50% were HDV positive [22]. On an average, 5 to 10% of 
HBsAg-positive patients who admit to tertiary centers are tested positive for HDV. The 
calculation of total number of people affected by CHD 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 very limited. Previously, 
according to the European Association for the Study of the Liver (EASL) 2017 Clinical Practice 
Guidelines on the management of HBV infection [23], pegylated interferon alpha (Peg-IFNα) 
was the only available drug that has been proven to have some antiviral efficacy against chronic 
HDV infection [24, 25]. Studies applying Peg-IFNα showed on-treatment virologic response 
rates of about 17-47% [24]. The rate of undetectable HDV RNA 24 weeks after treatment 
cessation was, however, rather low (approximately 25%), and late relapses of HDV replication 
beyond Week 24 after stopping therapy occurred in more than 50% of the responder patients, 
thus challenging the concept of sustained virologic response in HDV-HBV co-infection [26]. 
Hence, long-term follow-up HDV RNA monitoring is recommended for all treated patients as 
long as HBsAg is present in serum. HBsAg loss may develop in the long-term follow-up in 
approximately 10% of Peg-IFNα treated patients and can be taken as a marker of cure for 
HDV infection [26, 27].
Several studies tried to increase efficacy by increasing treatment duration [28, 29]. However, 
clear evidence is lacking to confirm that this approach is beneficial for most chronically 
HDV infected patients. Even after 96 weeks of Peg-IFNα therapy, alone or in combination with 
tenofovir, 24-week posttherapy relapses occurred in 36-39% of the patients with on-treatment 
response [30].
Neither nucleoside/nucleotide analogues nor ribavirin showed significant effects on HDV RNA 
levels in patient with HDV infection [24]. Although HDV is often the predominant virus in this 
co-infection, considerable fluctuating activity of HDV and HBV or both viruses, including 

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alternating predominance can be seen during the natural history of this chronic co-infection [24]. 
Nucleoside/nucleotide analogue treatment is recommended for those patients with HBV DNA 
levels being persistently above 2,000 IU/mL, and might be considered in order to block residual 
HBV replication in those with advanced liver disease. In patients with decompensated liver 
disease, Peg-IFNα should not be used and these patients should be evaluated for liver 
transplantation. Nucleoside/nucleotide analogue should be considered in all patients with 
decompensated disease if HBV DNA is detectable [23].
Thus, there is an urgent unmet medical need for new medications to treat chronic HDV infection 
as the success rate of currently available de-facto treatment is low. Several candidates are being 
evaluated in clinical trial drugs inhibiting the release of HBsAg (nucleic acid polymers), 
inhibitors of the prenylation of the large HDAg and bulevirtide – currently the only 
representative of a novel class of HBV/HDV entry inhibitors [23].
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 (SC) 
injection (SC).
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 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 2 clinical studies are 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]

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
Study MYR201 (Part I): A Phase 1b/2a Randomized, Open-label Clinical Trial of Daily 
Bulevirtide Versus Entecavir in Patients 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 Patients 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 Patients 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 Patients With Chronic Hepatitis B With Delta-agent (Russia) [completed]

Study MYR204: 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 [ongoing]

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 1 single-dose study (MYR101) was conducted in 36 healthy male patients. 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 SC administration was carried out with 800 μg, 5 mg, and 10 mg. 
Each dose was administered to a cohort of 3 consecutive patients. 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 electrocardiograms (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, 9 moderate, and only 2 were 
severe (Grade 3) according to Common Terminology Criteria for Adverse Events (CTCAE) 
Version 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 patients, no serious adverse event (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.

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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 SC administration was 
estimated to be 88%. The release after SC 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 20 hours in a simulated steady-state after SC administration.
MYR102 Study
A Phase 1 drug-interaction study (MYR102) in healthy patients investigated the influence of 
receptor-saturating dose on pharmacokinetics of anti-HBV drug tenofovir disoproxil fumarate 
(TDF). Twelve healthy patients received 245 mg of oral TDF for 5 days alone followed by 
6 days of co-administration of 10 mg SC 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 cytochrome P450 
enzyme (CYP)3A activity.
The combination of bulevirtide and tenofovir was well tolerated. A total of 28 AEs 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 [1], nausea 
[1], injection site hypersensitivity [2], increased alanine aminotransferase (ALT) [5], increased 
amylase [1], increased aspartate aminotransferase (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 AEs were mild. Lipase levels showed marked day to day fluctuations in this 
participant. Two patients 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 plasma pharmacokinetics and renal 
clearance with TDF administration. Bulevirtide pharmacokinetic parameters after first and 
repeated dosing were comparable to those observed in 2 other clinical studies with the substance. 
Therefore, a clinically relevant influence of TDF 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 TDF, and 724.8 mL/min 
(592.5, 886.7; P -value 0.02 vs baseline) under TDF and bulevirtide treatment.
Differences were significant between baseline and co-administration of TDF and bulevirtide, but 
not between TDF 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 TDF or its prodrug might account for the statistically inconclusive results. Co-administration 
of regular TDF doses with bulevirtide was well tolerated and revealed no clinically relevant 

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Group E: bulevirtide 10 mg (10 mg once a day) + pegylated interferon 180 μg
Group F: bulevirtide 10 mg (5 mg twice daily) + TDF
The primary efficacy endpoint was defined as the proportion of participants with a negative 
polymerase chain reaction (PCR) result of HDV RNA (undetectable HDV RNA) 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 twice daily + 
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:

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 (< lower limit of quantification [LLOQ], target not detected) 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:

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
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 bulevirtide treatment groups and the delayed treatment group were as 
follows; the differences were statistically significant for both bulevirtide 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)
Bulevirtide was generally well tolerated by participants with CHD. There were no deaths, SAEs 
related to study drug, SAEs reported for > 1 participant in any of the treatment groups, or AEs 
that led to premature discontinuation of study drug. Common AEs were generally consistent with 
those expected in the participant population and the known safety profile of the study drug. 
Injection site reactions were very commonly observed in participants treated with bulevirtide, 
with incidences of 16.3% and 30.0% observed in the 2 mg and 10 mg treatment groups, 
respectively.
Most hepatic laboratory abnormalities were Grade 1 or 2; there were 2 participants who had 
Grade 3 or 4 hepatic abnormalities. There does not appear to be an association between the 
development of pruritus and elevated bile salt levels with bulevirtide, given that similar changes 
in bile salt levels were seen in those participants with or without these AEs.
MYR204 Study (Ongoing)
MYR204 is an ongoing that is comparing the efficacy and safety of bulevirtide (2 and 
10 mg) + pegylated interferon alpha with bulevirtide monotherapy (10 mg per day) and 
pegylated interferon alpha monotherapy in participants with CHD. Participants were randomized 
in a 1:2:2:2 ratio to 1 of the following 4 treatment groups for the treatment period, which is 
96 weeks:

Group A (n = 25): pegylated interferon alpha 180 μg once weekly SC for 48 weeks, with an 
additional 48 weeks of follow-up

Group B (n = 50): Bulevirtide 2 mg once daily SC in combination with pegylated interferon 
alpha 180 μg once weekly SC for 48 weeks followed by bulevirtide 2 mg once daily SC for 
48 weeks and an additional 48 weeks of follow-up

Group C (n = 50): Bulevirtide 10 mg once daily SC in combination with pegylated interferon 
alpha 180 μg once weekly SC for 48 weeks followed by bulevirtide 10 mg once daily SC for 
48 weeks and an additional 48 weeks of follow-up

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
Group D (n = 50): Bulevirtide 10 mg once daily SC for 96 weeks, with an additional 
48 weeks of follow-up
Randomization was stratified for liver cirrhosis status (no/yes).
The primary efficacy endpoint is the sustained virological response 24 (SVR 24) defined as 
undetectable HDV RNA (HDV RNA < LLOQ, target not detected) at 24 weeks after the 
scheduled end of treatment (study Week 120 for Arm B, Arm C, and Arm D).
The secondary efficacy endpoints are as follows:

Undetectable HDV RNA at Week 48 (all arms) or Week 96 (Arm B, Arm C, and Arm D)

Combined sustained response at Week 24 and Week 48 after the scheduled end of treatment, 
where combined response is defined as fulfilment of 2 conditions simultaneously:
Undetectable HDV RNA or decrease by ≥ 2 log10 IU/mL from baseline
ALT normalization, defined as an ALT value within the normal range, based on the 
central laboratories [Russian sites: ≤ 31 U/L for females and ≤ 41 U/L for males; all other 
sites: ≤ 34 U/L for females and ≤ 49 U/L for males])

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, Week 96, 
and Week 144
Both the primary and secondary efficacy endpoints have not been reached and thus not presented 
herein.
Treatment with bulevirtide monotherapy and in combination with pegylated interferon alpha was 
generally safe and well tolerated. The majority of AEs which occurred in the combination arms, 
where 2 mg or 10 mg of bulevirtide was administered with pegylated interferon alpha, are 
consistent with the known toxicity profile of pegylated interferon alpha, whereas no trends for 
augmentation of pegylated interferon alpha associated toxicities by bulevirtide were evident. 
Refer to the bulevirtide investigator’s brochure for details on nonclinical and clinical studies.
1.4.
Study Rationale
Currently, information about efficacy and safety of bulevirtide in participants with CHD is 
available for 24-week treatment (MYR202 study). This study is designed to assess the long-term 
efficacy and safety of bulevirtide in patients with CHD. Primary efficacy and safety data will be 
assessed at Week 48, when bulevirtide at 2 and 10 mg daily doses will be compared with delayed 
treatment. After Week 48, patients of delayed treatment group in this study will be switched to 
bulevirtide at 10 mg daily dose for additional 96 weeks. The total duration of treatment period in 
this Phase 3 study will be 144 weeks.

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The period of 48 weeks of no treatment in this Phase 3 study is justified by the absence of any 
approved therapy or an effective treatment regime for the respective indication; furthermore, 
patients of the delayed treatment arm shall receive a 96-week treatment of the 10 mg bulevirtide 
after the assessment of the primary endpoint.
After the analysis of the primary endpoint, the treatment will be continued for the period of up to 
3 years to investigate the optimal therapy duration. During the treatment free follow-up period, 
the possibility of the sustained virologic response shall be assessed. Whereas the study is not 
powered to investigate the difference in clinical outcomes such as death, cirrhosis 
decompensation or liver transplantation, those endpoints will be captured, and the information 
will be used in the overall concept of the clinical confirmation.
1.4.1.
Rationale for Patient Population
In patients with HDV infection, therapeutic options are very limited or absent, as no drug is 
approved for treatment of this condition. In previous clinical trial administration of bulevirtide in 
participants with HDV infection resulted in a 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. Patients 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 American Association for the 
Study of Liver Diseases [AASLD]). Inclusion of the described population is considered to be 
ethically appropriate and justified by data obtained in the previous study.
Patients with ALT ≥ 10  ULN, creatinine clearance < 60 mL/min, total bilirubin ≥ 34.2 µmol/L, 
hepatitis C virus (HCV), HCC, 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
Bulevirtide dose of 10 mg/day SC was selected as HDV RNA response and combined HDV 
RNA/ALT response rate at Week 24 in MYR202 Phase 2 study were numerically higher in the 
respective patients compared with patients who received other doses of bulevirtide in MYR202 
study (see Section 1.3.2).
Bulevirtide dose of 2 mg/day SC will be investigated as it was shown to be active and has 
demonstrated excellent safety profile. Compared with the 5 and 10 mg bulevirtide doses, the 
2 mg bulevirtide dose has been shown to be associated with still notable efficacy and to be safe 
and well tolerated. Specifically, the 2 mg dose had a lower virological effect compared with the 
10 mg dose, but the response was still very significant. The effects of both doses on ALT 
normalization were similar, whereas the effect on bile salts increase was less pronounced with 
2 mg dose.

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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.
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 trial 
management may need to be adjusted due to unexpected risks which may increase due to 
external unavoidable circumstances, including COVID-19 pandemic spread in the world, eg, for 
participant 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 CHD, 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 flares. The treatment interruption should be avoided and each case of 
interruption, where it is inevitable, 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 patient and each single procedure with regard to the safety 
of the subject and the integrity of the trial data, with priority given to the safety of the subject. 
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 SC for 
48 weeks at a dose of 2 mg or 10 mg once daily for treatment of CHD in comparison to delayed 
treatment.
Secondary Objectives:

To evaluate optimal treatment duration

To assess the safety of bulevirtide
2.2.
Endpoints
Primary Efficacy Endpoint:
Combined response at Week 48. Combined response is defined as fulfilment of the following 
2 conditions simultaneously:

Undetectable (< LLOQ, target not detected) HDV RNA or decrease by ≥ 2 log10 IU/mL from 
baseline;

ALT normalization.
Secondary Efficacy Endpoints:

Undetectable HDV RNA at Week 48

ALT normalization at Week 48 

Undetectable HDV RNA 24 weeks after scheduled end of treatment (SVR24)

Undetectable HDV RNA 48 weeks after scheduled end of treatment (SVR48)
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3.1.
Randomization
Patients eligible for the study are randomized after completion of all procedures scheduled for 
screening and Day 1 (except study drug administration, Patient Diary dispensing, sample 
collection for pharmacokinetics and assessment of AEs; see Table 1) and confirmation of 
participant’s eligibility (See Section 4).
Patients 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 patients 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 1:1:1 allocation ratio with stratification for the presence 
of liver cirrhosis (no/yes); each patient will be assigned a unique randomization code.
3.2.
Blinding
This is an open-label study. Central laboratories (except the laboratories for pharmacokinetics, 
, NTCP polymorphism, and resistance tests) will be blinded to actual treatment 
allocation.
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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 24 study sites across approximately 6 countries. A total of 150 participants will be 
randomized. Enrolment will stop as soon as the target number of randomized participants is 
reached.
Before randomization of study subject eligibility must be confirmed by the medical monitor. 
Investigator should record all relevant information about the study subject 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 subject’s eligibility.
The laboratory results from Day 1 are not supposed to be used for patient’s eligibility 
assessment.
All inclusion and exclusion criteria should be confirmed according to APPENDIX 1 in 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 (ICF).
2) Male or female, aged 18-65 years (inclusive). 
3) Positive serum anti-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) ALT level > 1  ULN, but less than 10  ULN. 
6) Serum albumin > 28 g/L.
7) Negative urine pregnancy test for females of childbearing potential. 
8) Inclusion criteria for female participants: 
a) Postmenopausal for at least 2 years, or 
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 study, or 

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d) Willingness to use highly effective contraception (double barrier method or barrier 
contraception in combination with hormonal or intrauterine contraceptive) throughout the 
study and for 3 months after the last dose of the study medication for patients 
discontinued during the treatment period. 
9) 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 study and for 3 months after the last 
dose of the study medication for patients discontinued during the treatment period.
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 over 7 points. 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 uncontrolled HIV co-infection. Participants with HCV antibodies can be enrolled, if 
screening HCV RNA test is negative. Participants with HIV infection can be enrolled if 
CD4+ cell counts are > 500/mL and HIV RNA is below limit of detection (LOD) for at least 
12 months.
3) Creatinine clearance < 60 mL/min as estimated using Cockcroft-Gault formula. 
4) Total bilirubin ≥ 34.2 µmol/L. Patients 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 a history of malignancy, or an untreated 
premalignancy disorder 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) New York Heart Association (NYHA) Class III-IV congestive heart failure. 
8) Patients 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 subject’s enrolment into 
the study. 
10)
Patients with mental disorders or social circumstances that preclude them from following 
protocol requirements. 

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11)
Current or previous (within last 2 years) 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 (eg, 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 patients 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 patients). 
14)
Neutrophil count < 1500 cells/mm3 (< 1000 if African patients).
15)
Platelet count < 60,000 cells/mm3. 
16)
Use of prohibited psychotropic agents at Screening. 
17)
Use of interferons within 6 months before Screening. 
18)
History of solid organ transplantation. 
19)
Current alcohol abuse or alcohol abuse within 6 months prior to enrolment in this study; 
past or current drug addict. 
20)
History of disease requiring regular use of systemic glucocorticosteroids (inhalative 
glucocorticosteroids are allowed) or other immunosuppressants.
21)
Pregnant or breast-feeding females. 
22)
Participation in another clinical study with investigational drugs within 30 days prior to 
randomization. 
23)
Receipt of bulevirtide previously, eg, in clinical trial.
24)
Inability to follow protocol requirements and undergo all protocol procedures.
NOTE: Patients with medical contraindication for liver biopsy are allowed to participate in 
this study. Such patients will exempt from liver biopsy requirements in this study.
Patients receiving prohibited treatment at Screening cannot be included into the study 
unless this treatment is withdrawn prior to randomization.

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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 subject’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 subject.
2) Investigator believes that it is not in the subject’s best interests to continue participation in 
the study.
3) Investigator decides to withdraw the study subject 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 subject’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 subject from the study.
8) Pregnancy during the study.
9) Subject is lost to follow-up.
Investigator is responsible for obtaining and documenting the reason(s) for subject’s withdrawal 
from the study after randomization and entering all relevant information into eCRF, including 
detailed information about the reason for the subject’s withdrawal from the study when 
participants agrees to provide such information. If the subject 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.

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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: 2R injection vial, colorless glass, European Pharmacopoeia Hydrolytic class I. 
Closure: Lyophilization rubber stopper for 2R vials, European Pharmacopoeia 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 a dark place with temperature monitoring.
At home, it is allowed for study participants to store the drug at +2 °С to 8 °С (in the 
refrigerator).
Temporary storage of the drug at room temperature up to 25 °C for not more than 3 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.
5.2.
Labelling of Bulevirtide
Labelling of packages of the study product, 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 Patients With Bulevirtide
Investigator or designated person is responsible for supplying patient with the study drug. 
Patients 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
Patients 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 patient to visit the site for drug supplying, upon consent of the 
patients and by the decision of investigator, the drug may be delivered to the patient.

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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. Patients 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 
 and pharmacokinetics of the study drug (ie, sample for 
 assessment is taken before administration of bulevirtide and sample for 
pharmacokinetics is taken 1h ± 15 min after bulevirtide dose).
Study site staff will instruct patients on procedures for storage, preparation, and SC 
administration of bulevirtide. Instructions for patients will be provided within the Patient Diary.
Patients randomized to receive bulevirtide at 2 mg daily dose administer bulevirtide by 1 SC 
injection. Patients randomized to receive bulevirtide at 10 mg daily dose administer bulevirtide 
by 2 SC injections (5 mg of bulevirtide twice). For patients randomized to receive bulevirtide at 
10 mg daily dose 2 injections are performed one after another without time lag between 
injections. Bulevirtide is administered daily.
Patient 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 of ± 1 hour. Deviation 
of ± 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 administered with the supplied 
syringe. Study drug should be reconstituted immediately before injection. Reconstituted solution 
is stable for 2 hours.
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.
5.4.
Dose Adjustments/Modifications/Delays
General Aspects
If investigator believes that the patient 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 patient’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 patient 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 Patient Diary 
and eCRF.
Treatment Adherence
Patient Diary (see Section 6.7) will be in place to monitor dosing and adherence for each 
participant.
5.5.
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 patient, batch, and patient numbers must be kept. 
5.6.
Treatment Compliance
Both patient’s diary information and drug accountability information will be used to estimate 
treatment compliance. Information about each study drug administration (ie, time of 
administration and administered dose) will be captured in patient’s diary by patient. All empty 
vials of the study drug and unused drug are returned by patient to investigator at each visit. 
Patient’s diary information and drug accountability information (ie, number of dispensed vials 
with the study drug and the number of returned empty vials of the study drug) is entered in eCRF 
at each visit of patient to study site.
5.7.
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 nonprescription medications.

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5.7.1.
Treatment With Nucleoside/Nucleotide Analogues
Patients who are receiving the treatment with nucleoside/nucleotide analogue for chronic HBV 
infection will continue their treatment as prescribed at Screening and during the study 
participation.
For patients not receiving the treatment with nucleoside/nucleotide analogue for chronic HBV 
infection it should be initiated at baseline visit or later in the study if indicated in accordance 
with the current EASL/AASLD treatment guidelines [23, 33](current as of November 2018). In 
particular, treatment should be started if one of following conditions is met:

HBV DNA > 2,000 IU/mL, ALT > ULN and/or at least moderate liver necroinflammation or 
fibrosis

Liver cirrhosis with any detectable HBV DNA level

Patients with HBV DNA > 20,000 IU/mL and ALT > 2  ULN should start treatment 
regardless of the degree of fibrosis

Family history of cirrhosis or HCC

Presence of extrahepatic manifestations
The sponsor will be providing tenofovir (tablets) during the course of the study if the drug cannot 
be made available for patients through routine medical care. In patients in whom tenofovir is 
contraindicated, entecavir (tablets) will be provided.
5.7.2.
Prohibited Treatments
Treatment with the following drugs will not be permitted unless discussed with and approved by 
the study medical monitor. 

Systemic glucocorticosteroids (inhalative glucocorticosteroids are allowed)

Immunomodulatory agents (drugs intended for treatment of common cold are allowed)

Antiviral drugs for HBV and/or HDV treatment, apart from allowed nucleoside/nucleotide 
analogues and rescue therapy with BLV for hepatitis exacerbation in the posttreatment period 
as specified in Section 5.7.1 and Section 7.1.3.2.

Hematopoiesis-stimulating agents

Sulfasalazine

Ezetimibe

Cyclosporine

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
Substrates of organic anion transporting polypeptide (OATP)1B1: 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 
patient’s condition,

In case of abnormal laboratory results,

In case of sample sent to central laboratory was considered to be not analyzable,

In case necessity to dispensing of additional study materials and/or study drug.
In case of early discontinuation of the study by study subject 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 patient from the study. Patients prematurely withdrawn during the 
treatment period should complete procedures of Visit 19/Week 144.
Patients prematurely withdrawn during the follow-up period should complete procedures of 
follow-up 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 study and for 3 months after the last dose of the study medication for patients 
discontinued during the treatment period.
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 (ie, bilateral tubal ligation 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 
2 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 patient. 
[Periodic abstinence (eg, 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, eg, 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 2 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 patient 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 study and 
for 3 months after the last dose of the study medication for patients discontinued during the 
treatment period.
The procedures to be followed if a female subject or female partner of a male subject becomes 
pregnant while enrolled in the study are described in Section 7.4.

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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 patients 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 patient 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, benzodiazepines, 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 in 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 HCC. 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 patients 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 patient can be enrolled into the study.
The below listed laboratory test will be done at central virology laboratory at Screening:

HDV RNA

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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 study site for a patient. If agreed with medical 
monitor and project manager, FibroScan procedure can be performed at other institution or any 
other study site.
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, ie, AEs monitoring.
6.5.1.
Physical Examination
A complete physical examination will be 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 eCRF as medical history and 
its importance for including the patient into the study must be considered. Any clinically 
significant worsening of conditions which were present at baseline (last assessment before 
randomization) or clinically significant worsening as a result of study procedure must be 
reported as AE in the eCRF.
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 bulevirtide 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 Volunteers Enrolled in Preventive 
Vaccine Clinical Trials” (Table 3).

In case of clinical significance (abnormality corresponds to any of the below grade), register 
it as an AE 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 
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Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” and the grade 
according to National Cancer Institute (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 Volunteers Enrolled in Preventive Vaccine 
Clinical Trials” or above the photo should be taken by the investigator. The photo should be 
uploaded into eCRF.
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 patient 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 AE or not. See Section 7 for definition and reporting 
requirements for results of vital signs assessment that qualify as AEs.
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 (mm Hg). 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). 

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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.
6.5.3.
Electrocardiogram
A 12-lead 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 AEs.
If, in the case of external unavoidable circumstances, including COVID-19 pandemic spread in 
the world, it is not possible for patient to visit the site, upon consent of the patients and if agreed 
with medical monitor and project manager, ECG can be performed at other institution or any 
other study site.
6.5.4.
Hematology, Biochemistry, Coagulogram, Vitamin D
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 (eg, 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 patients 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 AE or not. See 
Section 7 for definition and reporting requirements for results of laboratory tests that qualify as 
AEs.
Hematology will include:

Hematocrit

Hemoglobin

Platelets

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
Reticulocytes

Red blood cell (RBC) count

WBC count

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

International normalized ratio (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

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
Potassium

Sodium

Chloride

Phosphorus

C-reactive protein (CRP)
Biochemistry (abbreviated panel) will include:

Albumin

ALT

AST

GGT

Total bilirubin

Direct bilirubin

Creatinine

P-amylase

Lipase

CRP
Additionally, level of vitamin D will be 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 performed by central laboratory using standard methods. Schedule of urine 
sampling is given in Table 1.
The following parameters will be measured:

pH

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7.
ADVERSE EVENTS
7.1.
Definitions
7.1.1.
Adverse Event (AE)
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product 
(International Council for Harmonisation [ICH] E2A).
NOTE: Conditions that existed before randomization (eg, ALT elevation before randomization) 
should not be reported as AE unless a notable deterioration has occurred, or SAE has occurred 
after signature of informed consent.
7.1.2.
Serious Adverse Event
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 subject 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 AE or an SAE:

Hospitalization for respite care,

Planned hospitalization required by the protocol (eg, planned hospitalization for 
conducting liver biopsy),

Hospitalization for a preexisting condition, provided that all of the following criteria are 
met:
The hospitalization was planned prior to the study or was scheduled during the study 
when elective surgery became necessary because of the expected normal progression 
of the disease,

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The patient has not experienced an AE,
An event that leads to hospitalization under the following circumstances is not considered to be 
an SAE, but should be reported as an AE instead:
Hospitalization that was necessary because of patient 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 patient 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 adverse event of special interest (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 Bulevirtide Injection Site
Local reactions at the bulevirtide injection site belong to AESI 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.
Management of Posttreatment Exacerbation of Hepatitis
Monitoring for ALT Elevations:
If laboratory results indicate an ALT elevation of > 2 × baseline and > 5 × ULN in the 
posttreatment period, patients should be managed according to the guidance below:
1) Unscheduled visit: Schedule the patient to return to the clinic as soon as possible (ideally no 
later than 3 days after the initial laboratory values are reported to sites). During the visit;
a)  Perform a clinical assessment of the patient.

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b) Collect samples for abbreviated biochemistry panel, coagulogram, HDV RNA, and 
additional reflex testing.
2) Local HDV RNA testing: While the results for HDV RNA from the central laboratory could 
be expedited by sponsor, it is additionally recommended to use local laboratory to test for 
HDV RNA, if available.
Note: For Arm A, the ALT value at Week 48 should be used as baseline ALT value.
Refer to APPENDIX 2 and APPENDIX 3 for additional requirements for the clinical assessment 
and sample collection.
Management of ALT Elevations:
If the ALT elevation is confirmed after the unscheduled visit (ALT > 2 × baseline and 
> 5× ULN), the central laboratory will perform reflex testing from available samples (refer to 
APPENDIX 3 for full list of reflex tests performed at the central laboratory). 
Note: For Arm A, the ALT value at Week 48 should be used as baseline value.
Recommendations for management of ALT elevations:
1) All participants should be managed according to standard of care (including treatment, when 
applicable) and followed closely until laboratory parameters (such as ALT, total bilirubin, 
and INR) return to normal or baseline up to a maximum of 6 months after the onset of the 
event.
2) If a participant is not on therapy with NUCs, and plasma HBV DNA is detectable, the 
investigator should consider immediate initiation of therapy with TDF, tenofovir 
alafenamide, or entecavir (Section 5.7.1). 
3) If HDV flare is associated with risk of liver disease decompensation as assessed by the 
investigator, especially if abnormal laboratory parameters are suggestive of worsening 
hepatic function (eg, total bilirubin > 2 × baseline, INR 0.5 above baseline, provided both are 
> ULN), the investigator should consider immediare rescue therapy with BLV 2 mg upon 
discussion with the medical monitor (Section 5.7.2). 
a) Participants receiving rescue therapy with BLV can remain in the study; therapy should 
be reported per Section 5.7.
b) If a participant receives rescue therapy due to a posttreatment hepatitis flare event, such 
an event should be considered medically important and therefore reported as an SAE. 
Information related to the outcome of these events should be reported.
c) Sponsor will provide BLV 2 mg for up to 12 months of rescue therapy if approved by the 
medical monitor upon the investigator’s request if it is not available through routine 
medical care. 

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7.1.4.
Liver-related Adverse Events
Investigators should closely monitor liver-related clinical events (such as cirrhosis development; 
liver decompensation including development or worsening jaundice, coagulopathy, ascites, 
hepatic encephalopathy; bleeding from varices, and liver failure; HCC development; liver 
transplantation and liver-related death) at all postbaseline assessments. Number of liver-related 
hospitalization and duration of each hospitalization at all postbaseline assessments should also be 
closely monitored. In 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.
7.1.5.
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an AE. A laboratory test result must be reported as 
an AE if it meets any of the following criteria:

Is accompanied by clinical symptoms,

Results in a change in study treatment (eg, treatment interruption, or treatment 
discontinuation),

Results in a medical intervention (eg, 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 
ULN is both asymptomatic and judged by investigator to be clinically insignificant it should 
not be reported as AE.
It is the investigator’s responsibility to review all laboratory findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an AE.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, alkaline 
phosphatase and bilirubin 5  ULN associated with cholestasis), only the diagnosis 
(ie, cholestasis) should be recorded on the AE 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 AE eCRF. If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should be 
recorded as the AE.

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7.1.6.
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an AE. A vital sign result must be reported as an 
AE if it meets any of the following criteria:

Is accompanied by clinical symptoms,

Results in a change in study treatment (eg, treatment interruption, or treatment 
discontinuation),

Results in a medical intervention, change in concomitant therapy or close medical 
monitoring,

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 AE.
7.1.7.
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 
(ADRs). The phrase responses to a medicinal product means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility, ie, the relationship cannot be 
ruled out.
7.1.8.
Unexpected Adverse Drug Reaction
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (eg, investigator’s brochure for an unapproved investigational product or package 
insert/summary of product characteristics for an approved product) (ICH E6).
7.1.9.
Suspected Unexpected Serious Adverse Reaction (SUSAR)
Serious ADR that is classified as unexpected, ie, 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 AE should follow the NCI CTCAE (Version 5.0), and the highest level of 
severity that the AE reached should be entered in the eCRF.

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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 daily activity.
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 patient.
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 patient 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 bulevirtide injections site.
7.2.2.
Relationship to Study Medication
For all collected AEs, the investigator who examines and evaluates the patient 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 (ie, suggestive evidence 
or arguments) that there is a causal relationship irrespective of the dose administered

Between the study drug and the AE, and/or

Between the clinical trial protocol procedure and the AE

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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 patient is stabilized, but with sequelae from this AE.
Recovering/resolving:
The patient is recovering from this AE/this AE is resolving.
Fatal:
The patient 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. 
Gilead may request that certain AEs be followed beyond the protocol -defined follow-up period 
(Section 7.3.1). 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 2 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 AEs at each patient contact. All AEs, whether reported by 
the patient or noted by study personnel, will be recorded in the patient’s medical record and on 
the AE eCRF.
Reporting period for SAEs starts after informed consent has been obtained and ends at the End of 
Study visit (inclusive of participants who remain on study while receiving rescue therapy of 
bulevirtide). These SAEs include events caused by a protocol-mandated intervention (eg, 
invasive procedures such as biopsies, discontinuation of medications). If the SAE is considered 
to be related to the study drug or study procedure, or if the SAE concerns posttreatment 

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exacerbation of hepatitis (Section 7.1.3.2), it must be reported to the sponsor regardless of the 
reporting period. For information on reporting of SAEs to sponsor and following up on ongoing 
SAEs after the End of Study visit see Section 7.3.3. 
Reporting period for nonserious AEs starts with the randomization and ends at the End of Study 
visit. Nonserious AEs at Screening period which are in the investigator’s opinion related to study 
procedures (eg, biopsy) also should be reported.
Investigators should also report any safety events related to rescue therapy of bulevirtide as 
spontaneous reports to the relevant authorities or marketing authorization holders (MAHs) 
locally as required.
7.3.2.
Adverse Event Reporting
A consistent methodology of nondirective questioning should be adopted for eliciting AE 
information. Example of nondirective 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 drugs 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, 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 (eg, laboratory test results) and send it via email or by fax 
within 24 hours of receipt of this relevant information to:

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Contact information for Investigator’s notification in case of SAEs
Gilead Patient Safety
Email: 
or
Fax: 
NOTE: Before sending the SAE report, please inform 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, including those SAEs that were ongoing at the 
End of Study visit. For all additional follow-up evaluations, the paper SAE form must be 
completed and sent via email or by fax to Gilead 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 AE 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 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 (SUSAR). The sponsor will inform all the investigators of the 
occurrence of any SUSAR during the clinical conduct of the study.
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 
SAEs 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.
PPD
PPD

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If a subject becomes pregnant, the investigator must:

Withdraw the subject 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 information to:
Gilead 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 subject receiving/received bulevirtide becomes pregnant, the 
investigator should propose signing of the Information Sheet for pregnant partner and ICF to the 
provision of information about pregnancy and its outcome.
PPD
PPD

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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Populations
All Enrolled Analysis Set: All patients screened and enrolled into this study.
All Randomized Analysis Set: All enrolled and randomized patients.
Full Analysis Set (FAS): All patients randomized to delayed treatment arm or randomized to 
bulevirtide and received bulevirtide at least once after randomization.
Per-Protocol (PP) Analysis Set: All patients of the FAS whom no protocol deviations are judged 
to have an impact on the analysis of the primary efficacy endpoint of combined response (or on 
secondary efficacy endpoint of SVR48 at follow-up Week 48 [FU 4], ie, study Week 192). 
Details will be specified in the statistical analysis plan (SAP) and final decision on exclusion 
from PP Analysis Set will be made in a data review meeting before database lock.
Safety Population: All patients randomized to delayed treatment arm or randomized to 
bulevirtide and received bulevirtide at least once after randomization.
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 patients in the FAS.
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 time point.
Primary Analysis:
The primary endpoint of this study is the response rates at Week 48 where response is defined as 
undetectable HDV RNA or decrease by ≥ 2 log10 IU/mL from baseline combined with ALT level 
within reference range. Two two-sided Fisher tests at an overall significance level of 0.05 will be 
performed to sequentially test the hypotheses 
H01: pO = pM10mg vs H11: pO ≠ pM10mg 
H02: pO = pM2mg vs H12: pO ≠ pM2mg 

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where pO, pM2mg and pM10mg are the expected response rate for delayed treatment arm, bulevirtide 
2 mg and bulevirtide 10 mg, respectively. Patients with missing assessment at 48 weeks in the 
primary endpoint will be handled as nonresponders unless it is related to COVID-19 in which 
case missing values will be imputed using the last observation carried forward (LOCF) approach. 
In terms of a hierarchical testing procedure, the second null hypothesis will not be rejected if the 
first null hypothesis could not be rejected. Confidence intervals (CIs) with confidence probability 
adjusted to the respective significance levels using exact unconditional confidence limits based 
on the score statistic will be presented for the rate differences. Clopper-Pearson 95%-CIs will be 
calculated for the single rates. 
An interim analysis will be performed on the response rates at Week 24. To account for the 
repeated analysis of response the nominal two-sided significance level will be split among the 
time points with 0.01 for 24 weeks and 0.04 for 48 weeks.
The primary analysis will be based on the FAS. The analysis will be repeated for the PP Analysis 
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.
Due to the expected low number of responders under delayed treatment the analysis will not be 
stratified by covariables. The effect of region and the presence of liver cirrhosis will be analyzed 
descriptively.
Key Secondary Analysis
The proportion of patients with undetectable HDV RNA at Week 48 is the key secondary 
endpoint and will be used to test differences between the bulevirtide doses and hence evaluate 
the dose response relationship. Patients with missing assessment at 48 weeks in undetectable 
HDV RNA will be handled in the same way as the primary endpoint described above.
A two-sided Fisher tests will be performed to test the hypotheses 
H03: rM2mg = rM10mg vs H13: rM2mg ≠ rM10mg
where rM2mg, rM10mg are the expected rates of patients with undetectable HDV RNA for 
bulevirtide 2 mg and bulevirtide 10 mg, respectively.
Continuing the hierarchical testing procedure used for the primary endpoint this test will only be 
performed if both primary null hypotheses have been rejected. Otherwise, null hypothesis H03 
will not be rejected. To maintain control of the family-wise error rate the same nominal levels of 
significance will be employed that was used for the primary analyses.
CIs with confidence probability adjusted to the respective significance levels using exact 
unconditional confidence limits based on the score statistic will be presented for the rate 
differences. Clopper-Pearson 95%-CIs will be calculated for the single rates.
The same methods will be applied at the interim analysis on response at Week 24.

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Other Secondary Analyses
All other efficacy data will be analyzed descriptively.
Rates of patients with ALT normalization at Week 48, undetectable HDV RNA 24 and 48 weeks 
after scheduled end of treatment (sustained virological response) will be analyzed analogously to 
the primary endpoint in the framework of explorative analysis without adjusting for multiple 
testing. Patients with missing assessment at 48 weeks in the other secondary endpoints 
 
 will be handled as nonresponder, regardless the reason for the absence.
Change from baseline in liver stiffness as measured by elastography will be analyzed in a 
mixed-effects model for repeated measures (MMRM) with fixed-effect factors treatment, region, 
presence of cirrhosis, visit and treatment-by-visit interaction and the baseline values as 
covariable. CIs will be based on estimated means (least square means) and corresponding 
t-statistics. Restricted maximum likelihood (REML) will be employed to fit the model for 
primary analysis. Within-patient variation will be modeled as random effect with unstructured 
covariance structure. The Kenward-Roger [34] approximation will be used to estimate the 
denominator degrees of freedom. If the model still fails to converge, the model will be fit using 
covariance matrices of the following order specified by a decreasing number of covariance 
parameters until convergence is met: heterogeneous Toeplitz, heterogeneous autoregressive, 
Toeplitz, and autoregressive.
Patients receiving nucleoside/nucleotide analogues will be subject to an additional descriptive 
subgroup analysis.
8.2.3.
Analysis of Safety
Adverse Events
Adverse events will be coded using MedDRA and will be presented by primary SOC and PT. 
The analysis will focus on the treatment-emergent AEs (TEAE), ie, AEs which started or 
worsened after randomization (delayed treatment group) or after start of treatment (bulevirtide 
groups) and no later than 30 days after permanent discontinuation of treatment. The frequency of 
TEAEs will be summarized by incidences. In these summaries, each patient will be counted only 
once within each PT and SOC. 
Frequencies of TEAEs will also be presented by relationship to study treatment and by maximum 
severity. Additional analyses will be performed for SAEs, treatment-emergent SAEs, and AEs 
leading to discontinuation.
CCI
CCI

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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).
Electrocardiogram
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 patients in each treatment group with QTc values 451–480 ms, 
481-500 ms or > 500 ms and the number and percent of patients in each treatment group who 
experienced a change versus baseline > 30 ms or a change > 60 ms will be presented by visit.
Other Safety Assessments
The number and percentages of patients with normal/abnormal findings in physical examinations 
as well as with production of bulevirtide antibodies will be presented by visit.
8.2.4.
Determination of Sample Size
The primary analysis of the study will be the separate comparisons of bulevirtide 2 mg and 
bulevirtide 10 mg with delayed treatment after a period of 48 weeks, respectively. The primary 
endpoint is defined as the response rate at Week 48 measured by undetectable HDV RNA or a 
decrease by ≥ 2 log10 IU/mL from baseline combined with normal ALT values within the 
reference range. The overall significance level will be 0.05. An interim analysis will be 
performed on the response rates at Week 24. To account for the repeated analysis of response the 
nominal two-sided significance level will be split among the time points with 0.01 for 24 weeks 
leaving 0.04 for 48 weeks. At each time point the bulevirtide doses will be compared to delayed 
treatment in terms of a hierarchical testing procedure starting with the higher dose at the 
respective adjusted two-sided significance levels.

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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 
representatives of insurance companies.

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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.
In the case of external unavoidable circumstances, including COVID-19 pandemic spread in the 
world, on-site visit is not possible, remote monitoring will be performed, given that all regulatory 
and essential data protection requirements are met and appropriate arrangements to ensure 
patients’ 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 PI, 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 (Good Clinical Practice [GCP]).
11.2.
Independent Ethics Committee and/or Institutional Review Board 
The protocol, ICF(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 ICF 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 ICF 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.
In the case of external unavoidable circumstances, including COVID-19 pandemic spread in the 
world, it is not possible for patient to visit the site, however, any urgent measures need to be 
implemented in the interest of patient’s safety, informed consent can be received in form of the 
participant’s oral consent by phone supplemented with an email confirmation (if it is possible) 
before the respective action. Updated patient information sheet and ICF should be signed at the 
subsequent visit, where applicable. Any consent obtained this way should be documented 
clearly. 

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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 patients participating in the study. Therefore, the eCRFs should be completed as soon as 
possible during or after the patient’s visit. To avoid interobserver 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
Electronic case report form 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.

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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. 
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 patients 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
1.
Radjef, N., Gordien, E., Ivaniushina, V. et al. Molecular phylogenetic analyses indicate a wide 
and ancient radiation of African hepatitis delta virus, suggesting a Deltavirus genus of at least 
seven major clades. J Virol. 2004; 78(5):2537-44.
2.
Taylor, J. Hepatitis delta virus. Virology. 2006; 344(1):71-6.
3.
Niro, G., Smedile, A. Current concept in the pathophysiology of hepatitis delta infection. Curr 
Infect Dis Rep. 2012; 14(1):9-14.
4.
Niro, G., Gravinese, E., Martini, E. et al. Clearance of hepatitis B surface antigen in chronic 
carriers of hepatitis delta antibodies. Liver. 2001; 21(4):254-9.
5.
Cole, S., Gowans, E., Macnaughton, T. et al. Direct evidence foe cytotoxicity associated with 
expression of hepatitis delta virus antigen. Hepatology. 1991; 13(5):845-51.
6.
Lacombe, K., Boyd, A., Desvarieux, M. et al. Impact of chronic hepatitis C and/or D on liver 
fibrosis severity in patients co-infected with HIV and hepatitis B virus. AIDS. 2007; 
21(18):2546-9.
7.
Zachou, K., Yurdaydin, C., Drebber, U. et al. Quantitative HBsAg and HDV-RNA levels in 
chronic delta hepatitis. Liver Int. 2010; 30(3):430-7.
8.
Verme, G., Amoroso, P., Lettieri, G. et al. A histological study of hepatitis delta virus liver 
disease. Hepatology. 1986; 6(6):1303-7.
9.
Yurdaydın, C., Idilman, R., Bozkaya, H., Bozdayi, A. Natural history and treatment of chronic 
delta hepatitis. J Viral Hepat. 2010; 17(11):749-56.
10. Wedemeyer, H. Re-emerging interest in hepatitis delta: new insights into the dynamic 
interplay between HBV and HDV. J Hepatol. 2010; 52(5):627-9.
11. Rizzetto, M. Hepatitis D: thirty years after. J Hepatol. 2009; 50(5):1043-50.
12. Wedemeyer, H., Manns, M. Epidemiology, pathogenesis and management of hepatitis D: 
update and challenges ahead. Nat Rev Gastroenterol Hepatol. 2010; 7(1):31-40.
13. de Man, R., Sprey, R., Niesters, H. et al. Survival and complications of a cohort of patients 
with anti-Delta positive liver disease presenting in a tertiary referral clinic. J Hepatol. 1995; 
23(6):662-7.
14. Gaeta, G., Stroffolini, T., Chiaramonte, M., et al. Chronic hepatitis D: a vanishing Disease? 
An Italian multicenter study. Hepatology. 2000; 32(4 Pt 1):824-7.
15. Manesis, E., Vourli, G., Dalekos, G. et al. Prevalence and clinical course of hepatitis delta 
infection in Greece: a 13-year prospective study. J Hepatol. 2013; 59(5): 949-56.
16. Romeo, R., Del Ninno, E., Rumi, M.et al. A 28-year study of the course of hepatitis Delta 

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infection: a risk factor for cirrhosis and hepatocellular carcinoma. Gastroenterology. 2009; 
136(5): 1629-38.
17. Buti, M., Homs, M., Rodriguez-Frias, F. Clinical outcome of acute and chronic hepatitis delta 
over time: a long-term follow-up study. J Viral Hepat. 2011; 18(6):432-42.
18. Heidrich, B., Manns, M., Wedemeyer, H. Treatment options for hepatitis delta virus infection. 
Curr Infect Dis Rep. 2013; 15(1):31-8.
19. Niro, G., Smedile, A., Ippolito, A. et al. Outcome of chronic delta hepatitis in Italy: a long-
term cohort study. J Hepatol. 2010; 53(5):834-40.
20. Cornberg, M., Protzer, U., Dollinger, M. et al. Prophylaxis, Diagnosis and Therapy of 
Hepatitis-B-Virus-(HBV-) Infection: upgrade of the guideline, AWMF-Register 021/011. Z 
Gastroenterol. 2007; 45(6):525-74.
21. Gish, R., Yi, D., Kane, S. et al. Coinfection with hepatitis B and D: epidemiology, prevalence 
and disease in patients in Northern California. J Gastroenterol Hepatol. 2013; 28(9):1521-5.
22. Kucirka, L., Farzadegan, H., Feld, J. et al. Prevalence, correlates and viral dynamics of 
hepatitis delta among injection drug users. J Infect Disease. 2010; 202(6):845-52.
23. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on 
the management of hepatitis B virus infection. J Hepatol. 2017; 67(2):370-98.
24. European Association for the Study of the Liver. EASL clinical practice guidelines: 
Management of chronic hepatitis B virus infection. J Hepatol. 2012; 57:167-85.
25. Triantos C., Kalafateli M., Nikolopoulou V., Burroughs A. Meta-analysis: antiviral treatment 
for hepatitis D. Aliment Pharmacol Ther. 2012; 35:663-73.
26. Heidrich, B., Yurdaydın, C., Kabaçam, G. et al. Late RNA HDV relapse after peginterferon 
alfa-based therapy of chronic hepatitis delta. Hepatology. 2014; 60(1):87-97. 
27. Wranke A., Serrano B.C., Heidrich B. et al. Antiviral treatment and liver-related 
complications in hepatitis delta. Hepatology. 2017; 65:414-25.
28. Karaca C., Soyer O.M., Baran B. et al. Efficacy of pegylated interferon-α treatment for 24 
months in chronic delta hepatitis and predictors of response. Antivir Ther. 2013; 18:561-66.
29. Heller T., Rotman Y., Koh C. et al. Long-term therapy of chronic delta hepatitis with 
peginterferon alfa. Aliment Pharmacol Ther. 2014; 40:93-104.
30. Wedemeyer, H., Yurdaydin, C., Ernst, S., et al. HIDIT-2 Study Group. Prolonged therapy of 
hepatitis delta for 96 weeks with pegylated-interferon-α-2a plus tenofovir or placebo does not 
prevent HDV RNA relapse after treatment: the HIDIT-2 study. J Hepatol. 2014; 60(1):S2–S3.
31. Guideline on the clinical evaluation of medicinal products intended for treatment of hepatitis 
B. CHMP/EWP/6172/03, 23 February 2006.

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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. Kenward, M. and Roger, J. (1997). Small Sample Inference for Fixed Effects from Restricted 
Maximum Likelihood. Biometrics 53, 983-997.
35. http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteracti
onslabeling/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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15.
APPENDICES

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APPENDIX 1.
CONFIRMATION OF PATIENTS’ 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 anti-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 aminotransferase level > 1  ULN, but less than 
10  ULN
Central Lab test report
6
Serum albumin > 28 g/L
Central Lab test report
7
Negative urine pregnancy test for females of childbearing 
potential
Urine pregnancy test result at site 
documented in medical records
Female subject: Postmenopausal for at least 2 years
Female subject: Surgically sterile (total hysterectomy or 
bilateral oophorectomy, bilateral tubal ligation, staples, or 
another type of sterilization)
Female subject: Abstinence from heterosexual intercourse 
throughout the study
8
Female subject: Willingness to use highly effective 
contraception (double barrier method or barrier contraception 
in combination with hormonal or intrauterine contraceptive) 
throughout the study and for 3 months after the last dose of the 
study medication for patients discontinued during the treatment 
period
Assessed and documented by 
investigator in medical record
9
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 study and for 3 months after the last dose of the study 
medication for patients discontinued during the treatment 
period
Assessed and documented by 
investigator in medical record 

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Exclusion Criteria
Confirmation
1
Child-Pugh hepatic insufficiency score over 7 points. 
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 uncontrolled HIV coinfection. Participants with HCV 
antibodies can be enrolled, if screening HCV RNA test is 
negative. Participants with HIV infection can be enrolled if 
CD4+ cell counts are > 500/mL and HIV RNA is below limit of 
detection for at least 12 months.
HCV: Central Lab test report
HIV: Copy of lab test report or copy of 
discharge with the results for HIV 
RNA (quantitative) and CD4+ count at 
least 12 months before Screening and 
at least 1 month before Screening.
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. [Patients 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 
premalignancy 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
New York Heart Association (NYHA) Class III-IV congestive 
heart failure
Assessed and documented by 
investigator in medical record.
8
Patients 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 subject’s enrolment into the study.
Assessed and documented by 
investigator in medical record.
10
Patients 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 (within last 2 years) 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 (eg, 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 patients 
Assessed and documented by 
investigator in medical record.

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Exclusion Criteria
Confirmation
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 patients).
Central Lab test report.
14
Neutrophil count < 1500 cells/mm3 (< 1000 if African patients).
Central Lab test report.
15
Platelet count < 60,000 cells/mm3.
Central Lab test report.
16
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.
18
History of solid organ transplantation.
Assessed and documented by 
investigator in medical record.
19
Current alcohol abuse or alcohol abuse within 6 months prior to 
enrolment in this study; past or current drug addict.
Alco-test result at site documented in 
medical record;
Assessed and documented by 
investigator in medical record.
20
History of disease requiring regular use of systemic 
glucocorticosteroids (inhalative glucocorticosteroids are 
allowed) or other immunosuppressants
Assessed and documented by 
investigator in medical record.
21
Pregnant or breast-feeding females.
Pregnancy urine test result at site 
documented in medical record;
Assessed and documented by 
investigator in medical record.
22
Participation in another clinical study with investigational drug 
within 30 days prior to randomization.
Assessed and documented by 
investigator in medical record.
23
Receipt of bulevirtide previously, eg, in clinical trial.
Assessed and documented by 
investigator in medical record.
24
Inability to follow protocol requirements and undergo all 
protocol procedures. NOTE: Patients with medical 
contraindication for liver biopsy are allowed to participate in this 
study. Such patients will exempt from liver biopsy requirements 
in this study.
Patients 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.
CD = cluster determinant; HCV = hepatitis C virus; HDV = hepatitis delta virus; HIV = human immunodeficiency virus; 
PCR = polymerase chain reaction; RNA = ribonucleic acid; ULN = upper limit of normal

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APPENDIX 2.
Monitoring Study Participants for Posttreatment ALT Elevation: 
Flowchart
ALT = alanine aminotransferase; HDV = hepatitis delta virus; RNA = ribonucleic acid; ULN = upper limit of normal
Lab results indicate an ALT elevation of
> 2 × baseline and > 5 × ULN
in the posttreatment period
Unscheduled visit: Schedule the participant to return to the clinic and 
perform a complete clinical assessment (Appendix 3).
Collect samples for abbreviated biochemistry panel, coagulogram, HDV 
RNA, and additional reflex testing (Appendix 3).
Local HDV RNA testing: while the results for HDV RNA from the central 
laboratory will be expedited, it is recommended to use local laboratory to 
test for HDV RNA, if available.
Did lab results confirm an ALT elevation of
> 2 x baseline and > 5 x ULN?

The central laboratory will 
perform reflex testing from 
available samples (investigators 
will be notified by central 
laboratory).

Investigators to follow 
recommended procedures for 
management of ALT elevations 
(Section 7).
Follow protocol schedule for 
routine procedures
Yes
No
 
 
 

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APPENDIX 3.
Unscheduled Visit for Management of Posttreatment ALT Elevations 
96-week Follow-up Phase
Study Phase 
V (Visit)
UNSCHEDULED 
CLINICAL AND INSTRUMENTAL EVALUATIONS
Physical examination
X
Vital signs 1 
X
Adverse events 
X
ANALYSES PERFORMED IN CENTRAL LABORATORY 2 
Biochemistry (abbreviated panel) 3
X
Coagulogram 4
X
HDV RNA 
X
Additional samples for reflex testing 5
X
RECOMMENDED ANALYSES PERFORMED AT THE LOCAL LAB
HDV RNA (if available)
X
REFLEX TESTS PERFORMED IN CENTRAL LABORATORY(if ALT elevation criteria are met)
Plasma HBV DNA
X
Serology for HBV (HBsAg and HBsAb)
X
HAV Immunoglobulin M (IgM)
X
HCV Ab (with reflex to HCV RNA)
X
Hepatitis E virus IgM
X
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CRP = C-reactive protein; DNA = deoxyribonucleic acid; 
GGT = gamma-glutamyl transferase; HAV = hepatitis A virus; HBV = hepatitis B virus; HCV = hepatitis C virus; 
HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HDV = hepatitis delta virus; RNA = ribonucleic 
acid; ULN = upper limit of normal
1.
Vital signs include body temperature, heart rate, and blood pressure
2.
Samples to be sent to central laboratories at once
3.
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. Abbreviated biochemistry includes: albumin, ALT, AST, GGT, total bilirubin, 
direct bilirubin, creatinine, lipase, P-amylase, CRP. 
4.
Coagulogram includes prothrombin time, international normalized ratio, and activated partial thromboplastin time.
5.
Reflex testing is done on available samples by central lab if ALT elevation criteria is met
 
 
 
 
 
 
 
 

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APPENDIX 4.
COUNTRY-SPECIFIC REQUIREMENTS
Not applicable.
Per Russia Ministry of Health guidance, a standalone country-specific amendment (Version 7.1) 
has been developed to reflect the changes in this global amendment.

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APPENDIX 5.
AMENDMENT HISTORY
A high-level summary of the history of this study’s amendments is provided in tabular form in 
the subsections below (from most recent amendment to oldest), with changes listed in each table 
in order of importance. Minor changes such as the correction of typographic errors, grammar, or 
formatting are not detailed.
Earlier separate summaries of changes are available upon request.
A separate tracked change (red-lined) document comparing Version 6.0 (or Amendment 5) to 
this amendment will be made available upon the publication of this protocol.
Version 7.0 (25 January 2023)
Rationale for Key Changes Included in Version 7
Affected Sections
A Week 180 visit was added with additional assessments to allow a more 
standardized approach for study investigators to monitor and manage 
posttreatment hepatitis exacerbation. 
Table 1
Updated the definition of hepatitis delta virus (HDV) ribonucleic acid (RNA) 
“undetectable” to “< lower limit of quantification (LLOQ), target not detected.”
Throughout, as needed
To identify and monitor participants at risk of developing a hepatitis flare, specific 
procedures were added for the management of posttreatment exacerbation of 
hepatitis, ie, if laboratory results indicated alanine aminotransferase (ALT) 
elevations.
Section 7.1.3.2
An optional third liver biopsy was added to the list of assessments.
Table 1 and Section 6.4.6
The timing of an exploratory analysis was changed from Week 168 to Week 192.
Section 8.2.5
Clarified details of adverse event (AE)/serious AE reporting procedures period 
and liver-related clinical events.
Sections 2.2, 6.9, 7.1.3.2 
and 7.2.1.4, 7.3.1, and 7.3.3
Addition of Appendix 2 (Monitoring Study Participants for Posttreatment ALT 
Elevation: Flowchart) and Appendix 3 (Unscheduled Visit for Management of 
Posttreatment ALT Elevations).
Section 15 
Definition of Per Protocol Analysis Set was updated
Section 8.1
Updated the word ‘Subject’ to ‘Participants’ and other style-related changes 
included where possible.
Throughout, as needed

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