Clinical trial NCT03852719
Conditions: Chronic Hepatitis Delta
Sponsor: Gilead Sciences
Start date: 2019-04-17; Completion date: 2024-08-08
Enrollment: 150 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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 (CHD) in comparison to delayed treatment.

The main goal of this study is to determine the effectiveness of bulevirtide in participants randomized to bulevirtide 2 mg or 10 mg once daily SC as compared to participants randomized to delayed treatment for 48 weeks. Treatment will continue through Week 144 (participants randomized to delayed treatment will change to bulevirtide 10 mg once daily SC after Week 48 through Week 144). All participants will be followed off-treatment for an additional 96 weeks.

Detailed description:

Arms: arm 1: After an observational period of 48 weeks, participants will receive treatment with bulevirtide 10 mg/day subcutaneously (SC) for 96 weeks and will be followed for up to 96 weeks (Up to Week 240). arm 2: Participants will receive bulevirtide 2 mg/day SC for 144 weeks and will be followed for up to 96 weeks (Up to Week 240). arm 3: Participants will receive bulevirtide 10 mg/day SC for 144 weeks and will be followed for up to 96 weeks (Up to Week 240).
Interventions: intervention 1: Bulevirtide
Intervention descriptions: intervention 1: Administered via SC injections

Protocol documents:
SAP_004.pdf: 
Bulevirtide (BLV)
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Statistical Analysis Plan – Week 144 
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STATISTICAL ANALYSIS PLAN
Study Title:
A Multicenter, Open-label, Randomized Phase 3 Clinical 
Study to Assess Efficacy and Safety of Bulevirtide in 
Participants with Chronic Hepatitis Delta
Name of Test Drug:
Bulevirtide 
Study Number:
MYR301
Protocol Version (Date):
Version 7.0 dated 25 January 2023
Analysis Type:
Week 144
Analysis Plan Version:
Final 2.0
Analysis Plan Date:
26 June 2023
Analysis Plan Author(s):
Qi An, PhD
CONFIDENTIAL AND PROPRIETARY INFORMATION


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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................2
LIST OF ABBREVIATIONS.........................................................................................................................................5
1.
INTRODUCTION..................................................................................................................................................7
1.1.
Study Objectives........................................................................................................................................7
1.2.
Study Design .............................................................................................................................................7
1.3.
Sample Size and Power .............................................................................................................................8
2.
TYPE OF PLANNED ANALYSIS........................................................................................................................9
2.1.
Week 24 Analysis......................................................................................................................................9
2.2.
Week 48 Analysis (Primary Analysis) ......................................................................................................9
2.3.
Week 96 Analysis......................................................................................................................................9
2.4.
Week 144 Analysis (End of Treatment)....................................................................................................9
2.5.
Week 192 Analysis....................................................................................................................................9
2.6.
Final Analysis (Week 240)........................................................................................................................9
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.............................................................................10
3.1.
Analysis Sets ...........................................................................................................................................10
3.1.1.
All Randomized Analysis Set................................................................................................10
3.1.2.
All Enrolled Analysis Set ......................................................................................................10
3.1.3.
Full Analysis Set....................................................................................................................10
3.1.4.
Per-Protocol Analysis Set......................................................................................................11
3.1.5.
Safety Analysis Set................................................................................................................11
The Safety Analysis Set includes all participants who were randomized to the study 
and took at least 1 dose of BLV, or who were randomized to delayed 
treatment group. This is the primary analysis set for safety analyses. ..................................11
3.1.6.
Anti-drug Antibody Analysis Set ..........................................................................................11
3.1.7.
Pharmacokinetic Analysis Set ...............................................................................................11
3.2.
Participant Grouping ...............................................................................................................................12
3.3.
Strata and Covariates...............................................................................................................................13
3.4.
Examination of Participant Subgroups....................................................................................................13
3.5.
Multiple Comparisons .............................................................................................................................13
3.6.
Missing Data and Outliers.......................................................................................................................14
3.6.1.
Missing Data..........................................................................................................................14
3.6.2.
Outliers ..................................................................................................................................14
3.7.
Data Handling Conventions and Transformations ..................................................................................14
3.8.
Analysis Visit Windows..........................................................................................................................15
3.8.1.
Definition of Study Day ........................................................................................................15
3.8.2.
Analysis Visit Windows........................................................................................................15
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window .................................................................................................................................17
4.
PARTICIPANT DISPOSITION ..........................................................................................................................18
4.1.
Participant Enrollment and Disposition...................................................................................................18
4.2.
Extent of Study Drug Exposure and Compliance....................................................................................19
4.2.1.
Study Drug Exposure ............................................................................................................19
4.2.2.
Study Drug Compliance ........................................................................................................19
4.2.3.
Summaries of Study Drug Exposure and Compliance..........................................................20
4.3.
Protocol Deviations .................................................................................................................................20
4.4.
Assessment of COVID-19 Impact...........................................................................................................20
4.4.1.
Protocol Deviations Due to COVID-19 ................................................................................21


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5.
BASELINE CHARACTERISTICS .....................................................................................................................22
5.1.
Demographics and Baseline Characteristics ...........................................................................................22
5.2.
Other Baseline Characteristics ................................................................................................................22
5.3.
Substance Use..........................................................................................................................................25
5.4.
Medical History.......................................................................................................................................25
6.
EFFICACY ANALYSES.....................................................................................................................................26
6.1.
General Considerations ...........................................................................................................................26
6.2.
Primary Efficacy Endpoints ....................................................................................................................26
6.2.1.
Primary Analysis of the Primary Efficacy Endpoint.............................................................27
6.2.2.
Sensitivity Analysis of the Primary Efficacy Endpoint.........................................................27
6.2.3.
Per-protocol Analysis of the Primary Efficacy Endpoint......................................................27
6.2.4.
Subgroup Analysis of the Primary Efficacy Endpoint ..........................................................28
6.3.
Secondary Efficacy Endpoints ................................................................................................................28
6.3.1.
Analysis of Secondary Efficacy Endpoints ...........................................................................28
6.4.
Exploratory Efficacy Endpoints ..............................................................................................................29
6.4.1.
Definition of Exploratory Efficacy Endpoints ......................................................................31
6.4.1.1.
Necroinflammation and Fibrosis Assessed at Liver Biopsy............................31
6.4.1.2.
HBsAg Loss with/without Seroconversion .....................................................31
6.4.1.3.
Liver Related Clinical Events..........................................................................31
6.4.1.4.
EuroQol 5-Dimentions 3-Levels (EQ-5D-3L).................................................32
6.4.1.5.
Fatigue Severity Scale (FSS)...........................................................................33
6.4.1.6.
Hepatitis Quality of Life Questionnaire™ (HQLQ™)....................................33
6.4.2.
Analysis of Exploratory Efficacy Endpoints.........................................................................33
7.
SAFETY ANALYSES.........................................................................................................................................35
7.1.
Adverse Events and Deaths.....................................................................................................................35
7.1.1.
Adverse Event Severity .........................................................................................................35
7.1.2.
Relationship of Adverse Events to Study Drug.....................................................................35
7.1.3.
Serious Adverse Events.........................................................................................................35
7.1.4.
Treatment-Emergent Adverse Events....................................................................................35
7.1.4.1.
Definition of Treatment-Emergent Adverse Events........................................35
7.1.4.2.
Incomplete Dates .............................................................................................36
7.1.5.
Summaries of Adverse Events and Deaths............................................................................36
7.1.5.1.
Summaries of AE incidence in Combined Severity Grade 
Subsets .............................................................................................................36
7.1.6.
Additional Analysis of Adverse Events ................................................................................38
7.1.6.1.
Hepatic Adverse Events...................................................................................38
7.1.6.2.
Subgroup Analyses of Adverse Events............................................................38
7.2.
Laboratory Evaluations ...........................................................................................................................38
7.2.1.
Summaries of Numeric Laboratory Results ..........................................................................39
7.2.2.
Summaries of Qualitative Laboratory Results ......................................................................41
7.2.3.
Graded Laboratory Values ....................................................................................................41
7.2.3.1.
Treatment-Emergent Laboratory Abnormalities .............................................41
7.2.3.2.
Summaries of Laboratory Abnormalities ........................................................41
7.2.3.3.
Potential Drug Induced Liver Injury (DILI)....................................................42
7.2.4.
Shifts Relative to the Baseline Value ....................................................................................42
7.3.
Body Weight and Vital Signs..................................................................................................................42
7.4.
Physical Examination ..............................................................................................................................43
7.5.
Prior and Concomitant Medications........................................................................................................43
7.5.1.
Prior and Concomitant Medications......................................................................................43
7.5.2.
HBV Medications..................................................................................................................44
7.6.
Electrocardiogram Results.......................................................................................................................45


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7.6.1.
Investigator Electrocardiogram Assessment .........................................................................45
7.6.2.
Other Electrocardiogram Assessment ...................................................................................45
7.7.
Other Safety Measures ............................................................................................................................45
8.
IMMUNOGENICITY ANALYSES ....................................................................................................................46
8.1.
ADA Incidence and Prevalence...............................................................................................................46
9.
PHARMACOKINETIC (PK) ANALYSES.........................................................................................................47
9.1.
PK Sample Collection .............................................................................................................................47
9.2.
PK Analyses ............................................................................................................................................47
10.
OTHER EVALUATIONS....................................................................................................................................48
10.1.
HBeAg.....................................................................................................................................................48
10.2.
Liver Biopsy - Molecular Analysis and Gene Expression ......................................................................48
11.
SOFTWARE.........................................................................................................................................................50
12.
APPENDICES......................................................................................................................................................51
Appendix 1. Sample SAS Code............................................................................................................................51
Appendix 2. Schedule of Assessments.................................................................................................................52
Appendix 3. Imputation of incomplete AE start or end date................................................................................59
Appendix 4. Version History................................................................................................................................62
LIST OF IN-TEXT TABLES
Table 3-1.
Virology LLOQ and LOD .......................................................................................................15
Table 6-1.
Definition of Potential Liver Related Clinical Events.............................................................32
Table 8-1.
Definition of ADA Incidence ..................................................................................................46
LIST OF IN-TEXT FIGURES
Figure 1.
Study Plan..................................................................................................................................8


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LIST OF ABBREVIATIONS
ADA
anti-drug antibody 
AE
adverse event
ALP
ANCOVA
alkaline phosphatase
analysis of covariance
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BLV
bulevirtide 
BMI
CHD
body mass index
chronic hepatitis delta
CI
confidence interval
CRF
case report form
CRP
c-reactive protein
CS
clinically significant
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DILI
DT
drug-induced liver injury
delayed treatment
ECG
electrocardiogram
EOT
end of treatment
EQ-5D-3L
EuroQol 5-dimentions 3-levels 
ET
early termination
FAS
full analysis set
FSS
GGT
HAI
fatigue severity scale 
gamma glutamyl transferase
histological activity index
HBeAg
hepatitis B e antigen
HBsAg
HBV
HDV
HQRQ
HLT
hepatitis B surface antigen
hepatitis B virus
hepatitis Delta virus
hepatitis quality of life questionnaire
high-level term
LLOQ
LOCF
lower limit of quantification
last observation carried forward
LOD
limit of detection
MedDRA
Medical Dictionary for Regulatory Activities
MEF
missing equals failure 
NCS
not clinically significant


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


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study MYR301 Week 144 end of treatment (EOT) analysis. This SAP is based on the study 
protocol Version 7.0 dated 25 January 2023 and the electronic case report form (eCRF). The 
SAP will be finalized before Week 144 database finalization. Any changes made after the 
finalization of the SAP will be documented in the CSR.
1.1.
Study Objectives
The primary objective of this study is to evaluate the efficacy of bulevirtide (BLV) administered 
subcutaneously for 48 weeks at a dose of 2mg or 10mg once daily for treatment of chronic 
hepatitis delta (CHD) in comparison to delayed treatment.
The secondary objectives of this study are:
•
To evaluate optimal treatment duration
•
To assess the safety of BLV
The exploratory objectives of this study are:
•
To investigate the immunogenicity of BLV
•
To investigate influence of BLV on quality of life
•
To assess HBV/HDV genotyping
•
To perform resistance testing
1.2.
Study Design
This is a randomized, open-label, parallel group, multicenter Phase 3 study to evaluate the 
efficacy and safety of BLV in participants with CHD who have no adequate treatment options.
A total of 150 participants were randomized, with stratification by presence of liver cirrhosis to 
3 treatment arms in the ratio of 1:1:1 and treated as follows:
•
Arm A (N = 51): Delayed treatment with BLV 10 mg/day for 96 weeks after an observational 
period of 48 weeks with a further follow-up period of 96 weeks
•
Arm B (N = 49): BLV 2mg/day for 144 weeks with a further follow-up period of 96 weeks
•
Arm C (N = 50): BLV 10mg/day for 144 weeks with a further follow-up period of 96 weeks


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A scheme of the study design is presented in Figure 1. The schedule of events to be conducted 
during the 144-week treatment period and the safety follow-up period is presented in the 
Schedule of Assessments, Appendix 2. 
Figure 1.
Study Plan
EOT = end of treatment; EOS = end of study
1.3.
Sample Size and Power
The primary analysis of the study is the separate comparisons of BLV 2mg and BLV 10mg 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 is 0.05. An interim analysis was performed on the response rates at Week 24. 
To account for the repeated analysis of response, the nominal two-sided significance level was 
split among the time points with 0.01 for 24 weeks and 0.04 for 48 weeks. At each time point the 
BLV doses was compared to 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 Week 48 for the BLV 2mg and BLV 10mg doses were 45% or 
greater. The conservative expectation for the delayed treatment response rates was 8% or less. 
These assumptions were based on results from the preceding Phase 2 study (MYR202).
With a sample size of 47 participants per treatment group, a Fisher's exact test with a 0.04 
two-sided significance level has 97.8% power to detect this difference between the BLV 10mg 
and the delayed treatment proportions and between the BLV 2mg and the delayed treatment 
proportions. The power to reject both null hypotheses simultaneously is 95.6%.
This sample size was slightly increased to 50 participants per treatment group to account for a 
few potential early withdrawals. Hence 150 patients were randomized.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Week 24 Analysis
The Week 24 analysis was conducted when all the participants completed the Week 24 visit or 
prematurely discontinued the study.
2.2.
Week 48 Analysis (Primary Analysis)
The Week 48 analysis was conducted when all the participants completed the Week 48 visit or 
prematurely discontinued the study.
2.3.
Week 96 Analysis
The Week 96 analysis was conducted when all the participants completed the Week 96 visit or 
prematurely discontinued the study.
2.4.
Week 144 Analysis (End of Treatment)
The Week 144 analysis will be conducted when all the participants complete the Week 144 visit 
or prematurely discontinue the study.
2.5.
Week 192 Analysis
The Week 192 analysis will be conducted when all the participants complete the Week 192 visit 
or prematurely discontinue the study.
2.6.
Final Analysis (Week 240)
The final analysis will be performed after all participants complete the study or prematurely 
discontinue the study, outstanding data queries have been resolved or adjudicated as 
unresolvable, and the data have been cleaned and finalized.
This is the SAP for the Week 144 analysis. The details of the Week 24, 48, and 96 analysis 
methods were specified in the separate SAPs.


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


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3.1.4.
Per-Protocol Analysis Set
The Per-Protocol (PP) Analysis Set is defined as all participants of the FAS for whom no 
protocol deviations are judged to have an impact on the analysis of the primary efficacy endpoint 
of combined response (or on secondary efficacy endpoint of sustained virological response at 
follow-up Week 48 [SVR48], ie, study Week 192). The PP Analysis Set is the secondary 
analysis set for efficacy analyses.
There are three PP Analysis Sets in the study:
•
The PP 24Week Analysis Set (defined for the Week 24 interim analysis)
•
The PP 48Week Analysis Set (defined for the Week 48 primary efficacy analysis)
•
The PP 192Week Analysis Set (defined for the Week 192 interim analysis)
The decision of whether a particular protocol deviation is considered as reason for exclusion 
from each of the PP Analysis Set should be made at data review meeting for each analysis and 
documented in each corresponding data review meeting report (ie, clean file report). 
For Week 144 analysis, efficacy analyses using the PP 48Week Analysis Set will be repeated for 
primary efficacy endpoint of combined response at Week 48, key secondary endpoint of 
undetectable HDV RNA at Week 48, and secondary endpoint of ALT normalization at Week 48 
and endpoint of virologic response at Week 48 (virologic response is defined as undetectable 
HDV RNA or decrease in HDV RNA by ≥ 2 log10 IU/mL from baseline) using the updated 
Week 144 database.
3.1.5.
Safety Analysis Set
The Safety Analysis Set includes all participants who were randomized to the study and took at 
least 1 dose of BLV, or who were randomized to delayed treatment group. This is the primary 
analysis set for safety analyses.
3.1.6.
Anti-drug Antibody Analysis Set
The Anti-drug Antibody (ADA) Analysis Set includes all participants who took at least 1 dose of 
BLV and had at least 1 non-missing ADA data. This is the primary analysis set for the 
immunogenicity analyses.
3.1.7.
Pharmacokinetic Analysis Set
The Pharmacokinetic (PK) Analysis Set includes all randomized participants who took at least 
1 dose of BLV and had at least 1 non-missing concentration value reported by the PK laboratory. 
This is the primary analysis set for the PK analyses. 


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3.2.
Participant Grouping
For analyses based on the All Randomized Analysis Set and FAS, participants will be grouped 
according to the treatment to which they were randomized. For analyses based on the PP 
Analysis Set, Safety Analysis Set, ADA Analysis Set, and PK Analysis Set, participants will be 
grouped according to the actual treatment received. The actual treatment received will differ 
from the randomized treatment only when their actual treatment differs from randomized 
treatment for the entire treatment duration.
For cumulative data summary, data will be presented as listed below:
Group A:
•
DT (ie, delayed treatment): baseline (ie, baseline at randomization) to prior to the first 
dose of BLV at Week 48 visit or to early termination (ET) before Week 48 visit (N = 51)
•
DT to BLV 10mg: first dose of BLV at Week 48 visit to Week 144 visit (N = 50, 1 
participant from DT group terminated early before the Week 48 visit). The baseline will 
be reset at Week 48 visit (ie, re-baseline)
Groups B and C (BLV 2mg and BLV 10mg):
•
Baseline to Week 48 visit period or to ET before Week 48 visit (N = 49 for Group B,      
N = 50 for Group C)
•
Overall BLV treatment period: baseline to Week 144 visit (N = 49 for Group B, N = 50 
for Group C)
For by-visit summary, data will be presented as follows: DT group, DT to BLV 10mg group, 
Group B, and Group C. For Group A, the AEs that occurred prior to the first dose of BLV and 
lab values that were tested on or prior to the first dose of BLV, or up to premature 
discontinuation study before receiving BLV will be allocated to DT group, while the AEs 
occurring at or after the first dose of BLV and lab values generated after the first dose of BLV 
will be allocated to DT to BLV 10mg group. 
For the DT to BLV 10mg group, the baseline will be reset as the last non-missing value on or 
prior to the first dose of BLV (the re-baseline liver stiffness is the available value from Week 48 
visit). 
For Groups B and C, the data prior to the Week 48 visit or up to ET before Week 48 visit will be 
allocated to the baseline to Week 48 visit period; the data up to Week 144 visit will be allocated 
to overall BLV treatment period.


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3.3.
Strata and Covariates
Participants eligible for the study were randomly assigned to treatment group via electronic 
randomization system in a 1:1:1 ratio using a stratified randomization schedule. Stratification 
was based on the following variables:
•
Cirrhosis status at randomization (presence vs. absence)
Efficacy endpoints will be evaluated using stratification factors as covariates for analyses, as 
specified in Section 6.
3.4.
Examination of Participant Subgroups
The efficacy endpoints will be examined using the following subgroups. Details will be specified 
in the corresponding sections.
•
Cirrhosis status at randomization (presence vs. absence)
•
Concomitant HBV treatment (Yes vs. No)
The safety endpoints will be examined using the following subgroups. Details will be specified 
in the corresponding sections.
•
ADA incidence at Week 144 (positive vs. negative)
3.5.
Multiple Comparisons
One interim analysis at Week 24 and one primary analysis at Week 48 were conducted to 
compare the efficacy of treatment groups using the primary efficacy endpoint. To account for the 
repeated analysis of response (interim analysis at Week 24 and primary analysis at Week 48) the 
nominal two-sided significance level of 0.05 was split among the time points with 0.01 for Week 
24 and 0.04 for Week 48. At each time point, the BLV doses were compared to DT group in 
terms of a hierarchical testing procedure starting with the higher dose (BLV 10mg) at the 
respective adjusted two-sided significance levels.
Multiple group comparisons for the primary endpoint and a key secondary endpoint were 
handled with a hierarchical testing procedure. Details are described in Sections 6.2.1 and 6.3.1.
All other analyses will be considered explorative and no adjustment for multiple testing will be 
performed.


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3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. 
The handling of missing or incomplete dates for AE is described in Appendix 3, and for prior 
and concomitant medications in Section 7.5. Imputation rules adopted in the efficacy analyses 
are specified in Section 6.
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis, unless 
otherwise specified.
3.7.
Data Handling Conventions and Transformations
In general, age in years at the time when informed consent was signed will be used for analyses 
and presented in listings. For DT to BLV 10mg group, re-baseline age in years at Week 48 visit 
will be used for the analyses.
For virology laboratory data, pharmacokinetics data, molecular analysis data, and gene 
expression analysis data, the following rules will be applied:
•
Values below the lower limit of quantification (< LLOQ) with specification of target not 
detected (ie, < limit of detection [LOD]) will be imputed as 0.
•
Values < LLOQ (without specification of target not detected) will be imputed as half of the 
LLOQ value, if LLOQ does not equal the LOD.
•
Values < LLOQ (without specification of target not detected) will be imputed as 0, if LLOQ 
equals LOD (ie, HBV DNA by MLM).
•
Values above the upper limit of quantification (ULOQ) will be imputed as the ULOQ.
•
Non-measurable data will be considered as missing data.
For log10 transformed data, the following rules will be applied:
•
Untransformable value of 0 will be imputed as 0 if LOD > 1.
•
Untransformable value of 0 will be imputed as log10(LOD/2) if LOD < 1.


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The LLOQ, ULOQ and LOD for virology are specified in the Table 3-1.
Table 3-1.
Virology LLOQ and LOD 
Parameters
Lab Institutes
LLOQ
LOD
HDV RNA
University Hospital Frankfurt (data 
transferred through MLM)
50 IU/mL
6 IU/mL
HBV DNA
University Hospital Frankfurt (data 
transferred through MLM)
10 IU/mL
10 IU/mL
HBV DNA
Invitro
100 IU/mL
20 IU/mL
HBsAg
University Hospital Frankfurt (data 
transferred through MLM)
not applicable
0.05 IU/mL
Safety laboratory data that are continuous in nature but less than the LLOQ or above the ULOQ 
(reported in the form of “< xx.xx” or “> xx.xx”) will be imputed as one half of LLOQ, or as the 
same as ULOQ to calculate summary statistics.
3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day will be calculated from the randomization date for DT group or from the first dosing 
date of BLV for Group B/C and for DT to BLV 10mg group and derived as follows: 
•
For postdose study days: Assessment Date – First Dosing Date (or randomization date for DT 
group) + 1
•
For days prior to the first dose: Assessment Date – First Dosing Date (or randomization date 
for DT group)
Therefore, Study Day 1 is the day of randomization for DT group or the day of the first dose of 
BLV administration for Group B/C and DT to BLV 10mg group.
3.8.2.
Analysis Visit Windows
The nominal visit as recorded on the CRF will be used when data are summarized by visit. 
However, when the nominal visit was made outside the analysis visit window, the value will not 
be included in analysis.


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Table 3-2.
Analysis Visit Windows for by Visit Assessments for Group A/B/C
Visit Window Study Day
Analysis Visit
Target Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 4
29
2
59
Week X*
X × 7+1
X × 7+1-30
X × 7+1+30
* For Group A BLV treated participants, the upper limit at Week 48 (exclude liver stiffness and biopsy) is First 
Dose Date of BLV – Study Day 1 + 1
Table 3-3.
Analysis Visit Windows for by Visit Assessments for Group A DT 
group
Visit Window Study Day
Analysis Visit
Target Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 4
29
2
59
Week X
X × 7+1
X × 7+1-30
X × 7+1+30
Week 48*
337
307
First Dose Date of BLV 
– Study Day 1 + 1 (or 
367 for participants not 
treated by BLV)
* Liver stiffness at Week 48 is the available value from Week 48 visit.
Table 3-4.
Analysis Visit Windows for by Visit Assessments for Group A DT to 
BLV 10mg group
Visit Window Study Day
Analysis Visit
Target on-BLV 
Study Day
Lower Limit
Upper Limit
Baseline on BLV*
1
(none)
1
Week 4 on BLV
29
2
59
Week X on BLV
X × 7+1
X × 7+1-30
X × 7+1+30
* Liver stiffness baseline on BLV is the available value from Week 48 visit.
The data collected at unscheduled visits (including ET visits) will be used in the following ways:
•
An unscheduled visit on or prior to the randomization for DT group or the first dose of BLV 
may be included in the calculation of the baseline value, if applicable.
•
Unscheduled visits after the randomization for DT group or the first dose of BLV will be 
included in determining the maximum postbaseline toxicity grade.


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•
Record from unscheduled visit will be assigned to a visit when there is no available data in 
the corresponding analysis visit window. If multiple measurements from unscheduled visits 
exist, the selection rule specified in Section 3.8.3 will be followed.
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value.
If multiple valid, non-missing measurements exist in an analysis window, records will be chosen 
based on the following rules if a single value is needed:
•
For baseline, the last non-missing value on or prior to the randomization date for the DT 
group, or to the first dosing BLV for all other groups will be selected, unless specified 
differently. 
•
For postbaseline values, record from ET visit will be selected. If there is no available ET 
record, the data from unscheduled visits will be selected as below.
The record closest to the target day for that visit will be selected.
If there are 2 records that are equidistant from the target day, the later record will be 
selected.


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4.
PARTICIPANT DISPOSITION
4.1.
Participant Enrollment and Disposition
A summary of participant enrollment will be provided by treatment group for each region. The 
summary will present the number and percentage of participants enrolled. For each column, the 
denominator for the percentage calculation will be the total number of participants analyzed for 
that column.
A similar enrollment table will be provided by randomization stratum. The denominator for the 
percentage of participants in the randomization stratum will be the total number of enrolled 
participants.
A summary of participant disposition will be provided by treatment group. This summary will 
present the number of participants screened, the number of participants who met all eligibility 
criteria but were not randomized with reasons participants not randomized, the number of 
participants enrolled, the number of participants randomized, the number of participants 
randomized but not dosed, and the number of participants in each of the categories listed below:
•
Safety Analysis Set 
•
Full Analysis Set
•
Per-Protocol Analysis Set
•
Completed Week 24
•
Completed Week 48
•
Completed Week 96
•
Completed Week 144
•
Continuing study at Week 144
•
Did not complete the study with reasons for premature discontinuation of study
For the reasons of premature discontinuation, the number and percentage of participants in each 
category will be provided. The denominator for the percentage calculation will be the total 
number of participants in the Safety Analysis Set corresponding to that column. 
The following by-participant listings will be provided by participant identification (ID) number 
in ascending order to support the above summary tables:
•
Reasons for premature study discontinuation


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•
Reasons for screen failure (will be provided by screening ID number in ascending order)
4.2.
Extent of Study Drug Exposure and Compliance
The sponsor will capture, clean, and validate the missing doses that are not documented in the 
participant diary (hereafter referred to as “sponsor identified missed doses”) in an excel file 
(included in the clean file report as an appendix).
4.2.1.
Study Drug Exposure
The total duration of BLV exposure in weeks will be computed as (last dose date of BLV – first 
dose date of BLV + 1)/7 regardless of any temporary interruptions and will keep 2 decimal 
places (ie, 4.56 weeks).
The total dose of BLV (in mg) administered will be computed as the sum of all doses 
administered (as reported in the participant diary, which takes participant reported missed doses 
into consideration) minus sponsor identified missed doses (the number of days without dosing 
times the planned daily dose for BLV).
The dose intensity (in mg/week) will be computed as the total dose administered divided by the 
total duration of exposure.
4.2.2.
Study Drug Compliance
The compliance rate of the full regimen will be computed as the ratio of the total dose 
administered to the expected full regimen dose and expressed as a percentage. The expected full 
regimen dose for BLV is defined as 96 weeks of planned daily dosage (10mg) for participants in 
DT to BLV 10mg group, and 144 weeks of planned daily dosage (2mg or 10mg) for participants 
in Groups B and Group C.
The total number of missed doses will be computed as the expected total number of doses minus 
the number of doses administered by Week 144, or study day 1006 (ie, 144×7-2 per protocol 
visit window), whichever comes first (as reported in the participant diary), plus the number of 
additional sponsor identified missed doses. If this results in a negative number, the total number 
of missed doses will be set to the number of sponsor identified missed doses, or zero if there 
were no sponsor identified missed doses.
The expected total number of BLV doses will be defined as:
(last on-treatment visit date, or study day 1006, or ET from study date, whichever comes first) – 
first dose date + 1 
The proportion of missed doses will be computed as the ratio of the total number of missed doses 
to the expected total number of doses and expressed as a percentage.


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4.2.3.
Summaries of Study Drug Exposure and Compliance
Descriptive statistics for following parameters will be presented by treatment group (Group B, 
Group C, DT to BLV 10mg) for BLV at Week 144.
•
Total duration of exposure
•
Total dose administered
•
Dose intensity
•
Compliance rate
•
Participants with ≥ 1 missed dose
•
Total number of missed doses
•
Proportion of missed doses
In addition, the by-participant listings of BLV administration and accountability will be 
provided. No formal statistical testing is planned.
4.3.
Protocol Deviations 
Participants who did not meet the eligibility criteria for study entry but enrolled in the study will be 
summarized regardless of whether they were exempted by the sponsor or not. The summary will 
present the number and percentage of participants who did not meet at least 1 eligibility criterion 
and the number of participants who did not meet specific criteria by treatment group based on the 
All Randomized Analysis Set. A by-participant listing will be provided for those participants who 
did not meet at least 1 eligibility (inclusion or exclusion) criterion. The listing will present the 
eligibility criterion (or criteria if more than 1 deviation) that participants did not meet and related 
comments, if collected.
Protocol deviations occurring after participants entered the study are documented during routine 
monitoring. The number and percentage of participants with important protocol deviations by 
deviation reason will be summarized by treatment group for the All Randomized Analysis Set. A 
by-participant listing will be provided for those participants with important protocol deviation.
4.4.
Assessment of COVID-19 Impact
This study was ongoing during the novel coronavirus (COVID-19) pandemic which had an 
impact on the study conduct. This section describes how special situations due to COVID-19 will 
be handled in the analysis.


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


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
Participant demographic and baseline characteristics variables will be summarized by treatment 
group (eg, DT group, BLV 2mg group, BLV 10mg group, and DT to BLV 10mg group), and 
total, using descriptive statistics for continuous variables, and number and percentage of 
participants for categorical variables, where the total number is the sum of the DT group, BLV 
2mg group, and BLV 10mg group. The summary of demographic and baseline characteristics 
data will be provided for the FAS and PP 48Week Analysis Set, for the following:
•
Age (years)
•
Sex (male, female)
•
Race (Asian, Black or African American, White, Other)
•
Height (cm)
•
Body weight (kg)
•
Body mass index (BMI, kg/m2)
•
BMI categories (<30 kg/m², ≥30 kg/m²)
If the Safety Analysis Set differs from the FAS, or there are participants whose actual treatment 
differs from randomized treatment for the whole treatment period, this summary will be provided 
for the Safety Analysis Set as well.
A by-participant demographic and baseline characteristics listing, including the informed consent 
date will be provided. No formal statistical testing is planned.
5.2.
Other Baseline Characteristics
Participants’ other baseline characteristics variables will be summarized by treatment group, and 
total using descriptive statistics for continuous variables, and number and percentage of 
participants for categorical variables. The summary of other baseline characteristics data will be 
provided for the FAS and PP 48Week Analysis Set for the following:
•
Cirrhosis status at randomization (Presence, Absence)
•
Child–Pugh score for cirrhotic participants
•
Child–Pugh class for cirrhotic participants


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


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•
Baseline gamma glutamyl transferase (GGT) (U/L)
•
Baseline platelet count (×109/L)
•
Baseline total bilirubin (μmol/L)
•
Baseline total bile salts (μmol/L)
•
Concomitant HBV medication (Yes/No)
For DT to BLV 10mg, unless otherwise specified, a baseline value will be defined as the last 
measurement obtained on or prior to the date of first dose of BLV at Week 48 visit. And baseline 
liver stiffness is the available measurement from Week 48 visit.
In summary tables of demographic and baseline characteristics, the original baseline values at 
randomization will be used for the DT to BLV 10mg group for the following variables: 
•
Sex (male, female)
•
Race (Asian, Black or African American, White, Other)
•
Height (cm)
•
Cirrhosis status at randomization (Presence, Absence)
•
Child–Pugh score for cirrhotic participants
•
Child–Pugh class for cirrhotic participants
•
Abdominal ultrasound (abnormal clinically significant [CS], abnormal not clinically 
significant [NCS], normal)
•
Serum alpha-fetoprotein (AFP; IU/mL)
•
Prior PEG-IFNα (prior medication preferred name contains the word ‘interferon’) (yes, no)
•
HIV antibody (positive, negative, missing)
•
HCV antibody (positive, negative, missing)
•
HDV antibody (positive, negative, missing)
•
HBeAg (positive, negative, missing)
•
HBeAg antibody (positive, negative, missing)


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•
Qualitative HBV DNA at screening (positive, negative, missing)
•
HDV genotype
•
HBV genotype
Estimated on-study creatinine clearance will be calculated by the Cockcroft-Gault method: 
creatinine clearance = [(140 – age (yrs)) × weight (kg) × (0.85 if female)] /(0.814 × creatinine 
(μmol/L)), where weight is total body mass in kilograms. 
If the Safety Analysis Set differs from the Full Analysis Set, or there are participants whose 
actual treatment differs from randomized treatment for the whole treatment duration, this 
summary will be provided for Safety Analysis Set as well.
A by-participant listing of other baseline characteristics will be provided. No formal statistical 
testing is planned.
5.3.
Substance Use
Participant substance use will be summarized by treatment group, and overall using number and 
percentage of participants. The summary will be provided for the FAS and PP 48Week Analysis 
Set, for the following:
•
Alcohol breath test at screening (Positive, Negative)
•
Alcohol breath test at baseline (Positive, Negative)
•
Alcohol consumption status (Current, Former, Never) 
•
Smoking status (Current, Former, Never)
•
Urine drug test at screening (Positive, Negative)
•
Drug abuse status (Current, Former, Never)
5.4.
Medical History
Medical history collected at screening will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) v26.0.
Medical history will be summarized for Safety Analysis Set by system organ class (SOC), 
preferred term (PT), treatment group, and overall. Participants who reported 2 or more medical 
history terms that are coded to the same SOC and/or PT will be counted only once by the unique 
coded term in the summary. No formal statistical is planned. A by-participant listing of medical 
history will be provided.


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6.
EFFICACY ANALYSES
6.1.
General Considerations
The primary analysis set for efficacy analyses will be the FAS, defined in Section 3.1.2.
Derivation of Multi-component Endpoints
For the derivation of multi-component endpoints including combined response and virological 
response, the following steps will be used unless otherwise specified:
•
Step 1: assign individual components to analysis visit windows specified in Section 3.8.2
•
Step 2: impute missing data for individual components
•
Step 3: derive the multi-component endpoint with the corresponding imputed individual 
components
Missing Data Imputation
Below are the descriptions for the imputation methods that will be used in the efficacy analyses:
•
Missing Equals Failure (MEF): For binary response endpoints, missing value will be imputed 
as nonresponder. For all analyses of the primary endpoint and undetectable HDV RNA at 
Week 24 and Week 48 using FAS, MEF will be adopted when missing was not related to 
COVID-19. In addition, MEF will be adopted for all analyses of the secondary and 
exploratory endpoints using FAS.
•
Last observation carrying forward (LOCF): Missing value will be imputed using the last 
observation (including observation from unscheduled visit). For all analyses (except the 
sensitivity analysis) of the primary efficacy endpoint and undetectable HDV RNA at Week 
24 and Week 48 using FAS, LOCF will be used when missing was related to COVID-19.
•
Observed Case (OC): Missing values remain missing. The OC will be used for analyses of 
continuous endpoints and analyses using PP 48Week Analysis Set.
6.2.
Primary Efficacy Endpoints
The primary efficacy endpoint is combined response at Week 48. Combined response is defined 
as fulfilling both of the following 2 conditions simultaneously: 
•
Undetectable (< LLOQ, target not detected) HDV RNA or decrease in HDV RNA by ≥ 2 
log10 IU/mL from baseline 
•
ALT normalization


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6.2.1.
Primary Analysis of the Primary Efficacy Endpoint
Two 2-sided Fisher’s exact 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
where pO, pM2mg, and pM10mg are the expected response rate for delayed treatment, BLV 2mg and 
BLV 10mg, respectively. In terms of a hierarchical testing procedure, the second null hypothesis 
will not be rejected if the first null hypothesis could not be rejected. These hypotheses were 
tested at the Week 24 interim analysis and at the Week 48 primary analysis. To account for the 
repeated analysis, the nominal two-sided significance level of 0.05 will be split among these two 
time points with 0.01 for Week 24 and 0.04 for Week 48.
The primary analysis of combined response at Week 24 is the estimated rate difference between 
BLV and delayed treatment group with 99% exact unconditional CI for the difference based on 
the score statistic. The p-value from 2 two-sided Fisher’s exact tests will also be provided. There 
is a statistically significant difference at Week 24 if p < 0.01. In addition, for each group, the 
response rate with Clopper-Pearson 95% CIs will be presented.
The primary analysis of combined response at Week 48 is the estimated rate difference between 
BLV and delayed treatment group with 96% exact unconditional confidence interval (CI) for the 
difference based on the score statistic. The p-value from 2 two-sided Fisher’s exact tests will also 
be provided. There is a statistically significant difference at Week 48 if p < 0.04. The comparison 
of BLV 2mg versus delayed treatment is considered significant only if the comparison of BLV 
10mg versus delayed treatment is significant. In addition, for each group, the response rate with 
Clopper-Pearson 95% CIs will be presented.
The primary analysis will be based on the FAS.
6.2.2.
Sensitivity Analysis of the Primary Efficacy Endpoint
The same analysis as specified in Section 6.2.1 will be repeated using the data for which missing 
values were imputed as failure regardless of whether it was related to COVID-19 (Section 6.1).
6.2.3.
Per-protocol Analysis of the Primary Efficacy Endpoint
The same analysis as specified in Section 6.2.1 will be repeated using the PP 48Week Analysis 
Set based on actual treatment on the observed cases without imputing missing values, as a 
supportive analysis.


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6.2.4.
Subgroup Analysis of the Primary Efficacy Endpoint
With an expected low number of responders in the delayed treatment group, the primary efficacy 
analysis will not be stratified by cirrhosis or other covariables. Descriptive analyses of combined 
response will be presented by subgroups for efficacy endpoints as defined in Section 3.4.
6.3.
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
•
Undetectable HDV RNA at Weeks 48 (key secondary efficacy endpoint)
•
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)
•
Change from baseline in liver stiffness as measured by elastography at Weeks 48, 96, 144, 
192, and 240
The SVR24, SVR48 and the change from baseline in liver stiffness at Weeks 192 and 240 will be 
analyzed in future analyses.  
6.3.1.
Analysis of Secondary Efficacy Endpoints
Undetectable HDV RNA at Weeks 48 (key secondary endpoint)
The proportion of participants with undetectable HDV RNA at Week 48 is the key secondary 
endpoint and will be used to test differences between the BLV doses and hence evaluate the dose 
response relationship. 
A two-sided Fisher’s exact test will be performed to test the hypotheses
H03: rM2mg = rM10mg vs. H13: rM2mg ≠ rM10mg
where rM2mg, rM10mg are the expected rates of participants with undetectable HDV RNA at Week 
48 for BLV 2mg and BLV 10mg, respectively.
This test will only be performed if the two null-hypotheses for the primary variable (H01 and H02 
in 6.2.1) both have been rejected. As for the primary analysis, the above hypotheses will also be 
tested at Week 24 and hence the nominal two-sided significance level of 0.05 will be split among 
the time points with 0.01 for Week 24 and 0.04 for Week 48, respectively. 
The estimated rate differences between BLV 10mg and BLV 2mg with exact unconditional CI 
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Fisher’s exact test will be provided using FAS and PP 48Week Analysis Set. The Clopper-
Pearson 95% CIs of undetectable HDV RNA rate in each group will also be presented. The same 
summary will be repeated by subgroups for efficacy endpoints as defined in Section 3.4.
ALT Normalization at Week 48
The proportion of participants with ALT normalization at Week 48 will be compared between 
BLV 2mg and the delayed treatment group and BLV 10mg and the delayed treatment group 
using two-sided Fisher’s exact tests. Nominal p-values without multiple comparison adjustment 
and 95% exact unconditional confidence intervals based on score statistic for the proportion 
differences will be provided. The same analysis will be performed at Week 24 and at Week 48, 
using FAS and using PP 48Week Analysis Set. In addition, for each group, the Clopper-Pearson 
95% CIs of response rate will also be presented. The same summary will be repeated by 
subgroups for efficacy endpoints as defined in Section 3.4.
Change from Baseline in Liver Stiffness at Week 48, Week 96, and Week 144
For the change from baseline in liver stiffness at Week 48, an ANCOVA model will be used to 
compare the least squares (LS) means between BLV 2mg and the delayed treatment group, and 
BLV 10mg and the delayed treatment group using FAS and PP 48Week Analysis Set. The model 
includes treatment, region, presence of cirrhosis and baseline liver stiffness as covariate. 
Nominal p-values without multiple comparison adjustment and the 95% CI for the LS mean 
difference between each BLV group and the delayed treatment group will be provided. In 
addition, for each treatment group, the LS mean will be provided.
For the change from baseline in liver stiffness at Week 96 and Week 144, a mixed-effects model 
for repeated measurements (MMRM) will be used to evaluate treatment effect using FAS. The 
model includes treatment (BLV 2mg, BLV 10mg, and DT to BLV 10mg group), region, 
presence of cirrhosis, visit and treatment by visit interaction as fixed effects, and baseline liver 
stiffness (the baseline for DT to BLV 10mg group is the reset baseline) as covariable. An 
unstructured variance-covariance matrix will be used. The Kenward-Roger method will be used 
to estimate the degrees of freedom. Restricted maximum likelihoods (REML) will be used to fit 
the model. Missing change values will not be otherwise imputed using MMRM. For each 
treatment group, the LS mean with 95% CI at Week 96 (for DT to BLV 10mg group, Group B 
and Group C) and at Week 144 (for Group B and Group C only) will be presented respectively. 
In addition, the difference in LS means and the 95% CI for the LS mean difference between BLV 
2mg (Group B) and BLV 10mg (Group C) at each visit will be provided.
Descriptive statistics of liver stiffness at each visit, as well as the change from baseline, will be 
provided by treatment group. The summary will be repeated by subgroups for efficacy endpoints 
defined in Section 3.4 using FAS. The plots of mean ± SD of change from baseline in liver 
stiffness over time, as well as by subgroup of cirrhosis status, will be presented.
6.4.
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are:


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•
Change from baseline in necroinflammation as assessed at liver biopsy
•
Change from baseline in fibrosis as assessed at liver biopsies
•
Combined response at all postbaseline assessments of HDV RNA and ALT
•
HDV RNA decrease by ≥ 2 log10 IU/mL from baseline at all postbaseline assessments
•
Undetectable HDV RNA at all postbaseline assessments
•
HDV RNA decrease by ≥ 2 log10 IU/mL from baseline or undetectable HDV RNA at all 
postbaseline assessments (virologic response)
•
Change from baseline in HDV RNA at all postbaseline assessments
•
ALT normalization at all postbaseline assessments
•
Change from baseline in ALT at all postbaseline assessments
•
Change from baseline in serum alpha-2-macroglobulin (fibrosis marker) at all postbaseline 
assessments
•
HBsAg response (HBsAg decrease by ≥ 1 log10 IU/mL) at all postbaseline assessments
•
HBsAg loss without seroconversion at all postbaseline assessments
•
HBsAg loss with seroconversion (presence of anti-HBsAg) at all postbaseline assessments
•
Change from baseline in HBsAg (log10 IU/mL) at all postbaseline assessments
•
Change from baseline in HBV DNA (log10 IU/mL) at all postbaseline assessments
•
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 hospitalizations and duration of each hospitalization at all 
postbaseline assessments
•
Change from baseline in quality of life assessed with questionnaires at all postbaseline 
assessments:
EuroQol (5 dimensions) (EQ-5D)
Fatigue Severity Scale (FSS)


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The Hepatitis Quality of Life Questionnaire™ (HQLQ™)
6.4.1.
Definition of Exploratory Efficacy Endpoints
6.4.1.1.
Necroinflammation and Fibrosis Assessed at Liver Biopsy
The analysis of the liver biopsy samples will be used to assess necroinflammation and fibrosis 
endpoints. The histological activity index (HAI) is an additive score calculated as the sum (range 
0 to18) of the semi-quantitative scores for 3 individual features: periportal necrosis with the 
presence of bridge like necrosis or without them (range 0 to 10), intralobular degeneration and 
focal necrosis (range 0 to 4), and portal inflammation (range 0 to 4). Stage of histological activity 
based on Metavir score will be assigned as Metavir activity grade. The stage of liver fibrosis on a 
scale of Knodell, Ishak, Metavir will be assessed.
6.4.1.2.
HBsAg Loss with/without Seroconversion
HBsAg loss is defined as undetectable HBsAg. Seroconversion is defined as presence of anti-
HBsAg.
HBsAg loss without seroconversion response values are:
•
Responder: HBsAg result less than the LOD, with negative anti-HBsAg
•
Non-responder: participants who do not meet criteria of responder
HBsAg loss with seroconversion response values are:
•
Responder: HBsAg result less than the LOD, with presence of anti-HBsAg
•
Non-responder: participants who do not meet criteria of responder
6.4.1.3.
Liver Related Clinical Events
The potential liver related clinical events include liver-related death, and other events as defined 
in the Table 6-1.


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Table 6-1.
Definition of Potential Liver Related Clinical Events
Potential Liver Related Clinical Events
MedDRA v26.0 Preferred Term
Cirrhosis development
•
Hepatic cirrhosis
Development or worsening of jaundice
•
Jaundice
Development or worsening of coagulopathy
•
Coagulopathy
Development or worsening of ascites
•
Ascites
•
Bacterascites
•
Spontaneous bacterial peritonitis
Development or worsening of hepatic encephalopathy
•
Hepatic encephalopathy
•
Coma hepatic
•
Asterixis
Bleeding from varices
•
Oesophageal varices haemorrhage
•
Gastric varices haemorrhage
•
Intestinal varices haemorrhage
•
Anorectal varices haemorrhage
Hepatocellular carcinoma development
•
Hepatic cancer
•
Hepatocellular carcinoma
•
Liver carcinoma ruptured
•
Mixed hepatocellular cholangiocarcinoma
Liver transplantation
•
Liver transplant
•
Renal and liver transplant
Liver failure
•
Acute hepatic failure
•
Subacute hepatic failure
•
Acute on chronic liver failure
•
Hepatic failure
•
Hepatorenal syndrome
•
Hepatorenal failure
•
Hepatopulmonary syndrome
Liver-related death
Potential liver related clinical event with fatal 
outcome
6.4.1.4.
EuroQol 5-Dimentions 3-Levels (EQ-5D-3L)
EQ-5D-3L is a standardized questionnaire describing health outcomes in 5 domains (mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has 3 levels: 
no problems, some problems, and extreme problems. In addition to the five domains, the EQ 
visual analogue scale (EQ VAS) is used to assess the participant’s self-rated health. The EQ 
VAS ranges from 0 to 100, and higher score indicates better health.


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6.4.1.5.
Fatigue Severity Scale (FSS)
The FSS is a 9 items scale measuring the severity of fatigue and its physical, social, and 
cognitive impact on participants’ activities and lifestyle. Each item is scored using a 7-point 
Likert scale where a low value indicates strong disagreement with the statement, and a high 
value indicates agreement with the statement. An overall mean score will be computed as the 
arithmetic mean (range 1 to 7) of the item scores. The mean score will be computed when there 
are at least half of the item scores are non-missing; otherwise, the mean score will be set to 
“missing.”
6.4.1.6.
Hepatitis Quality of Life Questionnaire™ (HQLQ™)
The HQLQ™ assesses the functional health and well-being of the participant. It comprises 
36 questions from the second version of the Short Form 36 Health Survey, and 15 additional 
questions that measure other generic health concepts. The Short Form 36 Health Survey items 
are organized into eight scales: physical functioning, role limitations due to physical health, 
bodily pain, general health perceptions, vitality, social functioning, role limitations due to 
emotional problems, and general mental health. In addition, 2 summary measures are also 
constructed: physical component summary and mental component summary. The additional 
questions are organized into 5 scales: health distress, positive wellbeing, hepatitis-specific 
limitations, and hepatitis-specific health distress. The scale scores and summary measures will be 
computed by Optum®.
6.4.2.
Analysis of Exploratory Efficacy Endpoints
The FAS will be used for analyses of exploratory efficacy endpoints. Descriptive statistics will 
be provided by treatment group at all scheduled visits for each exploratory efficacy endpoint and 
HBsAg loss. For binary endpoints, the Clopper-Pearson 95% CIs of response rate in each 
treatment group will be presented. Subgroup analysis specified in Section 3.4 will be performed 
for binary endpoints: proportions of participants achieving combined response, undetectable 
HDV RNA, virologic response, HDV RNA decrease ≥ 2 log10 from baseline, and ALT 
normalization. The subgroup analysis will be also provided for HDV RNA, ALT, HBsAg, and 
HBV DNA change from baseline by visit.
To analyze change from baseline in necroinflammation and fibrosis, the number and percentage 
of participants with change status (improving, no change or worsening) at Week 48 visit will be 
summarized by treatment group for Metavir histological activity grade, histological activity 
index (HAI), and Ishak, Knodell and Metavir fibrosis scores, respectively. The HAI original 
value (range 0 to18) will be categorized into category levels as in the table below for analysis, 
unless specified otherwise
HAI Original Value
HAI Category Level
 HAI Clinical Interpretation
 0
0
No inflammation
 1-4
1
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HAI Original Value
HAI Category Level
 HAI Clinical Interpretation
 5-8
2
Some inflammation
9-12
3
Moderate inflammation
13-18
4
Significant inflammation
The improving is defined as decrease at least 1 point (or 1 category level for HAI) from baseline, 
and the worsening is defined as increase at least 1 point (or 1 category level for HAI) from 
baseline. Participants with missing value at baseline or postbaseline will be summarized but will 
not be included in the denominator for percentage calculation. 
The shift tables will be provided by showing changes in results from baseline to Week 48 by 
treatment group for Metavir histological activity grade, HAI, and Ishak, Knodell and Metavir 
fibrosis scores. 
The number and percentage of participants having histological improvement (defined as decrease 
at least 2 points from baseline in HAI original value without worsening of Knodell fibrosis 
score) at Week 48 will be summarized by treatment group. The number and percentage of 
participants having at least 2 points reduction from baseline in HAI original valueat Week 48 
will be also summarized by treatment group.
The potential liver-related clinical events will be summarized for the DT group, DT to BLV 
10mg group, Group B/C baseline to Week 48 visit period and baseline to Week 144 visit period, 
respectively. The events will be allocated to treatment group based on event onset dates. A 
similar summary for liver related hospitalizations will also be provided, and the duration of 
hospitalization calculated as (end date – start date + 1) will be presented in the listing.
The proportions of participants achieving response will be plotted over time by treatment for 
combined response, ALT normalization, undetectable HDV RNA, and virologic response, as 
well as HDV RNA decrease ≥ 2 log10 from baseline. In addition, plots of mean ± SD of changes 
from baseline for HDV RNA and ALT will be presented. The same plots will be repeated by 
cirrhosis status.
In addition, a by-participant listing will be provided for combined response, virological response, 
HDV RNA decrease by ≥ 2 log10 IU/mL from baseline, undetectable HDV RNA, ALT 
normalization, HDV RNA, HDV RNA change from baseline, ALT, ALT change from baseline, 
liver stiffness, HBV DNA, and HBsAg at all visits. The same listing will be repeated for non-
responders of combined response at Week 48.
Separate by-participant listings for other exploratory efficacy endpoints may be generated as 
appropriate.


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
Clinical and laboratory adverse events (AEs) will be coded using the MedDRA v26.0. System 
organ class (SOC), high-level group term (HLGT), high-level term (HLT), preferred term (PT), 
and lower-level term (LLT) will be provided in the AE dataset.
7.1.1.
Adverse Event Severity
Adverse events are graded as Grade 1, 2, 3, 4, or 5 according to the Common Terminology 
Criteria for Adverse Events (CTCAE, Version 5.0). Events for which a CTCAE term cannot be 
found will be assigned a severity grade according to the classification of AEs specified in the 
study protocol. The severity grade of events for which the investigator did not record severity will 
be categorized as “missing” for tabular summaries and data listings. The “missing” category will 
be listed last in summary presentation.
7.1.2.
Relationship of Adverse Events to Study Drug
The related AEs for each study drug are those for which the investigator selected “Reasonable 
possibility” on the AE CRF to the question of causality. Relatedness will always default to the 
investigator’s choice, not that of the medical monitor. Events for which the investigator did not 
record relationship to study drug will be considered related to study drug for summary purposes. 
However, by-participant data listings will show the relationship as missing.
7.1.3.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs meet the 
definitions of SAEs that were specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with the SAEs captured and stored in the Gilead global safety 
database before data finalization.
For SAEs with multiple reports (initial reports and one or more follow-up reports), only the last 
report will be included in the summary tables and listings.
7.1.4.
Treatment-Emergent Adverse Events 
7.1.4.1.
Definition of Treatment-Emergent Adverse Events
For the DT group, treatment-emergent adverse events (TEAEs) are defined as the following:
•
Any AEs with an onset date on or after the randomization date and before participants’ BLV 
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•
Any AEs with an onset date on or after the randomization date, and prior to the Week 48 visit 
date, or up to study discontinuation date if the participant discontinued the study before the 
Week 48 visit
For the DT to BLV 10mg group, BLV 2mg and BLV 10mg, TEAEs are defined as 1 or both of 
the following:
•
Any AEs onset on or after the study drug start and no later than 30 days after permanent 
discontinuation of study drug
•
Any AEs leading to premature discontinuation of study drug
For delayed treatment participants who switched to BLV 10mg, TEAEs with onset prior to the 
first dose of BLV will be allocated to the DT group. TEAEs onset on or after the first dose of 
BLV will be allocated to the DT to BLV 10mg group.
For BLV 2mg and BLV 10mg, TEAE onset prior to the Week 48 visit will be allocated to the 
baseline to Week 48 visit. 
7.1.4.2.
Incomplete Dates
If the onset or end date of an AE is fully or partially unknown, the incomplete date will be 
imputed before analysis according to the rules in Appendix 3.
7.1.5.
Summaries of Adverse Events and Deaths
TEAEs will be summarized based on the Safety Analysis Set and repeated for the following 
categories. The AEs will be allocated to time periods based on AE onset dates.
•
TEAE prior to Week 48 visit for all groups
•
TEAE by Week 144 for the Group B and Group C
•
TEAE from Week 48 to Week 144 for the DT to BLV 10mg group
7.1.5.1.
Summaries of AE incidence in Combined Severity Grade Subsets 
A brief, high-level summary of the number and percentage of participants who experienced at 
least 1 TEAE in the categories described below will be provided by treatment group. All deaths 
observed in the study will also be included in this summary.
The number and percentage of participants who experienced at least 1 TEAE will be provided 
and summarized by SOC, PT, and treatment group for the AE categories described below:
•
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•
TEAEs with Grade 3 or higher 
•
TEAEs with Grade 2 or higher
•
TE treatment-related AEs
•
TE treatment-related AEs with Grade 3 or higher 
•
TE treatment-related AEs with Grade 2 or higher
•
TE SAEs
•
TE treatment-related SAEs 
•
TEAEs leading to premature discontinuation of study drug
•
TEAEs leading to death (ie, outcome of death)
Multiple events will be counted only once per participant in each summary. Adverse events will 
be summarized and listed first in alphabetic order of SOC, and then by PT in descending order of 
BLV 2mg frequency within each SOC. For summaries by severity grade, the most severe grade 
will be used for those AEs that occurred more than once in an individual participant during the 
study. 
In addition to the above summary tables, all TEAEs, TEAEs with Grade 3 or higher, TEAEs 
occurring in ≥ 10% of participants of any treatment group, TE SAEs, TE treatment-related AEs, 
and TE treatment-related SAEs will be summarized by PT only, in descending order of BLV 
2mg frequency.
In addition, data listings will be provided for the following:
•
All AEs, indicating whether the event is treatment emergent
•
All SAEs
•
All Deaths
•
All AEs with severity of Grade 3 or higher
•
All AEs with severity of Grade 2 or higher
•
All AEs leading to premature discontinuation of study drug 


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7.1.6.
Additional Analysis of Adverse Events
7.1.6.1.
Hepatic Adverse Events
Hepatic AEs potentially indicative of hepatitis flare will be identified using MedDRA v26.0 
search terms. The number and percentage of participants who experienced any TE hepatic AE 
will be summarized by PT and treatment group. In addition, the hepatic AEs will be summarized 
as follows: from baseline to prior to Week 48 visit date for DT group, Group B and Group C, 
from baseline up to Week 144 for Group B and Group C, and from Week 48 to Week 144 for the 
DT to BLV 10mg group. The by-participant listing of hepatic AEs will also be provided.
7.1.6.2.
Subgroup Analyses of Adverse Events
Treatment-emergent AEs by anti-drug antibody (ADA) incidence at Week 144 will be provided 
by PT and treatment group: 
•
For Group B and Group C, TEAEs from baseline to Week 144 will be summarized by 
treatment and ADA incidence at Week 144. 
•
For DT to BLV 10mg, TEAEs from Week 48 visit to Week 144 will be summarized by ADA 
incidence at Week 144. The ADA incidence will be derived using ADA data prior to the first 
dose of BLV at the Week 48 visit as baseline and ADA data after participants receive BLV 
as postbaseline assessments.
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. All available data at the time of the database snapshot for 
participants who were ongoing at the time of an interim analysis. When values are below the 
LOQ, they will be listed as such, and the imputed value will be used for the purpose of 
calculating summary statistics as specified in Section 3.7. 
The summary of laboratory evaluation will be provided by:
•
Prior to Week 48 visit for DT group, Group B and Group C
•
Up to Week 144 for Group B and C
•
From Week 48 to Week 144 for DT to BLV 10mg
For DT to BLV 10mg grouping, a baseline laboratory value will be defined as the last 
measurement obtained on or prior to the first dose of BLV at Week 48 visit.
A by-participant listing for laboratory test results will be provided by participant ID number and 
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urinalysis separately. Values falling outside of the relevant reference range and/or having a 
severity grade of 1 or higher on the CTCAE severity grade will be flagged in the data listings, as 
appropriate. No formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics of baseline values, values at each postbaseline visit, change and percentage 
change from baseline at each postbaseline visit will be provided by treatment group for the 
following laboratory tests. White blood cell differential results from manual assay will not be 
included as they are not considered valid.
•
Hematology 
Haematocrit (%)
Haemoglobin (g/dL)
Platelet Count (×109/L)
Reticulocytes (ppth)
Red Blood Cells (×1012/L)
White Blood Cells (×109/L)
Absolute Neutrophils (×109/L)
Relative Neutrophils (%)
Absolute Eosinophils (×109/L)
Relative Eosinophils (%)
Absolute Basophils (×109/L)
Relative Basophils (%)
Absolute Monocytes (×109/L)
Relative Monocytes (%)
Absolute Lymphocytes (×109/L)
Relative Lymphocytes (%)
•
Total Bile Salts (μmol/L)


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•
Coagulogram
Prothrombin Time (%)
Activated Partial Thromboplastin Time (aPTT) (sec)
International Normalized Ratio (INR)
•
Chemistry
Albumin (g/L) 
ALP (U/L)
AST (U/L) 
Total Bilirubin (μmol/L) 
Direct Bilirubin (μmol/L) 
C-Reactive Protein 
Chloride (mmol/L) 
Total Cholesterol (mmol/L) 
Creatinine (μmol/L) 
GGT (U/L) 
Glucose (mmol/L) 
Lipase (U/L) 
Total Amylase (U/L) 
Pancreatic Amylase (U/L)
Phosphate (mmol/L) 
Potassium (mmol/L) 
Total Protein (g/L) 
Sodium (mmol/L) 


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Urea (mmol/L) 
•
Urinalysis
pH
Specific Gravity (g/L)
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
first dose of BLV or to the randomization for the DT group. Change from baseline to a 
postbaseline visit will be defined as the visit value minus the baseline value. The mean, median, 
Q1, Q3, minimum, and maximum values will be displayed to the reported number of digits; SD 
values will be displayed to the reported number of digits plus 1.
Median (Q1, Q3) of the observed values for these laboratory tests may be plotted using a line 
plot by treatment group and visit.
7.2.2.
Summaries of Qualitative Laboratory Results
The summary of clinical assessment of laboratory variables (abnormal high CS, abnormal high 
NCS, normal, abnormal low NCS, abnormal low CS) will be provided by visit and treatment 
group for laboratory tests listed in Section 7.2.1 as well as for urinalysis of protein, glucose, 
bilirubin, urobilinogen, ketones, erythrocytes, leukocytes, and nitrites.
7.2.3.
Graded Laboratory Values
The CTCAE Version 5.0 will be used to assign toxicity grades (0 to 4) to laboratory results for 
analysis. Grade 0 includes all values that do not meet the criteria for an abnormality of at least 
Grade 1. For laboratory tests with criteria for both increased and decreased levels, analyses for 
each direction (ie, increased, decreased) will be presented separately. 
7.2.3.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of BLV plus 30 days, or from randomization up to prior to the first dose of BLV or ET 
before Week 48 visit for DT group. If the relevant baseline laboratory value is missing, any 
abnormality of at least Grade 1 observed within the time frame specified above will be 
considered treatment emergent.
7.2.3.2.
Summaries of Laboratory Abnormalities
The following summaries (number and percentage of participants) for treatment-emergent 
laboratory abnormalities will be provided by lab test and treatment group; participants will be 
categorized according to the most severe postbaseline abnormality grade for a given lab test:


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•
Graded laboratory abnormalities
•
Grade 3 or 4 laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of participants 
with non-missing postbaseline values up to 30 days after last dosing date, or prior to the first 
dose of BLV or up to ET before Week 48 visit for DT group.
A by-participant listing of treatment-emergent laboratory abnormalities will be provided by 
participant ID number and visit in chronological order. This listing will include all test results 
that were collected throughout the study for the lab test of interest, with all applicable severity 
grades or abnormal flags displayed. In addition, the listing of treatment-emergent Grade 3 or 4 
laboratory abnormalities will also be provided.
7.2.3.3.
Potential Drug Induced Liver Injury (DILI)
The participants who meet any one of the following criteria for potential drug induced liver 
injury (DILI) at on-treatment visits will be summarized by treatment, and the corresponding 
listing will be provided:
•
Criteria 1: ALT and/or AST > 3×ULN and total bilirubin > 2×ULN
•
Criteria 2: ALT > 5×ULN
•
Criteria 3: Total bilirubin > 2×ULN
7.2.4.
Shifts Relative to the Baseline Value
Shift tables will be presented by showing changes in results from baseline value (abnormal high 
CS, abnormal high NCS, normal, abnormal low NCS, abnormal low CS) to Weeks 48, 96 and 
144 for laboratory tests listed in Section7.2.1 and 7.2.2. The number and percentage of 
participants in each cross-classification group of the shift table will be presented. Participants 
with a missing value at baseline or postbaseline will not be included in the denominator for 
percentage calculation.
7.3.
Body Weight and Vital Signs
Descriptive statistics will be provided by treatment group for body weight, and vital signs 
(systolic and diastolic blood pressures [mmHg], respiratory rate [breaths/min] and body 
temperature [C]) as follows:
•
Baseline value
•
Values at each postbaseline visit


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•
Change from baseline at each postbaseline visit
A baseline value will be defined as the last available value collected on or prior to the date/time 
of the first dose of study drug. Change from baseline to a postbaseline visit will be defined as the 
postbaseline value minus the baseline value. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No formal statistical testing is planned.
A by-participant listing of vital signs will be provided by participant ID number and visit in 
chronological order. Body weight will be included in the vital signs listing, if space permits. If 
not, they will be provided separately.
7.4.
Physical Examination
For each type of local reaction at injection site, the number and percentage of participants with at 
least one instance reported as an AE will be summarized by severity and treatment, and the 
maximum severity grade of the reaction type will be presented. In addition, a by-participant 
listing will be provided for local reaction at injection site.
7.5.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the World Health 
Organization (WHO) Drug dictionary.
7.5.1.
Prior and Concomitant Medications
Prior medications are defined as medications stopped prior to the first dose date of BLV (for 
Groups B, C, and DT to BLV 10mg group) or prior to randomization date for the DT group. For 
Group B, C, and DT to BLV 10mg group, concomitant medications are defined as ongoing 
medications or medications stopped on or after the first dose date of BLV, excluding medications 
started after the last dose date of BLV. For the DT group, concomitant medications are defined 
as ongoing medications or medications stopped on or after the date of randomization, excluding 
medications started on or after the first dose date of BLV.
If the medication start or stop date is partially unknown, the incomplete date will be imputed 
according to the rules in the Table 7-1. If a medication cannot be classified using the reported 
and/or imputed start and end dates, it will be considered as concomitant medication. The original 
reported dates will be presented in data listings.
Table 7-1.
Imputed Partial Medication Dates
Scenario
Imputed Start Date
Imputed End Date
Unknown year
Missing
Missing


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Scenario
Imputed Start Date
Imputed End Date
Unknown month
01 January
31 December
Unknown day
First day of month
Last day of month
Prior medications and concomitant medications will be summarized by therapeutic subgroup and 
preferred name using the number and percentage of participants for each treatment group and 
overall. A participant reporting the same medication more than once will be counted only once 
when calculating the number and percentage of participants who received that medication. The 
summary will be ordered by preferred term in order of descending overall frequency. For drugs 
with the same frequency, sorting will be done alphabetically.
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned. In 
addition, by-participant listings will be provided.
7.5.2.
HBV Medications
HBV medications are defined as oral medications with preferred names containing any of the 
following terms: tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, tenofovir 
disoproxil, entecavir, adefovir, adefovir dipivoxil, lamivudine, telbivudine.
The following HBV medications summaries will be provided by preferred name using the 
number and percentage of participants for each treatment group and overall; in addition, the 
corresponding listings will be generated:
•
Participants with concomitant HBV medications
•
HBV medications started before baseline and ongoing during treatment: participants with any 
HBV medication started prior to the first dose date of BLV or before randomization date for 
Group A DT group, and any concomitant HBV medication (same as or different from the 
previous one[s]) ongoing on/after the first dose date of BLV (randomization date for the DT 
group)
•
Participants with prior HBV medications (stopped before baseline): participants with all 
HBV medications stopped before the first dose date of BLV or before randomization date for 
the DT group
•
HBV medications started on-treatment: participants with all HBV medications started 
on/after the first dose date of BLV (randomization date for the DT group) and on/before the 
last dose date of BLV (before the first dose of BLV or until ET before Week 48 visit for the 
DT group)
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.


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


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8.
IMMUNOGENICITY ANALYSES
8.1.
ADA Incidence and Prevalence
The evaluable population for ADA prevalence is participants with at least one non-missing ADA 
data at any visit, including the baseline. The evaluable population for ADA incidence is 
participants with at least one non-missing ADA data at postbaseline visits.
•
ADA prevalence: participants with positive ADA at any visit including the baseline will be 
considered ADA positive. Otherwise, participants will be considered ADA negative.
•
ADA incidence: defined in Table 8-1
Table 8-1.
Definition of ADA Incidence
Baseline ADA
Postbaseline ADA
ADA Incidence
Negative/Missing
Positive (any visit)
Positive
Positive/Negative/Missing 
Negative (all visits)
Negative
Positive
Positive (any visit)
Negative
The number and percentage of ADA prevalence and incidence at Weeks 48 and 144 will be 
summarized by treatment group. The corresponding listing will also be provided.


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


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


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•
Relative expression level of MX1 mRNA
•
Relative expression level of OAS mRNA
•
Relative expression level of HLA-E mRNA
•
Relative expression level of TAP1 mRNA
•
Relative expression level of USP18 mRNA
•
Relative expression level of CXCL11 mRNA
•
Relative expression level of CXCL9 mRNA
•
Relative expression level of CXCR3 mRNA
•
Relative expression level of CCL5 mRNA
•
Relative expression level of CXCL8 mRNA
•
Relative expression level of IL18 mRNA
•
Relative expression level of TGFB1 mRNA
For the following parameters only the by-participant listings will be provided:
•
Molecular analysis: DNA content (ng/μL), RNA content (ng/μL), Beta globin (copies), 
cccDNA (copies/cell).
•
Gene expression: GAPDH CT, RPL30CT, SERPINA1 mRNA CT


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


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12.
APPENDICES
Appendix 1. Sample SAS Code 
The following statement will be used to construct the confidence interval for the binomial 
proportions described in Section 6:
proc freq data = final;
    table trtp*aval/riskdiff (cl=exact) fisher alpha=0.0x;
    exact riskdiff;
    where trtp = "Arm X" | trtp = "Arm Y";
run;
For combined reponse and undetectable HDV RNA, alpha=0.01 at Week 24 and alpha=0.04 at 
Week 48. Otherwise, alpha=0.05.
proc freq data = final;
     by trtp;
     table aval/bnomial;
     exact binomial;
run;
The following statement will be used to construct ANCOVA described in Section 6:
proc mixed data = final; 
    class usubjid trtp region;
    model chg = base region strata trtp /ddfm=kr;
    lsmeans trtp /diff cl alpha=0.05;
run;
The following statement will be used to construct MMRM model described in Section 6:
proc mixed data = final;
    class usubjid trtp avisit region strata;
    model chg = base region strata trtp avisit trtp*avisit/ddfm = kr;
    repeated avisit/subject=usubjid type=un;
    lsmeans trtp*avisit/diff cl;
run;


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Appendix 2. Schedule of Assessments
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


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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
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
Quality of life questionnaires (EQ-
5D, FSS, HQLQ™)
X
X (W24, 
W40 only)
X
X (W72, W96 
only)
X
X (W192 only)
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 
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
only)


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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
Coagulogram 16
X
X 6
X (W8, 
W24, W40 
only)
X
X (W64, W80, 
W96, W108, 
W120, W132 
only)
X
X (W168, W192, 
and W216 only)
X
Total blood bile salts
X
X
X
X
X
X
X
X
Alpha-fetoprotein test
X
Vitamin D
X
X (W24 
only)
X
X (W72, W96, 
W120 only)
X
X (W168 and 
W192 only)
X
HBV DNA for pts. not receiving 
nucleoside/nucleotide analogues 
X
Serum alpha-2-macroglobulin
X
X
X (W96 only)
X
X (W168 and 
W192 only)
X
ANALYSIS PERFORMED IN CENTRAL VIROLOGY LABORATORY/SAMPLES TO BE SENT TO CENTRAL LABORATORY AT ONCE
HDV RNA
X
ANALYSIS PERFORMED IN CENTRAL VIROLOGY LABORATORY/SAMPLES TO BE STORED AT SITE
HDV genotyping
X
HDV RNA 
X
X
X
X
X
X
X
X
HBV DNA (HBV genotyping at 
first positive HBV DNA) 
X
X
X
X
X
X
X
X
HBsAg 
X
X
X
X
X
X
X
X
HBsAg antibodies 17
X
X (W24 
only)
X
X (W96 only)
X
X (W168 only)
X
HBeAg and HBeAg antibodies 18
X
X
X (W96 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
Immunogenicity (bulevirtide 
antibodies) 19
X
X (W16, 
W24 only)
X
X (W64, W72, 
W96, W120 only)
X
X (W168)
X
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 the protocol.
2.
Signed and dated informed consent must be obtained before any procedure specific to the 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. 


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8.
Vital signs include body temperature, heart rate, and blood pressure. 
9.
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 and assessment of adverse events, sample collection for pharmacokinetics) and confirmation of participant’s eligibility.
10. Patients should be instructed NOT to administer study drug at home at days of visits to study sites. At these days study drug is administered at study site in accordance with 
schedule of events for assessment of immunogenicity and pharmacokinetics of the study drug. 
11. Only for women of childbearing potential.
12. Urinalysis is not needed at V2 (W4), V9 (W52), and FU 3 (W168), and FU 3.1 (W180).
13. Hematology includes hemoglobin, hematocrit, reticulocytes, RBC, platelet count, WBC with differential (absolute counts and percentage for neutrophils, eosinophils, 
basophils, monocytes, and lymphocytes).
14. 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. Full 
biochemistry includes total protein, albumin, ALT [this sample will be used to obtain ALT results for efficacy assessment as described in Section 6.5.4], AST, GGT, 
P-amylase, alkaline phosphatase, lipase, total bilirubin, direct bilirubin, total cholesterol, creatinine, urea, glucose, potassium, sodium, chloride, phosphorus, and CRP. 
15. 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:includes albumin, ALT [this sample will be used to obtain ALT results for efficacy assessment as described in Section 6.5.4], AST, GGT, 
total bilirubin, direct bilirubin, creatinine, lipase, P-amylase, CRP. 
16. Coagulogram includes prothrombin time, international normalized ratio, and activated partial thromboplastin time.
17. Collection of anti-HBsAg samples at designated time points; testing only if HBsAg becomes undetectable.
18. Collection and testing of HBeAg and HBeAg antibodies only if patient is HBeAg positive at SCR.
19. Samples for immunogenicity assessment should be taken before administration of the study drug, during first 48 weeks immunogenicity samples are taken only for Arms B 
and C.
20. Blood samples for determination of NTCP polymorphism are collected at Day 1 for all the patients. NTCP polymorphism will be performed in central laboratory as detailed 
in Section 6.4.4 of the protocol.
21. Dedicated samples for phenotypic assay are collected only at Day 1. For other resistance tests (HBV genome sequencing and HDV genome sequencing) and phenotypic assay 
at the other time points back-up virology samples are used. Full resistance tests are performed as detailed in Section 6.4.4 of the protocol.
22. During first 48 weeks pharmacokinetics samples are taken only for Arms B and C. One sample at each visit 1 hour ± 15 minutes post bulevirtide dose.
23. At Screening liver biopsy is performed after confirmation of eligibility. If a liver biopsy was performed within 1 year prior to Screening, and a patient can provide biopsy 
records and appropriate biopsy specimens, the available specimens can be used for the baseline evaluation and biopsy at Screening is not required. Otherwise, liver biopsy at 
screening is performed if feasible provided that patient is considered to be eligible after the review of all eligibility criteria. 
24. Liver biopsy should be performed within ± 7 days from the date of the visit for patients who do not have medical contraindications for the procedure. If baseline liver biopsy 
samples are not available (were not provided to central laboratory or were considered as non-evaluable by central laboratory) subsequent liver biopsy should not be 
performed.
25. Optional Liver biopsy should be performed at W192, or (if not possible at W192) at W216 in patients who previously had a baseline liver biopsy and who have provided their 
separate and specific consent.


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Appendix 3. Imputation of incomplete AE start or end date
1
For Group B and Group C
1.1
to impute partial AE date if year and month are available:
Imputed start date
Imputed end date
If AE year/month same as 1st dose 
year/month
Same as 1st dose date or AE 
end date whichever comes 
first.
Last of the month
If AE year/month before 1st dose 
year/month
First of the month
Last of the month
If AE year/month after 1st dose 
year/month
First of the month
Last of the month
1.2
to impute partial AE date if only year is available:
Imputed start month/date
Imputed end 
month/date
If AE year same as 1st dose year
Same as 1st dose month/date 
or AE end month/date 
whichever comes first
December 31
If AE year before 1st dose year
January 1
December 31
If AE year after 1st dose year
January 1
December 31
1.3
to impute partial AE start date if neither year nor month is available:
Imputed AE start 
year/month/date
If AE end date is before 1st dose date 
AE end date
If AE end date is at/after 1st dose date 
Same as 1st dose date 
1.4
to impute partial AE end date if neither year nor month is available:
Impute the missing AE end date using the last visit date in database for this participant, or AE 
start date, whichever comes last.


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2
For Arm A (i.e., delayed treatment)
2.1
to impute partial AE date if year and month are available:
Imputed start date
Imputed end date
If AE year/month before randomization 
year/month
First of the month
Last of the month
If AE year/month same as randomization 
year/month
Same as randomization date or 
AE end date whichever comes 
first.
Last of the month
If AE year/month after randomization 
year/month but before 1st BLV dose 
year/month 
First of the month
Last of the month
If AE year/month at 1st BLV dose 
year/month
1) if Relationship to 
bulevirtide=’not applicable 
(bulevirtide not administred)’, 
then first of the month
2) if Relationship to bulevirtide 
not equal to ’not applicable 
(bulevirtide not administred)’, 
then same as 1st BLV dose date 
or AE end date whichever 
comes first.
Last of the month
If AE year/month after 1st BLV dose 
year/month
First of the month
Last of the month
2.2
to impute partial AE date if only year is available:
Imputed start month/date
Imputed end 
month/date
If AE year before randomization 
year
January 1
December 31
If AE year same as randomization 
year and before 1st BLV dose year 
(randomization year < 1st BLV 
year)
Same as randomization month/date or AE end 
month/date whichever comes first
December 31
If AE year same as 1st BLV dose 
year (randomization year = 1st BLV 
year)
1) if Relationship to bulevirtide=’not 
applicable (bulevirtide not administred)’, then 
same as randomization month/date or AE end 
month/date whichever comes first.
2) if Relationship to bulevirtide not equal to 
’not applicable (bulevirtide not administred)’, 
then same as 1st BLV dose month/date or AE 
end month/date whichever comes first.
December 31


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GILEAD CONFIDENTIAL INFORMATION
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If AE year same as 1st BLV dose 
year (randomization year < 1st BLV 
year)
1) if Relationship to bulevirtide=’not 
applicable (bulevirtide not administred)’, then 
January 1.
2) if Relationship to bulevirtide not equal to 
’not applicable (bulevirtide not administred)’, 
then same as 1st BLV dose month/date or AE 
end month/date whichever comes first.
December 31
If AE year after 1st BLV dose year
January 1
December 31
2.3
to impute partial AE start date if neither year nor month is available:
Imputed AE start year/month/date
If AE end date is before randomization 
date  
AE end date.
If AE end date is at/after 
randomization date but before 1st BLV 
dose date 
Same as randomization date 
If AE end date is at/after 1st BLV dose 
date 
if Relationship to bulevirtide=’not applicable 
(bulevirtide not administered)’, then same as 
Randomization date.
2) if Relationship to bulevirtide not equal to 
’not applicable (bulevirtide not administered)’, 
then same as 1st BLV dose date.
2.4
to impute partial AE end date if neither year nor month is available: 
Impute the missing AE end date using the last visit date in database for this participant, or AE 
start date, whichever comes last.


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GILEAD CONFIDENTIAL INFORMATION
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Appendix 4. Version History
Version
Date
Description of Changes
1.0
06 June, 2023
Week 144 Final 1.0 corresponding to 
database lock on 8 June 2023.
2.0
21 June, 2023
Added biopsy analysis in Section 6.4.2 
and 10.2 corresponding to database lock 
expected on 30 June 2023 to include 
biopsy data.
Corrected the typo of 48 to 144 in Section 
4.2.2.


MYR301 W144 SAP v2.0
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Dmitry Manuilov
Clinical Development
eSigned
26-Jun-2023
22:47:37
YaPei Liu03
Biostatistics eSigned
26-Jun-2023
22:50:19

SAP_006.pdf: 
  
STATISTICAL ANALYSIS PLAN
Study Title:
A Multicenter, Open-label, Randomized Phase 3 Clinical 
Study to Assess Efficacy and Safety of Bulevirtide in 
Patients with Chronic Hepatitis Delta
Name of Test Drug:
Bulevirtide (BLV)
Study Number:
MYR301
Protocol Version (Date):
Version 7.0 dated 25 January 2023
Analysis Type:
Final (Week 240) Adverse Events of Interest Analysis
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
15 November 2024
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(rJ GILEAU 


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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................2
LIST OF ABBREVIATIONS.........................................................................................................................................3
1.
INTRODUCTION..................................................................................................................................................4
1.1.
Study MYR301..........................................................................................................................................4
2.
GENERAL CONSIDERATIONS FOR DATA ANALYSES...............................................................................5
2.1.
Analysis Sets .............................................................................................................................................5
2.1.1.
Safety Analysis Set..................................................................................................................5
2.1.2.
Posttreatment Safety Analysis Set...........................................................................................5
2.2.
Participant Grouping and Presentation......................................................................................................5
3.
EVALUATION OF ADVERSE EVENTS OF INTEREST ..................................................................................7
3.1.
Hepatic Adverse Events ............................................................................................................................7
3.2.
Other Adverse Events of Interest ..............................................................................................................7
3.2.1.
Designated Medical Events (DMEs).......................................................................................7
3.2.2.
Injection Site Reactions...........................................................................................................7
3.2.3.
Gallstone and Gallbladder Disorders.......................................................................................8
3.2.4.
Hypersensitivity.......................................................................................................................8
3.2.5.
Sex Hormone Disorders ..........................................................................................................8
3.2.6.
Lipid Metabolism Disorders....................................................................................................8
3.2.7.
Bone Events or Loss of Bone Density.....................................................................................8
3.2.8.
Eosinophilia or Eosinophil Count Increase .............................................................................8
3.2.9.
Vitamin D Deficiency..............................................................................................................9
3.2.10.
Renal Safety...........................................................................................................................10
3.2.11.
Cardiac Disorders ..................................................................................................................10
3.2.12.
Skin and Subcutaneous Disorders .........................................................................................10
3.2.13.
Laboratory Related Adverse Events......................................................................................10
3.3.
Other Analyses ........................................................................................................................................11


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LIST OF ABBREVIATIONS
AASLD
American Association for the Study of Liver Diseases
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BLV
bulevirtide 
CHD
chronic hepatitis delta
CM
concomitant medication
CTCAE
Common Terminology Criteria for Adverse Events
DILI
drug induced liver injury
DME
designated medical events
DT
delayed treatment
ECG
electrocardiogram
EOS
eosinophil
HDV
hepatitis D virus
HLGT
high-level group term
HLT
high-level term
HSAC
Hepatic Safety Adjudication Committee
ID
identification
INR
international normalized ratio 
LLN
lower limit of normal
LLOQ
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MST
MedDRA search term
PT
preferred term
Q1
first quartile
Q3
third quartile
SAP
statistical analysis plan 
SD
standard deviation 
SMQ
standardized MedDRA query
SOC
system organ class
TEAE
treatment-emergent adverse event
ULN
upper limit of normal


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in the Study MYR301 Final (Week 240) summary of adverse events of 
interest (AOIs). The safety data collected throughout the study will be included in the analysis. 
Unless otherwise specified, the same methods used for the analyses of safety specified in the 
MYR301 Final (Week 240) study SAP and/or protocol will be applied to the analysis of AOIs.
1.1.
Study MYR301
This is a randomized, open-label, parallel group, multicenter Phase 3 study to evaluate the 
efficacy and safety of bulevirtide (BLV) in participants with chronic hepatitis delta (CHD) with 
or without compensated cirrhosis who have no adequate treatment options.
A total of 150 participants were randomized in a 1:1:1 ratio, with stratification by presence of 
liver cirrhosis (yes, no) to 3 treatment arms and treated as follows:
•
Arm A (N = 51): Delayed treatment with BLV 10 mg/day for 96 weeks after an observational 
period of 48 weeks and with a further follow-up period of 96 weeks
•
Arm B (N = 49): BLV 2 mg/day for 144 weeks with a further follow-up period of 96 weeks
•
Arm C (N = 50): BLV 10 mg/day for 144 weeks with a further follow-up period of 96 weeks


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2.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of participants in each category will be presented; for continuous 
variables, the number of participants (n), mean, standard deviation (SD), median, first quartile 
(Q1), third quartile (Q3), minimum, and maximum will be presented.
By-participant listings will be presented for all participants in the Safety Analysis Set and sorted 
by participant identification (ID) number, visit date, and time (if applicable). Data collected on 
log forms, such as adverse events (AEs), will be presented in chronological order for each 
participant. The treatment group to which participants were randomized will be used in the 
listings. Age, sex at birth, and race will be included in the listings, as space permits.
2.1.
Analysis Sets
2.1.1.
Safety Analysis Set
The Safety Analysis Set includes all participants who were randomized into the study and took at 
least 1 dose of BLV study drug, or who were randomized to the delayed treatment group. The 
Safety Analysis Set will be used for all AEs of interest analyses (excluding those analyses that 
present data collected only during the posttreatment period).
2.1.2.
Posttreatment Safety Analysis Set
The Posttreatment Safety Analysis Set includes participants in the Safety Analysis Set who have 
at least 1 non-missing study assessment (eg, AE onset date, CM start date, laboratory collection, 
vital sign assessment, ECG assessment, physical exam, pregnancy, or death) performed after last 
BLV dose. This is the primary analysis set for safety displays during only the posttreatment 
period.
2.2.
Participant Grouping and Presentation
Participants will be grouped according to the actual treatment received. The actual treatment 
received is defined as the randomized treatment except for participants who received treatment 
that differs from the randomized treatment for the entire treatment duration.
Group A
•
Delayed Treatment (DT) (Baseline up to Week 48): includes AEs with onset date on or after 
randomization date and onset date/time prior to the first dose of BLV. The last laboratory 
value with a collection date on or prior to the randomization date is the baseline value; 
postbaseline laboratory collections (DT group) will be those with laboratory collection dates 
after randomization date and prior to the first dose date/time of BLV. For participants who 
prematurely discontinue from study prior to Week 48, events will be included up to early 
discontinuation from study if not receiving BLV (N = 51)


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•
DT to BLV 10 mg (Overall BLV treatment period): includes AEs with an onset date/time on 
or after the first dose date/time of BLV and up to the last dose date of BLV. The last 
laboratory value with collection date/time on or prior to first BLV dose date/time is assigned 
to the baseline laboratory value (ie, baseline is reset); postbaseline “on-treatment” laboratory 
collections after first BLV dose date/time and up to last dose date of BLV will be included. 
(N = 50, 1 participant from DT group terminated early before Week 48 visit).
•
DT to BLV 10 mg (Posttreatment period): includes AEs with an onset date after the last dose 
date of BLV and laboratory values with a collection date after the last dose date of BLV.
Groups B and C (groups are displayed separately)
•
Group B and C (BLV treatment period [Baseline up to Week 48]): event meets criteria for 
overall BLV treatment period (see next bullet) and AE onset is prior to Week 48 visit 
(laboratory collection is at or prior to Week 48) or participant discontinued study drug at or 
prior to Week 48. If the Week 48 visit is missing, AEs with onset prior to Study Day 338 
(48x7 + 2 days) are included. For lab data, the last analysis visit on/prior to Week 48 is 
selected [if visit is “not windowed” then the last value on/prior to Day 338 is selected].
•
Group B and C (Overall BLV treatment period): includes AEs with onset date/time on or 
after first dose date/time of BLV and up to last dose of BLV. The last laboratory value with 
collection date/time on or prior to BLV first dose date/time will be the baseline value; 
laboratory values with date/time of collection after first dose date/time of BLV and collection 
date up to last dose date of BLV) will be “on-treatment” values.
•
Group B and C (Posttreatment period): includes AEs with an onset date after the last dose 
date of BLV, and laboratory values collected after the last dose date of BLV.
In the above descriptions, if both the event date and time and BLV dosing date and time are used 
to determine the assigned treatment period and either of the 2 times is not available, then only 
event date and BLV dosing date will be compared to determine the assigned treatment period.
On-treatment and posttreatment data will be summarized on 2 separate tables for AOIs (where 
applicable). On-treatment displays will present data up to Week 48 (for comparison to control 
[DT group] through Week 48); and for all data collected while on BLV treatment (Weeks 0-144 
for Groups B and C; Weeks 48-144 for DT to BLV 10 mg group for those dosed per protocol). 
On-treatment data will be summarized for the Safety Analysis Set; posttreatment data (for BLV 2 
mg, BLV 10 mg, and DT to BLV 10 mg groups) will be summarized for the Posttreatment 
Safety Analysis Set.
Cumulative summaries displayed by visit will use the analysis visit windows as specified in 
Section 3.8.2 of the study SAP to assign data to analysis visits. For the DT group, baseline will 
be the last value on or prior to randomization. For DT to BLV 10 mg group, baseline will be 
reset as the last non-missing value on or prior to first dose of BLV.


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3.
EVALUATION OF ADVERSE EVENTS OF INTEREST
Adverse events of interest reported while the participant was on-treatment will be summarized 
for the following time periods. The AEs will be allocated to time periods based on AE onset (see 
Section 2.2 of this SAP).
•
TEAEs prior to Week 48 visit for all groups
•
TEAEs through Week 144 for Groups B and C
•
TEAEs from Week 48 to Week 144 for the DT to BLV 10 mg group
3.1.
Hepatic Adverse Events
All participants with hepatic AEs reported while the participant was on-treatment per Hepatic 
Safety Adjudication Committee (HSAC) criteria will be summarized by time period, treatment, 
and preferred term (PT). In addition, a data listing will be provided. The hepatic AEs per HSAC 
are defined as severe (CTCAE severity grade = 3, 4 or 5) events with:
•
MedDRA System Organ Class (SOC) equals “Hepatobiliary disorders”,  OR
•
MedDRA high-level group term (HLGT) equals “Hepatobiliary investigations”.
3.2.
Other Adverse Events of Interest
3.2.1.
Designated Medical Events (DMEs)
The TEAEs of designated medical events (DMEs) while on treatment will be summarized by 
time period, treatment, and PT. In addition, the corresponding data listing will be provided.
3.2.2.
Injection Site Reactions
The participants with TEAEs of injection site reactions (High-Level Term (HLT) = “Injection 
site reactions”) while on BLV treatment will be summarized by treatment (BLV 2 mg, BLV 
10 mg, and DT to BLV 10 mg) and PT, and the corresponding listings will be provided.
In addition, the by-treatment (BLV 2 mg, BLV 10 mg, and DT to BLV 10 mg) summary tables 
and corresponding listings will be provided for participants experiencing TEAEs of injection site 
reactions while on BLV treatment with the concurrent events listed below:
•
Concurrent AEs of eosinophilia or eosinophil (EOS) count increase (PT = “Eosinophilia” or 
“Eosinophil count increased”). Concurrence is defined as the onset of one event between 
1 week before the onset and 1 week after the end of the other event.
•
Concurrent absolute EOS > ULN while on-treatment. Concurrence is defined as any visit 
with absolute EOS > ULN with a laboratory collection date that was between 2 weeks before 
the onset and 2 weeks after the end of the injection site reaction event.


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•
Concurrent persistent absolute EOS increase (absolute EOS > ULN at ≥ 2 consecutive on-
treatment visits). If multiple consecutive EOS laboratory collections meet criteria, the 
“event” starts on the date of the first laboratory collection and ends on the date of the last 
consecutive laboratory collection meeting criteria. Concurrence is defined as the onset of one 
event between 2 weeks before the onset and 2 weeks after the end of the other event.
3.2.3.
Gallstone and Gallbladder Disorders
The participants with on-treatment TEAEs of gallstone related disorders (standardized MedDRA 
query [SMQ] narrow) and gallbladder related disorders (SMQ narrow) will be summarized by 
time period, treatment, and PT and the corresponding listing will be provided.
3.2.4.
Hypersensitivity
The participants with on-treatment TEAEs of hypersensitivity (SMQ narrow) will be 
summarized by time period, treatment, and PT and the corresponding listing will be provided.
3.2.5.
Sex Hormone Disorders
The participants with on-treatment TEAEs of sex hormone disorders (HLT = “Reproductive 
hormone analyses” or “Adrenal cortex tests”, or HLGT = “Endocrine disorders of gonadal 
function” or “Adrenal gland disorders”) will be summarized by time period, treatment, and PT 
and the corresponding listing will be provided.
3.2.6.
Lipid Metabolism Disorders
The participants with on-treatment TEAEs of lipid metabolism disorders (HLGT = “Lipid 
analyses” or “Lipid metabolism disorders”) will be summarized by time period, treatment, and 
PT, and the corresponding listing will be provided.
3.2.7.
Bone Events or Loss of Bone Density
The participants with on-treatment TEAEs of bone events or loss of bone density, based on a 
MedDRA search term (MST) list will be summarized by time period, treatment, and PT, and the 
corresponding listing will be provided.
3.2.8.
Eosinophilia or Eosinophil Count Increase
The participants with on-treatment TEAEs of eosinophilia or EOS count increase (PT = 
“Eosinophilia” or “Eosinophil count increased”) will be summarized by time period, treatment, 
and PT, and the corresponding listing will be provided.
For the subset of participants with absolute EOS > ULN while on-treatment, the on-treatment 
TEAEs will be summarized by time period, treatment, and PT, and the corresponding listing will 
be provided. A similar table and listing will also be provided for participants with persistent 
absolute EOS increase (absolute EOS > ULN at >= 2 consecutive on-treatment visits).


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By-treatment summary tables, and corresponding listings will be provided for the following 
conditions (excluding DT group), respectively:
•
Participants with on-treatment TEAE of hypersensitivity (defined in Section 3.2.4) and 
concurrent absolute EOS > ULN while on treatment. Concurrence is defined as any visit with 
absolute EOS > ULN between 2 weeks before the onset and 2 weeks after the end of the 
hypersensitivity event.
•
Participants with on-treatment TE hepatic AEs (identified using MST) and concurrent 
absolute EOS > ULN while on treatment. Concurrence is defined as any visit with absolute 
EOS > ULN that was between 2 weeks before the onset and 2 weeks after the end of the 
hepatic AE.
•
Participants with on-treatment potential hepatitis flare per AASLD criteria (ALT ≥ 3 × 
baseline and > 100 U/L) and concurrent (at the same visit) absolute EOS > ULN while on 
treatment.
•
Participants that meet on-treatment potential DILI criteria and with concurrent (at the same 
visit) absolute EOS > ULN while on-treatment.
•
Participants with on-treatment TEAE of hypersensitivity (defined in Section 3.2.4) and 
concurrent persistent absolute EOS increase (absolute EOS > ULN at ≥ 2 consecutive while 
on-treatment). Concurrence is defined as the onset of one event between 2 weeks before the 
onset and 2 weeks after the end of the other event.
•
Participants with on-treatment TE hepatic AEs (identified using MST) and concurrent 
persistent absolute EOS increase (absolute EOS > ULN at ≥ 2 consecutive visits while on 
treatment). Concurrence is defined as the onset of one event between 2 weeks before the 
onset and 2 weeks after the end of the other event.
•
Participants with on-treatment potential hepatitis flare per AASLD criteria (ALT ≥ 3 × 
baseline and > 100 U/L) and concurrent (at the same visit) persistent absolute EOS increase 
(absolute EOS > ULN at ≥ 2 consecutive visits while on treatment).
•
Participants that meet potential on-treatment DILI criteria and with concurrent (at the same 
visit) persistent absolute EOS increase (absolute EOS > ULN at ≥ 2 consecutive visits while 
on treatment).
3.2.9.
Vitamin D Deficiency
The number and proportion of participants with vitamin D deficiency (vitamin D < lower limit of 
normal [LLN]) will be summarized by treatment group and visit through the FU-96 visit (Week 
240 on study). For the subset of participants with vitamin D deficiency while on treatment, 
TEAEs by time period, treatment, and PT will be summarized in a table, and a corresponding 
listing will be provided.


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3.2.10.
Renal Safety
A listing of on-treatment AEs of renal and urinary disorders (SOC = “Renal and urinary 
disorders”) will be provided. In addition, on-treatment TEAEs will be summarized by time 
period, treatment, and PT for the subgroups of baseline creatinine clearance (≥ 60 to < 90 
mL/min vs. ≥ 90 mL/min). A similar summary of adverse events that were reported after the last 
dose of BLV study drug will be provided by treatment group (BLV 2 mg, BLV 10 mg, and DT 
to BLV 10 mg), and PT for the subgroups of BLV baseline creatinine clearance clearance (≥ 60 
to < 90 mL/min vs. ≥ 90 mL/min) for the Posttreatment Safety Analysis Set.
3.2.11.
Cardiac Disorders
The participants with on-treatment TEAEs of cardiac disorders (SOC = “Cardiac disorders”) will 
be summarized by time period, treatment, and PT and the corresponding listing will be provided.
For total bile salts (μmol/L) the baseline values, values at each postbaseline visit up to FU-96 
(Week 240 on study) and change from baseline at each postbaseline visit will be summarized by 
treatment and subgroup of on-treatment TEAEs of cardiac disorders (presence vs. absence). In 
addition, the summary of the maximum postbaseline change (this may be in either the + or – 
direction) from baseline in total bile salts (μmol/L) while on treatment will be provided by 
treatment and subgroup of on-treatment TEAEs of cardiac disorders (presence vs. absence).
3.2.12.
Skin and Subcutaneous Disorders
A listing of on-treatment TEAEs of skin and subcutaneous disorders (SOC = “Skin and 
subcutaneous tissue disorders”) will be provided.
The descriptive statistics of baseline values, values at each postbaseline visit up to FU-96 (Week 
240 on study) and change from baseline at each postbaseline visit for total bile salts by treatment 
and subgroup of on-treatment TEAEs of pruritus (PT= “Pruritus”; presence vs. absence) will be 
provided. The corresponding line plots of mean (± SD) and median (Q1, Q3) change in total bile 
salts by treatment and visit for pruritis (presence vs. absence) will also be presented for the BLV 
2 mg and BLV 10 mg groups.
3.2.13.
Laboratory Related Adverse Events
The number and proportion of participants with elevated on-treatment total bile salts (total bile 
salts > ULN) will be provided by treatment group (Group B, Group C and DT to BLV 10 mg) 
and visit.
The descriptive statistics of on-treatment total bile salts measurements (multiple records per 
participant) will be provided by time period and treatment (Week 0-48 and Week 0-144 for BLV 
2mg, BLV 10 mg, and BLV 2 mg + BLV 10 mg; and Week 48-144 for DT to BLV 10 mg 
group); and corresponding boxplots for BLV 2 mg and BLV 10 mg (Week 0-144) will be 
provided for the following subgroups (presence vs. absence), respectively:
•
On-treatment TEAEs of pruritus (PT= “Pruritus”)


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•
On-treatment TEAEs of skin and subcutaneous disorders (SOC = “Skin and subcutaneous 
tissue disorders”)
•
On-treatment TEAEs of eosinophilia or EOS count increase (PT = “Eosinophilia” or 
“Eosinophil count increased”)
•
On-treatment persistent absolute EOS increase (absolute EOS > ULN at >= 2 consecutive on-
treatment visits)
•
On-treatment TEAEs of cardiac disorders (SOC = “Cardiac disorders”)
•
On-treatment TEAE of bradycardia (PT= “Bradycardia” or “Sinus bradycardia”)
•
On-treatment Vitamin D deficiency (Vitamin D < LLN at any on-treatment visit)
•
On-treatment TEAEs of hypersensitivity (SMQ narrow)
•
On-treatment TEAEs of gallstone related disorders (SMQ narrow) and gallbladder related 
disorders (SMQ narrow)
•
On-treatment TEAEs of lipid metabolism disorders (HLGT = “Lipid analyses” or “Lipid 
metabolism disorders”)
•
On-treatment TEAEs of sex hormone disorders (HLT = “Reproductive hormone analyses” or 
“Adrenal cortex tests”, or HLGT = “Endocrine disorders of gonadal function” or “Adrenal 
gland disorders”)
•
On-treatment TEAE of bone events or loss of bone density (MST)
The descriptive statistics of total bile salts will be provided by treatment group, visit, and 
subgroup of baseline creatinine clearance (≥ 60 to < 90 mL/min vs. ≥ 90 mL/min) through FU-96 
(study Week 240), and the corresponding line plots of mean (± SD) and median (Q1, Q3) of total 
bile salts will be presented for the BLV 2 mg and BLV 10 mg groups.
3.3.
Other Analyses
Treatment-emergent AEs while on treatment will be summarized by time period, treatment, and 
PT at the maximum severity (for the PT). In addition, the TEAEs while on treatment will be 
summarized by time period, treatment, and PT for the subgroups of cirrhosis status (ie, 
stratification factor: presence vs. absence).
AEs with an onset date after last dose date of BLV study drug will be summarized by treatment 
groups (BLV 2 mg, BLV 10 mg, and DT to BLV 10 mg) and PT at the maximum severity (for 
the PT). In addition, the posttreatment AEs will be summarized by treatment group and PT for 
the subgroups of cirrhosis status (ie, stratification factor: presence vs. absence) for the same 
treatment groups during the posttreatment period. The Posttreatment Safety Analysis Set will be 
used to produce both posttreatment displays of adverse events.


MYR301 W240 AOI_SAP_v1.0
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Biostatistics eSigned
16-Nov-2024
20:00:48
Patient Safety eSigned
18-Nov-2024
16:39:40
Global Development
Lead (GDL) eSigned
20-Nov-2024
04:54:53
PPD
PPD
PPD

Prot_002.pdf: 
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.


Gilead Sciences, Inc.
PROTOCOL MYR301
Version 7.0 25 January 2023
CONFIDENTIAL
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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
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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.
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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 
cirrhosis, earlier onset of hepatic complications and likelihood of liver transplantation [17-19]. 


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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 
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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 
Abnormalities of the Guidance for Industry Toxicity Grading Scale for Healthy Adult and 


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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


Prot MYR301 amd-6
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Research eSigned 30-Jan-2023
17:28:17
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Prot_000.pdf: 
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 5.0 dated 25 April 2022
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.


Gilead Sciences, Inc.
PROTOCOL MYR301
Version 5.0 dated 25-Apr-2022
CONFIDENTIAL
Page 2 of 94
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....................................................................................................................................................................10
1.
INTRODUCTION................................................................................................................................................23
1.1.
Hepatitis Delta.........................................................................................................................................23
1.2.
Treatment Options for Hepatitis Delta ....................................................................................................24
1.3.
Background on Bulevirtide......................................................................................................................25
1.3.1.
Description of the Study Drug...............................................................................................25
1.3.2.
Summary of Clinical Data.....................................................................................................25
1.4.
Study Rationale .......................................................................................................................................34
1.4.1.
Rationale for Patient Population............................................................................................35
1.4.2.
Rationale for Selection of the Dose of the Study Drug.........................................................35
1.5.
Benefit/Risk Assessment.........................................................................................................................35
2.
STUDY OBJECTIVES ........................................................................................................................................37
2.1.
Objectives................................................................................................................................................37
2.2.
Endpoints.................................................................................................................................................37
3.
OVERALL STUDY DESIGN .............................................................................................................................40
3.1.
Randomization.........................................................................................................................................41
3.2.
Blinding ...................................................................................................................................................41
4.
SELECTION OF STUDY POPULATION..........................................................................................................42
4.1.
Inclusion Criteria.....................................................................................................................................42
4.2.
Exclusion Criteria....................................................................................................................................43
4.3.
Withdrawal Criteria.................................................................................................................................44
4.4.
Replacement of Participants....................................................................................................................45
4.5.
Premature Termination of Study .............................................................................................................45
5.
TREATMENTS....................................................................................................................................................47
5.1.
Treatments Administered ........................................................................................................................47
5.1.1.
Bulevirtide .............................................................................................................................47
5.2.
Labelling of Bulevirtide ..........................................................................................................................48
5.3.
Dosing and Administration......................................................................................................................48
5.3.1.
Supplying Patients with Bulevirtide......................................................................................48
5.3.2.
Administration of Bulevirtide................................................................................................48
5.4.
Dose Adjustments/Modifications/Delays................................................................................................49
5.5.
Accountability Procedures.......................................................................................................................50
5.6.
Treatment Compliance ............................................................................................................................50
5.7.
Concomitant Therapy ..............................................................................................................................50
5.7.1.
Treatment with Nucleoside/Nucleotide Analogues...............................................................50
5.7.2.
Prohibited Treatments ...........................................................................................................51
6.
STUDY PROCEDURES......................................................................................................................................52


Gilead Sciences, Inc.
PROTOCOL MYR301
Version 5.0 dated 25-Apr-2022
CONFIDENTIAL
Page 3 of 94
6.1.
Early Discontinuation Visit .....................................................................................................................52
6.2.
Restrictions During the Study .................................................................................................................52
6.3.
Demographic and Other Baseline Characteristics...................................................................................54
6.3.1.
Demographics........................................................................................................................54
6.3.2.
Medical History.....................................................................................................................54
6.3.3.
Prior and Concomitant Therapy ............................................................................................54
6.3.4.
Weight, Height, Body Mass Index ........................................................................................54
6.3.5.
Pregnancy Test ......................................................................................................................55
6.3.6.
Drug Screening......................................................................................................................55
6.3.7.
Breath Alcohol Test...............................................................................................................55
6.3.8.
Abdominal Ultrasound ..........................................................................................................55
6.3.9.
Serum Alpha-fetoprotein.......................................................................................................55
6.3.10.
Serology, HDV RNA, HCV RNA, and HBeAg Test at Screening.......................................55
6.4.
Efficacy Procedures.................................................................................................................................56
6.4.1.
Virology Tests .......................................................................................................................56
6.4.2.
ALT .......................................................................................................................................56
6.4.4.
NTCP Polymorphism and Resistance Tests..........................................................................56
6.4.5.
Serum Alpha-2-Macroglobulin .............................................................................................59
6.4.6.
Liver Biopsy ..........................................................................................................................59
6.4.7.
Transient Elastometry............................................................................................................59
6.5.
Safety Procedures ....................................................................................................................................60
6.5.1.
Physical Examination ............................................................................................................60
6.5.2.
Vital Signs .............................................................................................................................61
6.5.3.
Electrocardiogram .................................................................................................................61
6.5.4.
Hematology, Biochemistry, Coagulogram, Vitamin D.........................................................62
6.5.5.
Total Blood Bile Salts ...........................................................................................................64
6.5.6.
Urinalysis...............................................................................................................................64
6.5.7.
Adverse Events......................................................................................................................65
6.6.
Other Procedures .....................................................................................................................................65
6.6.2.
Pharmacokinetics...................................................................................................................65
6.7.
Patient Diary............................................................................................................................................66
6.9.
Liver Related Clinical Events..................................................................................................................66
7.
ADVERSE EVENTS ...........................................................................................................................................67
7.1.
Definitions ...............................................................................................................................................67
7.1.1.
Adverse Event (AE) ..............................................................................................................67
7.1.2.
Serious Adverse Event ..........................................................................................................67
7.1.3.
Adverse Event of Special Interest (AESI).............................................................................68
7.1.4.
Abnormal Laboratory Values................................................................................................69
7.1.5.
Abnormal Vital Sign Values .................................................................................................69
7.1.6.
Adverse Drug Reaction (ADR) .............................................................................................70
7.1.7.
Unexpected Adverse Drug Reaction .....................................................................................70
7.1.8.
Suspected Unexpected Serious Adverse Reaction (SUSAR):...............................................70
7.2.
Classification of an Adverse Event .........................................................................................................70
7.2.1.
Severity of Event ...................................................................................................................70
7.2.2.
Relationship to Study Medication .........................................................................................71
7.2.3.
Adverse Event Outcome........................................................................................................71
7.2.4.
Adverse Event Assessment and Follow-up ...........................................................................71
7.3.
Reporting Procedure................................................................................................................................72
7.3.1.
Adverse Event Reporting Period...........................................................................................72
7.3.2.
Adverse Event Reporting ......................................................................................................72
7.3.3.
Serious Adverse Event Reporting .........................................................................................73
7.4.
Events of Special Interest ........................................................................................................................73
CCI
CCI
CCI


Gilead Sciences, Inc.
PROTOCOL MYR301
Version 5.0 dated 25-Apr-2022
CONFIDENTIAL
Page 4 of 94
7.5.
Hepatic Safety Adjudication Committee.................................................................................................74
7.6.
Reporting of Pregnancy...........................................................................................................................74
8.
STATISTICAL CONSIDERATIONS.................................................................................................................75
8.1.
Analysis Populations ...............................................................................................................................75
8.2.
Description of Statistical Methods ..........................................................................................................75
8.2.1.
Demographic and Baseline Measurements ...........................................................................75
8.2.2.
Analysis of Efficacy ..............................................................................................................75
8.2.3.
Analysis of Safety..................................................................................................................77
8.2.4.
Determination of Sample Size...............................................................................................78
8.2.5.
Interim and Final Analyses....................................................................................................79
9.
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .............................................80
10.
QUALITY ASSURANCE AND QUALITY CONTROL ...................................................................................81
10.1.
Periodic Monitoring.................................................................................................................................81
10.2.
Audit and Inspection................................................................................................................................81
11.
ETHICS/PROTECTION OF HUMAN SUBJECTS............................................................................................82
11.1.
Ethical Standard.......................................................................................................................................82
11.2.
Independent Ethics Committee and/or Institutional Review Board........................................................82
11.3.
Informed Consent Process.......................................................................................................................82
11.4.
Participant and Data Confidentiality .......................................................................................................83
12.
DATA HANDLING AND RECORD KEEPING................................................................................................84
12.1.
The Entering of Data into the eCRF........................................................................................................84
12.2.
The Query Process...................................................................................................................................84
12.3.
Data Collection and Management Responsibilities.................................................................................84
12.3.1.
User ID ..................................................................................................................................85
12.3.2.
Audit Trail .............................................................................................................................85
12.4.
Study Records Retention .........................................................................................................................85
12.5.
Protocol Deviations .................................................................................................................................85
12.6.
Publication and Data Sharing Policy.......................................................................................................85
13.
FINANCING AND INSURANCE.......................................................................................................................87
13.1.
Financing .................................................................................................................................................87
13.2.
Insurance..................................................................................................................................................87
14.
LITERATURE REFERENCES ...........................................................................................................................88
APPENDIX 1. CONFIRMATION OF PATIENTS’ ELIGIBILITY ...........................................................................91
LIST OF IN-TEXT TABLES
Table 1.
Schedule of Events ..................................................................................................................18
Table 2.
Patients With HDV RNA Response and Combined Response at Week 24 (MYR202 
Study, Modified Intention-to-Treat Population)......................................................................31
Table 3.
Tables for Clinical Abnormalities ...........................................................................................61
LIST OF IN-TEXT FIGURES
Figure 1.
Study Plan................................................................................................................................41


Gilead Sciences, Inc.
PROTOCOL MYR301
Version 5.0 dated 25-Apr-2022
CONFIDENTIAL
Page 5 of 94
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.
[See appended electronic signature]
Signature: _________________________________________ Date: ______/______/______
day/month/year
Medical Monitor, Clinical Development
Gilead Sciences, Inc.
PPD


Gilead Sciences, Inc.
PROTOCOL MYR301
Version 5.0 dated 25-Apr-2022
CONFIDENTIAL
Page 6 of 94
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: 
_____________________________


Gilead Sciences, Inc.
PROTOCOL MYR301
Version 5.0 dated 25-Apr-2022
CONFIDENTIAL
Page 7 of 94
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.


Gilead Sciences, Inc.
PROTOCOL MYR301
Version 5.0 dated 25-Apr-2022
CONFIDENTIAL
Page 8 of 94
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 aminotransaminase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransaminase
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-Dimentions
EU
European Union 
FAS
Full analysis set
FSS
Fatigue Severity Scale
FU
Follow-up
GCP
Good Clinical Practice
GGT
Gamma glutamyltransferase
HBeAg
Hepatitis B virus e antigen
HBsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HDAg
Hepatitis delta antigen
HDV
Hepatitis delta virus


Gilead Sciences, Inc.
PROTOCOL MYR301
Version 5.0 dated 25-Apr-2022
CONFIDENTIAL
Page 9 of 94
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
IEC
Independent Ethics Committee
INR
International normalized ratio
IRB
Institutional Review Board
LOCF
Last observation carried forward
LoD
Limit of detection
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed effect repeated measurement models
NCI
National Cancer Institute
NTCP
Sodium-taurocholate cotransporting polypeptide
OATP
Organic anion transporting polypeptide 
PCR
Polymerase chain reaction
PI
Principal Investigator
PP
Per-protocol set
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
Subcutaneously
SOC
System Organ Class
SUSAR
Suspected unexpected serious adverse reaction 
SVR
Sustained virological response
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 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.
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
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Statistical Methods 
(continued):

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) 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 [SVR24] at 
follow-up Week 24 [FU-24], ie study Week 168). Details will be 
specified in the statistical analysis plan (SAP) and final decision on 
exclusion from PP 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 non-responder 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 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. 


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Statistical Methods 
(continued):
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 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.
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 response) 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 effect repeated measurement model (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-


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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 
(35) 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 AE (SAE), treatment-emergent SAE (TESAE), and AEs leading 
to discontinuation.
Vital signs 
Vital signs will be described by summary statistics for measured values and 
changes from baseline by visit.
Laboratory parameters
Laboratory parameters will be described by summary statistics for measured 
values and changes from baseline by visit.
The clinical assessment of laboratory variables (abnormal high/ clinically 
relevant, abnormal high/not clinically relevant, within normal limits, 
abnormal low/not clinically relevant, abnormal low/clinically relevant) will 
be tabulated by visit for each clinical laboratory analyte in frequency tables. 
Additionally, for each laboratory parameter shifts in assessments from 
baseline to Week 48 and Week 96 visit will be presented (shift tables).
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.
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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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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 virus 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 eight 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 virus 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 co-infection is associated with faster progression to fibrosis and 
cirrhosis, earlier onset of hepatic complications and likelihood of liver transplantation [17-19]. 


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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, 5-10% 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, 5-10% 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 was the only 
available drug that has been proven to have some antiviral efficacy against chronic HDV 
infection [24, 25]. Studies applying pegylated interferon alpha 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 pegylated interferon alpha 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 pegylated interferon alpha therapy, alone or in 
combination with tenofovir, 24-week post-therapy 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, pegylated interferon alpha 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 trials: 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 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 subcutaneous 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, nine 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 subcutaneous administration 
was estimated to be 88%. The release after subcutaneous administration was best described by a 
parallel slow and fast first-order process, where 59% of the bioavailable dose was absorbed fast 
and the remaining 41% of the dose was absorbed slowly with absorption half-lives of 1.3 h and 
5.4 h, respectively. A simulation of the impact of various doses of bulevirtide on the occupancy 
of the binding target revealed that at doses of 10 mg most of the binding target was occupied 
> 80% for at least twenty hours in a simulated steady-state after subcutaneous administration.
MYR102 Study
A Phase 1 drug-interaction study (MYR102) in healthy 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 subcutaneous bulevirtide. Plasma samples were collected 
and bulevirtide, tenofovir, and plasma bile salts were quantified. Repeatedly, a 30 μg midazolam 
microdose was administered to determine the impact of the antivirals on 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 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 two 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 
change in either drug’s pharmacokinetics or CYP3A activity, suggesting that these drugs can be 
safely combined without dose modification.








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The primary efficacy endpoint was HDV RNA response at Week 24 was defined as undetectable 
HDV RNA or a decrease by ≥ 2 log10 IU/mL from baseline. Combined response was defined as 
fulfilment of two conditions simultaneously: undetectable HDV RNA or decrease by 
≥ 2 log10 IU/mL from baseline; ALT normalization. The percentage of patients with HDV RNA 
response and combined response at Week 24 is shown in Table 2. There was significantly higher 
percentage of patients with HDV RNA response at Week 24 in all bulevirtide groups compared 
to TDF group (p < 0.0001 for all bulevirtide groups).
Table 2.
Patients With HDV RNA Response and Combined Response at 
Week 24 (MYR202 Study, Modified Intention-to-Treat Population)
Bulevirtide 2 mg + 
TDF (N=28)
Bulevirtide 
5 mg + TDF 
(N=32)
Bulevirtide 
10 mg + TDF 
(N=30)
TDF 
(N=28)
Patients with HDV RNA response at 
Week 24, n (%)
15 (53.6)*
15 (46.9)*
24 (80.0)*
1 (3.6)
Patients with combined HDV 
RNA/ALT response at Week 24, 
n (%)
6 (21.4)
8 (25.0)**
11 (36.7)***
0
* p<0.0001 compared to TDF (Wald test for superiority by margin of 5%)
** p<0.05 compared to TDF (Fisher’s exact test)
*** p<0.001 compared to TDF (Fisher’s exact test)
Reference: MYR202 Interim Clinical Study Report [32]
MYR203 Study (Completed)
MYR203 aimed to evaluate the efficacy and safety of bulevirtide at daily doses of 2, 5, or 10 mg 
in combination with pegylated interferon, bulevirtide at daily dose of 2 mg, and bulevirtide at 
daily dose of 5 mg twice daily in combination with TDF compared with pegylated interferon 
alone in participants with CHD.
A total of 90 participants were randomized into 6 treatment groups, each of 15 participants:
Group A: pegylated interferon 180 μg
Group В: bulevirtide 2 mg + pegylated interferon 180 μg
Group С: bulevirtide 5 mg + pegylated interferon 180 μg
Group D: bulevirtide 2 mg
Group E: bulevirtide 10 mg (10 mg once a day) + pegylated interferon 180 μg
Group F: bulevirtide 10 mg (5 mg 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 (HDV RNA negativation) at Week 72 
(end of the follow-up period).


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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 (< limit of detection [LoD]) HDV RNA or decreased by ≥ 2 log10 IU/mL from 
baseline

ALT normalization
At Week 48, there was a clear treatment effect for participants receiving bulevirtide 2 mg or 
bulevirtide 10 mg when compared with participants in the delayed treatment group. The 
proportion of participants who achieved combined response in the active treatment groups was as 
follows:

Bulevirtide 2 mg treatment group: 44.9% (95% CI: 30.7% to 59.8%); p < 0.0001 when 
compared with delayed treatment (2.0% [95% CI: 0.0% to 10.4%])

Bulevirtide 10 mg treatment group: 48.0% (95% CI: 33.7% to 62.6%); p < 0.0001 when 
compared with delayed treatment (2.0% [95% CI: 0.0% to 10.4%])


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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

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).


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The primary efficacy endpoint is the sustained virological response 24 (SVR 24) defined as 
undetectable HDV RNA (HDV RNA < LoD) 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.
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.


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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 trials administration of bulevirtide 
in subjects 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 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.
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, 
 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 
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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 subjects. In the context of the progressive, severe, and debilitating 
nature of CHD, the balance between risks that have been identified from cumulative safety data 
for bulevirtide and anticipated efficacy/benefits remains favorable.
The sponsor realizes that extraordinary measures may need to be implemented and trials 
management may need to be adjusted due to unexpected risks which may increase due to 
external unavoidable circumstances, including COVID-19 pandemic spread in the world, eg, for 
subjects 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 flairs. The treatment interruption should be avoided and each case of 
interruption, where it is inevitably, should be closely monitored for safety of the subjects.
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 
subcutaneously 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 two conditions 
simultaneously:

Undetectable (< LoD) 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)

Change from baseline in liver stiffness as measured by elastography at Weeks 48, 96, 144, 
192, and 240
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3.
OVERALL STUDY DESIGN
This is a randomized, open-label, parallel-group, multicenter Phase 3 study that will evaluate the 
efficacy and safety of bulevirtide in subjects with CHD who have no adequate treatment options.
This study will be conducted at approximately 24 sites across approximately 6 countries globally 
which may include Germany, Russia, Italy, Georgia, US, and Sweden. A total of 150 subjects 
will be randomized.
Subjects will be assessed for eligibility to enter the study during a 4-week Screening period. 
Eligible subjects will be randomized at Visit 1 in a 1:1:1 ratio with stratification for the presence 
of liver cirrhosis (no/yes) to receive delayed treatment with bulevirtide 10 mg/day after an 
observational period of 48 weeks (Arm A), immediate treatment with bulevirtide 2 mg/day (Arm 
B) or immediate treatment with bulevirtide 10 mg/day (Arm C) for 144 weeks. 
At Week 48 subjects from delayed treatment group (Arm A) for CHD will be switched to 
bulevirtide 10 mg/day for 96 weeks. The total duration of treatment period is 144 weeks. After 
completion of the treatment period, subjects will be followed for additional 96 weeks. For all 
subjects the total amount of time to complete the study will be 240-244 weeks (inclusive of the 
Screening, Treatment, and Follow-Up Periods).
The study will be considered to have started when the first patient has provided signed informed 
consent, and will be considered to have finished after the last patient has completed the last 
follow-up visit. A scheme of the study design is presented in Figure 1. The schedule of events to 
be conducted during the 144-week Treatment Period and the safety Follow-Up Period is 
presented in Table 1. Treatment and all study procedures will be performed on an outpatient 
basis (except for hospitalization for biopsy procedure, if required).


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Figure 1.
Study Plan
EOT = end of treatment; EOS = end of study; HDV = hepatitis delta virus
*Delayed treatment means no treatment for HDV infection for 48 weeks.
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.
Arm А (n≈50)
 Delayed treatment*, 
48 weeks
Bulevirtide 10 mg/day, 96 weeks
Arm B (n≈50)
Bulevirtide 2 mg/day, 144 weeks
Arm C (n≈50)
Bulevirtide 10 mg/day, 144 weeks
Screening
Treatment (144 weeks)
Follow-up 
(96 weeks)
Randomization
Day 1
EOT Visit
Week 144
EOS Visit
Week 240
Week 1 -144
Week 145-240
Day −28 to −1
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4.
SELECTION OF STUDY POPULATION
This is an international study and it is expected that subjects will be enrolled at approximately 
24 study sites across approximately 6 countries. A total of 150 subjects will be randomized. 
Enrolment will stop as soon as the target number of randomized subjects 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 to the 
Protocol.
4.1.
Inclusion Criteria
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria:
1) Provision of signed and dated informed consent form (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 subjects: 

Postmenopausal for at least 2 years, or 

Surgically sterile (total hysterectomy or bilateral oophorectomy, bilateral tubal ligation, 
staples, or another type of sterilization), or 

Abstinence from heterosexual intercourse throughout the study, or 


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
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 subjects 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; Subjects 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. Subjects with HCV antibodies can be enrolled, if 
screening HCV RNA test is negative. Subjects with HIV infection can be enrolled if CD4+ 
cell counts are > 500/mL and HIV RNA is below 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 
pre-malignancy 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 trials.
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.
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.


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Subjects 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 subjects 
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 subjects to the sponsor and the clinical 
research associate (CRA) within 24 hours.
4.4.
Replacement of Participants
Study subjects will not be replaced.
4.5.
Premature Termination of Study
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to investigator and 
regulatory authorities. If the study is prematurely terminated or suspended, the principal 
investigator (PI) will promptly inform the Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB) and will provide the reason(s) for the termination or suspension; the PI will 
also promptly inform the study subjects and will assure appropriate therapy and follow-up.


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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 the dark place with temperature monitoring.
At home, it is allowed for study subjects 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 three days is 
allowed.
In case of other deviations of the cold chain conditions such deviation should be promptly 
reported to the sponsor and the product should be placed to quarantine and should not be used 
prior to sponsor’s authorization.
After reconstitution of vial contents with water for injection the drug remains stable for 
120 minutes at room temperature.


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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.
5.3.2.
Administration of Bulevirtide
Bulevirtide is administered by study subjects 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 
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 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 subcutaneous 
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 two 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. 
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.
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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 non-prescription medications.
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 (33 and 34 are current as of 
November 2018). In particular, treatment should be started if one of following conditions is met:


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
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) 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

Hematopoiesis-stimulating agents

Sulfasalazine

Ezetimibe

Cyclosporine

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 [36, 37, 38, 39]

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 subjects 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 Visit 
FU 6/EOS.
6.2.
Restrictions During the Study
Diet Restrictions
Subjects 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 Subjects
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 two 
effective forms of contraception.
The following contraception forms are considered highly effective:

True abstinence when this is in line with the preferred and usual lifestyle of the 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 two forms of effective contraception are required. A double barrier 
method is acceptable which is defined as condom and occlusive cap (diaphragm or cervical/vault 
caps) if used together with spermicidal foam/gel/film/cream/suppository.
Should the female 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 Subjects
Male subjects 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 subjects 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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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 
Abnormalities of the Guidance for Industry Toxicity Grading Scale for Healthy Adult and 
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.


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Table 3.
Tables for Clinical Abnormalities
Reaction to
Injectable 
Product
Mild (Grade 1)
Moderate (Grade 
2)
Severe (Grade 3)
Potentially Life
Threatening
(Grade 4)
Pain 
Does not interfere with 
activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or interferes with 
activity 
Any use of narcotic pain 
reliever or prevents daily 
activity 
Emergency room 
(ER) visit or 
hospitalization 
Tenderness 
Mild discomfort to 
touch 
Discomfort with 
movement 
Significant discomfort at 
rest 
ER visit or 
hospitalization 
Erythema/
Redness * 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/
Swelling ** 
2.5 – 5 cm and does not 
interfere with activity 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or prevents daily 
activity 
Necrosis 
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be 
recorded as a continuous variable. 
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement.
6.5.2.
Vital Signs
Blood pressure, heart rate, and body temperature should be measured at Screening and during the 
study as indicated in Table 1. Vital signs are assessed before study drug administration and at 
additional times if clinically indicated.
Any finding present at the screening visit should be reported in the eCRF as medical history and 
its importance for including the 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). 
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.


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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

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


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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

Potassium

Sodium

Chloride

Phosphorus

C-reactive protein (CRP)


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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

Specific gravity

Protein

Glucose

Bilirubin

Urobilinogen






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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 (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 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.
Liver Related Adverse Events
Investigators should closely monitor the following liver-related clinical events starting from the 
randomization, including, but not limited to: cirrhosis development; development or worsening 
jaundice, coagulopathy, ascites, hepatic encephalopathy; bleeding from esophageal varices; HCC 
development; liver transplantation; liver related hospitalization: number of hospitalizations and 
duration of each hospitalization; liver related death. 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.


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7.1.4.
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 upper 
limit of normal 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.
7.1.5.
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an AE. A vital sign result must be reported as an AE 
if it meets any of the following criteria:

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.


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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.
7.1.6.
Adverse Drug Reaction (ADR)
In the pre-approval clinical experience with a new medicinal product or its new usages, 
particularly as the therapeutic dose(s) may not be established: all noxious and unintended 
responses to a medicinal product related to any dose should be considered adverse drug reactions. 
The phrase responses to a medicinal product means that a causal relationship between a medicinal 
product and an AE is at least a reasonable possibility, ie, the relationship cannot be ruled out.
7.1.7.
Unexpected Adverse Drug Reaction
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (eg, investigator’s brochure for an unapproved investigational product or package 
insert/summary of product characteristics for an approved product) (ICH E6).
7.1.8.
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.
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.


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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
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 


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AE outcome. Adverse Events assessed as related to the study drug and/or procedure will be 
monitored until they have resolved or reached a stable condition, with or without sequelae. Other 
AEs will be monitored until the last visit if they have not resolved or reached a stable condition. 
AEs will be characterized as intermittent if interval between the events with the same term does 
not exceed two days. For such AEs documentation of first episode onset and the last episode end 
date is required.
7.3.
Reporting Procedure
7.3.1.
Adverse Event Reporting Period
Investigators will seek information on 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. These SAEs include events caused by a protocol-mandated intervention (eg, invasive 
procedures such as biopsies, discontinuation of medications). If SAE is considered to be related 
to the study drug or study procedures it must be reported to the sponsor regardless of the 
reporting period. For information on reporting of SAEs to sponsor see Section 7.3.3. 
Reporting period for non-serious AEs starts with the randomization and ends at the End of Study 
visit. Non-serious AEs at Screening period which are in the investigator’s opinion related to 
study procedures (eg, biopsy) also should be reported. 
7.3.2.
Adverse Event Reporting
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information. Example of non-directive question:
“How have you felt since your last clinic visit?”
Any AE occurring during the AE reporting period, whether or not related to the study drug 
and/or study procedure, will be recorded immediately in the source document, and described on 
the AE form of the eCRF along with the date and time of onset, seriousness, severity, 
relationship to the study 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.


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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:
Contact information for Investigator’s notification in case of SAEs
Gilead Global 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. For all additional follow-up evaluations, the 
paper SAE form must be completed and sent via email or by fax to Gilead Global Patient Safety 
within 24 hours of receipt of the updated information. Other supporting documentation of the 
event may be requested by the study sponsor and should be provided as soon as possible, within 
24 hours of receipt of the updated information. As soon as it is possible to do so, any SAE 
reported via paper must be transcribed onto the 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 Global Patient Safety.
The study sponsor will be responsible for reporting to the competent authorities in all the 
Member States concerned of any unexpected fatal or life-threatening suspected adverse reaction 
as soon as possible (without delay) but in no case later than 7 calendar days after the sponsor’s 
initial receipt of the information, and no later than 15 days for other suspected unexpected 
serious adverse reaction. The sponsor will inform all the investigators of the occurrence of any 
SUSAR during the clinical conduct of the study.
7.4.
Events of Special Interest
See Section 7.1.3.
PPD
PPD


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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.
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 Global Patient Safety
Email: 
or
Fax: 

Complete the Pregnancy Report form in eCRF. Email alert will be sent to predefined 
recipients to highlight that a pregnancy has occurred.
If the pregnancy leads to an abortion (spontaneous abortion or therapeutic abortion), in utero 
death or congenital anomaly, follow the procedure for declaration of an SAE (see Section 7.3.3). 
Other cases, such as reports of induced termination of pregnancy without information on 
congenital malformation, reports of pregnancy exposure without outcome data, or reports which 
have a normal outcome should not be submitted as SAE.
If a female partner of a male 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
Enrolled Set: All patients screened and enrolled into this study.
Randomized 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) 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 SVR24 at follow-up Week 24 [FU-24], ie study Week 168). Details will be specified in the 
statistical analysis plan (SAP) and final decision on exclusion from PP 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 non-responders 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 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 non-responder, regardless the reason for the absence.
Change from baseline in liver stiffness as measured by elastography will be analyzed in a mixed 
effect repeated measurement model (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 (35) 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 SAE, TESAE and AEs leading to 
discontinuation.
CCI
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 principal investigator, the sponsor and the 
CRA should be informed in time.


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11.
ETHICS/PROTECTION OF HUMAN SUBJECTS
11.1.
Ethical Standard
The investigator will ensure that this study is conducted in full conformity with Declaration of 
Helsinki and the ICH E6 (GCP).
11.2.
Independent Ethics Committee 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 inter-observer variability, every effort should 
be made to ensure that the same individual who made the initial baseline determinations 
completes all corresponding follow-up evaluations. The investigator must verify that all data 
entries in the eCRFs are accurate and correct. If some assessments are not done, or if certain 
information is not available, not applicable or unknown, this should be indicated in the eCRF. 
The investigator will be required to electronically sign off the clinical data.
12.2.
The Query Process
The monitor will review the eCRFs and evaluate them for completeness and consistency. Each 
eCRF will be compared with the respective source documents to ensure that there are no 
discrepancies between critical data. All entries, corrections, and alterations are to be made by the 
investigator or designee. The monitor cannot enter data in the eCRFs. Once clinical data have 
been submitted to the central server via the eCRF, corrections to the data fields will be audit 
trailed, meaning that the reason for change, the name of the person who made the change, 
together with time and date will be logged. Roles and rights of the site personnel responsible for 
entering clinical data into the eCRF will be determined in advance. If additional corrections are 
needed, the responsible monitor or Data Manager will raise a query in the electronic data capture 
application. The appropriate study personnel will answer the queries in the eCRF. This will be 
audit trailed by the electronic data capture application meaning that the name of study personnel, 
time, and date are logged.
12.3.
Data Collection and Management Responsibilities
Data collection is the responsibility of the clinical study staff at the site under the supervision of 
the site PI. The investigator is responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. When making changes or corrections, cross out the original entry with a 
single line, and initial and date the change. Do not erase, overwrite, or use correction fluid or 
tape on the original.
Data reported in the eCRF derived from source documents should be consistent with the source 
documents.
The data system includes password protection and internal quality checks, such as automatic 
range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data 
will be entered directly from the source documents.


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


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


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13.
FINANCING AND INSURANCE
13.1.
Financing
The sponsor financially supports the study. The company will deliver the study drugs free of 
charge as well as paying the investigator/ investigational sites a fee for the 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 disese 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 


Gilead Sciences, Inc.
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Version 5.0 dated 25-Apr-2022
CONFIDENTIAL
Page 89 of 94
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. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on 
the management of hepatitis B virus infection. J Hepatol. 2017 Aug;67(2):370-398.
35. Kenward, M. and Roger, J. (1997). Small Sample Inference for Fixed Effects from Restricted 
Maximum Likelihood. Biometrics 53, 983-997.
36. http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteracti
onslabeling/ucm093664.htm#classInhibit (Table 5.1).
37. 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.
38. 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.
39. Talavera Pons S, Boyer A, Lamblin G, Chennell P, Châtenet FT, Nicolas C, Sautou V, Abergel 
A. Managing drug-drug interactions with new direct-acting antiviral agents in chronic 
hepatitis C. Br J Clin Pharmacol 2017;83:269-293.


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APPENDIX 1. CONFIRMATION OF 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 subjects 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; Subjects 
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. Subjects with 
HCV antibodies can be enrolled, if screening HCV 
RNA test is negative. Subjects 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 pre-malignancy disorder, or a history of 
malignancy within the last 5 years (with the exception 
of successfully treated carcinoma of the cervix in situ 
and successfully treated basal cell carcinoma and 
squamous cell carcinoma not less than 1 year prior to 
screening [and no more than 3 excised skin cancer 
within the last 5 years prior to screening]) or history 
of hepatic carcinoma
Assessed and documented by 
investigator in medical record
6
Systemic connective tissue disorders
Assessed and documented by 
investigator in medical record
7
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


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Exclusion Criteria
Confirmation
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 from 
participation in this trial. Autoimmune hepatitis 
stigmata attributed to HDV infection in the opinion of 
the investigator are allowed.
Assessed and documented by 
investigator in medical record
13
White blood cells (WBC) count < 3000 cells/mm3 
(< 1500 if African 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


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Exclusion Criteria
Confirmation
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 trials
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


protocol MYR301 Amendment 4
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Research eSigned
28-Apr-2022
19:52:49
PPD

SAP_005.pdf: 
Bulevirtide (BLV)
MYR301
Statistical Analysis Plan – Week 192 
Version 1.0
05 February 2024
GILEAD CONFIDENTIAL INFORMATION
Page 1 of 65
STATISTICAL ANALYSIS PLAN
Study Title:
A Multicenter, Open-label, Randomized Phase 3 Clinical Study 
to Assess Efficacy and Safety of Bulevirtide in Participants 
with Chronic Hepatitis Delta
Name of Test Drug:
Bulevirtide 
Study Number:
MYR301
Protocol Version (Date):
Version 7.0 dated 25 January 2023
Analysis Type:
Week 192
Analysis Plan Version:
Version 1
Analysis Plan Date:
05 February 2024
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
GILEAU 


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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN ...............................................................................................................................1
TABLE OF CONTENTS................................................................................................................................................2
LIST OF IN-TEXT TABLES .........................................................................................................................................4
LIST OF IN-TEXT FIGURES........................................................................................................................................4
1.
INTRODUCTION..................................................................................................................................................7
1.1.
Study Objectives........................................................................................................................................7
1.2.
Study Design .............................................................................................................................................7
1.3.
Sample Size and Power .............................................................................................................................8
2.
TYPE OF PLANNED ANALYSIS........................................................................................................................9
2.1.
Week 24 Analysis......................................................................................................................................9
2.2.
Week 48 Analysis (Primary Analysis) ......................................................................................................9
2.3.
Week 96 Analysis......................................................................................................................................9
2.4.
Week 144 Analysis (End of Treatment)....................................................................................................9
2.5.
Week 192 Analysis....................................................................................................................................9
2.6.
Final Analysis (Week 240)........................................................................................................................9
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.............................................................................10
3.1.
Analysis Sets ...........................................................................................................................................10
3.1.1.
All Randomized Analysis Set................................................................................................10
3.1.2.
All Enrolled Analysis Set ......................................................................................................10
3.1.3.
Full Analysis Set....................................................................................................................10
3.1.4.
Per-Protocol Analysis Set......................................................................................................11
3.1.5.
Safety Analysis Set................................................................................................................11
3.1.6.
Post-Treatment Safety Analysis Set ......................................................................................11
3.1.7.
Anti-drug Antibody Analysis Set ..........................................................................................12
3.1.8.
Pharmacokinetic Analysis Set ...............................................................................................12
3.2.
Participant Grouping ...............................................................................................................................12
3.3.
Strata and Covariates...............................................................................................................................13
3.4.
Examination of Participant Subgroups....................................................................................................14
3.5.
Multiple Comparisons .............................................................................................................................14
3.6.
Missing Data and Outliers.......................................................................................................................15
3.6.1.
Missing Data..........................................................................................................................15
3.6.2.
Outliers ..................................................................................................................................15
3.7.
Data Handling Conventions and Transformations ..................................................................................15
3.8.
Analysis Visit Windows..........................................................................................................................16
3.8.1.
Definition of Study Day ........................................................................................................16
3.8.2.
Analysis Visit Windows........................................................................................................16
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window .................................................................................................................................18
4.
PARTICIPANT DISPOSITION ..........................................................................................................................19
4.1.
Participant Enrollment and Disposition...................................................................................................19
4.2.
Extent of Study Drug Exposure and Compliance....................................................................................20
4.2.1.
Study Drug Exposure ............................................................................................................20
4.2.2.
Study Drug Compliance ........................................................................................................20
4.2.3.
Summaries of Study Drug Exposure and Compliance..........................................................21
4.3.
Protocol Deviations .................................................................................................................................21


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4.4.
Assessment of COVID-19 Impact...........................................................................................................21
4.4.1.
Protocol Deviations Due to COVID-19 ................................................................................22
5.
BASELINE CHARACTERISTICS .....................................................................................................................23
5.1.
Demographics and Baseline Characteristics ...........................................................................................23
5.2.
Other Baseline Characteristics ................................................................................................................23
5.3.
Substance Use..........................................................................................................................................26
5.4.
Medical History.......................................................................................................................................26
6.
EFFICACY ANALYSES.....................................................................................................................................27
6.1.
General Considerations ...........................................................................................................................27
6.2.
Primary Efficacy Endpoints ....................................................................................................................28
6.2.1.
Primary Analysis of the Primary Efficacy Endpoint.............................................................28
6.2.2.
Sensitivity Analysis of the Primary Efficacy Endpoint.........................................................29
6.2.3.
Per-protocol Analysis of the Primary Efficacy Endpoint......................................................29
6.2.4.
Subgroup Analysis of the Primary Efficacy Endpoint ..........................................................29
6.3.
Secondary Efficacy Endpoints ................................................................................................................29
6.3.1.
Analysis of Secondary Efficacy Endpoints ...........................................................................29
7.
SAFETY ANALYSES.........................................................................................................................................38
7.1.
Adverse Events and Deaths.....................................................................................................................38
7.1.1.
Adverse Event Severity .........................................................................................................38
7.1.2.
Relationship of Adverse Events to Study Drug.....................................................................38
7.1.3.
Serious Adverse Events.........................................................................................................38
7.1.4.
Treatment-Emergent Adverse Events....................................................................................38
7.1.4.1.
Definition of Treatment-Emergent Adverse Events........................................38
7.1.4.2.
Definition of Post Treatment Adverse Events.................................................39
7.1.4.3.
Incomplete Dates .............................................................................................39
7.1.5.
Summaries of Treatment-Emergent Adverse Events and Deaths (On-
Treatment Period)..................................................................................................................39
7.1.5.1.
Summaries of AE incidence in Combined Severity Grade 
Subsets (On-Treatment Period) .......................................................................39
7.1.6.
Additional Analysis of Adverse Events (On-Treatment Period)...........................................41
7.1.6.1.
Hepatic Adverse Events...................................................................................41
7.1.6.2.
Subgroup Analyses of Treatment-Emergent Adverse Events .........................41
7.1.7.
Summaries of Adverse Events (Post-Treatment Period).......................................................41
7.1.7.1.
Summaries of Posttreatment AEs by Preferred Term......................................42
7.1.8.
Additional Analysis of Adverse Events (Post-Treatment Period).........................................42
7.1.8.1.
Hepatic Adverse Events...................................................................................42
7.1.8.2.
Adverse Events Reported After Administration of 
Commercial BLV.............................................................................................42
7.2.
Laboratory Evaluations ...........................................................................................................................42
7.2.1.
Summaries of Numeric Laboratory Results ..........................................................................43
7.2.2.
Summaries of Qualitative Laboratory Results ......................................................................45
CCI
CCI


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7.2.3.
Shifts Relative to the Baseline Value ....................................................................................45
7.2.4.
Graded Laboratory Values ....................................................................................................45
7.2.4.1.
Treatment-Emergent Laboratory Abnormalities (On-
Treatment Period) ............................................................................................46
7.2.4.2.
Summaries of Laboratory Abnormalities (On-Treatment 
Period)..............................................................................................................46
7.2.4.3.
Summaries of Laboratory Abnormalities (Post-Treatment 
Period)..............................................................................................................47
7.2.5.
Liver-related Laboratory Evaluations....................................................................................47
7.2.5.1.
Potential Drug Induced Liver Injury (DILI) While on 
Treatment.........................................................................................................47
7.2.5.2.
Posttreatment ALT > 5 x ULN and ALT > 10 x ULN....................................47
7.3.
Body Weight and Vital Signs..................................................................................................................48
7.4.
Physical Examination ..............................................................................................................................48
7.5.
Prior, Concomitant, and Post-Treatment Medications ............................................................................48
7.5.1.
Prior, Concomitant, and Post-Treatment Medications ..........................................................48
7.5.2.
Summaries of Non-Study Drug Medications ........................................................................49
7.5.3.
HBV Medications..................................................................................................................49
7.5.4.
Commercial BLV ..................................................................................................................50
7.6.
Electrocardiogram Results.......................................................................................................................50
7.6.1.
Investigator Electrocardiogram Assessment .........................................................................50
7.6.2.
Other Electrocardiogram Assessment ...................................................................................50
7.7.
Other Safety Measures ............................................................................................................................51
8.
IMMUNOGENICITY ANALYSES ....................................................................................................................52
8.1.
ADA Incidence and Prevalence...............................................................................................................52
9.
PHARMACOKINETIC (PK) ANALYSES.........................................................................................................53
9.1.
PK Sample Collection .............................................................................................................................53
9.2.
PK Analyses ............................................................................................................................................53
10.
OTHER EVALUATIONS....................................................................................................................................54
10.1.
HBeAg.....................................................................................................................................................54
10.2.
Liver Biopsy - Molecular Analysis and Gene Expression ......................................................................54
11.
SOFTWARE.........................................................................................................................................................56
12.
APPENDICES......................................................................................................................................................57
Appendix 1 Sample SAS Code.............................................................................................................................57
Appendix 2 Schedule of Assessments..................................................................................................................58
Appendix 3. Imputation of incomplete AE start or end date................................................................................63
LIST OF IN-TEXT TABLES
Table 6-1.
Definition of Potential Liver Related Clinical Events.............................................................33
Table 8-1.
Definition of ADA Incidence ..................................................................................................52
LIST OF IN-TEXT FIGURES
Figure 1.
Study Plan..................................................................................................................................8


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LIST OF ABBREVIATIONS
ADA
anti-drug antibody 
AE
adverse event
AFP
alpha-fetoprotein
ALP
alkaline phosphatase
ANCOVA
analysis of covariance
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BLV
bulevirtide 
BMI
body mass index
CHD
chronic hepatitis delta
CI
confidence interval
COVID-19
Coronavirus 2019
CRF
case report form
CRP
c-reactive protein
CS
clinically significant
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DILI
drug-induced liver injury
DT
delayed treatment
ECG
electrocardiogram
EOT
end of treatment
EQ-5D-3L
EuroQol 5-dimentions 3-levels 
ET
early termination
FAS
full analysis set
FSS
fatigue severity scale
GGT
gamma glutamyl transferase
HAI
Histological Activity Index
HBeAg
hepatitis B e antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HDV
hepatitis Delta virus
HQLQ
hepatitis quality of life questionnaire
HLT
high-level term
LLOQ
lower limit of quantification
LOCF
last observation carried forward
LOD
limit of detection
LS
least squares


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MedDRA
Medical Dictionary for Regulatory Activities
MEF
missing equals failure 
MLM
MLM Medical Labs GmbH
MMRM
mixed effects model for repeated measurements
NCS
not clinically significant
NOCB
next observation carried backward
OC
observed case
PK
Pharmacokinetic
PP
per protocol
PT
preferred term
Q1, Q3
first quartile, third quartile
QRS
electrocardiographic deflection between the beginning of the Q wave and termination of the 
S wave representing time for ventricular depolarization
QT
electrocardiographic interval between the beginning of the Q wave and termination of the 
T wave representing the time for both ventricular depolarization and repolarization to occur
QTc
QT interval corrected for heart rate
RR
electrocardiographic interval representing the time measurement between the R wave of one 
heartbeat and the R wave of the preceding heartbeat
SAE
Serious Adverse Event
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SOC
system organ class
SVR24
sustained virological response 24 Weeks after scheduled end of treatment
SVR48
sustained virological response 48 Weeks after scheduled end of treatment
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
ULN
upper limit of normal
ULOQ
upper limit of quantification 
VAS
visual analogue scale
WHO
World Health Organization


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study MYR301 Week 192 analysis. This SAP is based on the study protocol Version 7.0 
dated 25 January 2023 and the electronic case report form (eCRF). The SAP will be finalized 
before Week 192 database finalization. Any changes made after the finalization of the SAP will 
be documented in the CSR.
1.1.
Study Objectives
The primary objective of this study is to evaluate the efficacy of bulevirtide (BLV) administered 
subcutaneously for 48 weeks at a dose of 2 mg or 10 mg once daily for treatment of chronic 
hepatitis delta (CHD) in comparison to delayed treatment.
The secondary objectives of this study are:
•
To evaluate optimal treatment duration
•
To assess the safety of BLV
1.2.
Study Design
This is a randomized, open-label, parallel group, multicenter Phase 3 study to evaluate the 
efficacy and safety of BLV in participants with CHD who have no adequate treatment options.
A total of 150 participants were randomized in a 1:1:1 ratio, with stratification by presence of 
liver cirrhosis (yes, no) to 3 treatment arms and treated as follows:
•
Arm A (N = 51): Delayed treatment with BLV 10 mg/day for 96 weeks after an observational 
period of 48 weeks with a further follow-up period of 96 weeks
•
Arm B (N = 49): BLV 2 mg/day for 144 weeks with a further follow-up period of 96 weeks
•
Arm C (N = 50): BLV 10 mg/day for 144 weeks with a further follow-up period of 96 weeks
CCI
I 
I 
I 
I 


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A schema of the study design is presented in Figure 1. The schedule of events to be conducted 
during the 144-week treatment period and the 96 week off-treatment safety follow-up period is 
presented in the Schedule of Assessments, Appendix 2. 
Figure 1. 
Study Plan 
Screenin 
Treatment (144 weeki 
Day-28 t< 
1 
Randomizatio 
Day 1 
Week 144 
EOT = end of treatment; EOS = end of study 
1.3. 
Sample Size and Power 
I 
: Fnlln• un 
I 
: (9 week! 
Week 14 240 
EOTVis 
Week 144 
EOS Vis 
Week240 
The prima1y analysis of the study was the separate comparisons ofBLV 10 mg versus delayed 
treatment and BL V 2 mg versus delayed treatment after a period of 48 weeks. The primaiy 
endpoint was defined as the response rate at Week 48 measured by undetectable HDV RNA or a 
decrease of~ 2 log10 IU/mL from baseline combined with nonnal ALT (ALT value falls within 
the reference range). The overall significance level is 0.05. An interim analysis was perfonned 
on the response rates at Week 24. To account for the repeated analysis ofresponse, the nominal 
two-sided significance level was split between the time points with 0.01 for 24 weeks and 0.04 
for 48 weeks. At each time point the BL V doses were compai·ed to delayed treatment in tenns of 
a hierarchical testing procedure staiiing with the higher dose at the respective adjusted two-sided 
significance levels. 
The expected response rates at Week 48 for the BL V 2 mg and BL V 10 mg doses were 45% or 
greater. The conservative expectation for the delayed treatment response rate was 8% or less. 
These assumptions were based on results from the preceding Phase 2 study (MYR202). 
With a sample size of 47 paiiicipants per treatment group, a Fisher's exact test with a 0.04 
two-sided significance level has 97.8% power to detect this difference between the BLV 10 mg 
and the delayed treatment propo1iions and between the BL V 2 mg and the delayed treatment 
propo1iions. The power to reject both null hypotheses simultaneously is 95.6%. 
This sample size was slightly increased to 50 paiticipants per trnatment group to account for a 
few potential early withdrawals. Hence 150 patients were randomized. 
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2.
TYPE OF PLANNED ANALYSIS
2.1.
Week 24 Analysis
The Week 24 analysis was conducted when all participants completed the Week 24 visit or 
prematurely discontinued the study.
2.2.
Week 48 Analysis (Primary Analysis)
The Week 48 analysis was conducted when all participants completed the Week 48 visit or 
prematurely discontinued the study.
2.3.
Week 96 Analysis
The Week 96 analysis was conducted when all participants completed the Week 96 visit or 
prematurely discontinued the study.
2.4.
Week 144 Analysis (End of Treatment)
The Week 144 analysis was conducted when all the participants completed the Week 144 visit or 
prematurely discontinued the study.
2.5.
Week 192 Analysis
The Week 192 analysis will be conducted when all the participants complete the Week 192 visit 
or prematurely discontinue the study.
2.6.
Final Analysis (Week 240)
The final analysis will be performed after all participants have completed the study (Week 240) 
or prematurely discontinued study, all outstanding data queries have been resolved or 
adjudicated as unresolvable, and the data have been cleaned and finalized.
This is the SAP for the Week 192 analysis. The details of the Week 24, 48, 96, and 144 statistical 
analysis methods were specified in separate SAPs for each of the analysis timepoints.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of participants in each category will be presented; for continuous 
variables, the number of participants (n), mean, standard deviation (SD) or standard error (SE), 
median, first quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
All statistical tests will be two-sided and performed at the 5% significance level unless otherwise 
specified.
By-participant listings will be presented for all participants in the All Randomized Analysis Set 
and sorted by participant ID number, visit date, and time (if applicable). Data collected on log 
forms, such as adverse event (AE) form, will be presented in chronological order for each 
participant. The treatment group to which participants were randomized will be used in the 
listings. Age, sex at birth, and race will be included in the listings, as space permits.
3.1.
Analysis Sets
Analysis sets define the participants to be included in an analysis. Analysis sets and their 
definitions are provided in this section. The analysis set will be identified and included as a 
subtitle for each table, figure, and listing.
For each analysis set, the number and percentage of participants eligible for inclusion, will be 
summarized by treatment group. In addition, separate listings will present the participants who 
were excluded from the Week 48 Per-Protocol (PP) and from the Week 192 PP Analysis Set and 
the reason(s) for their exclusion.
3.1.1.
All Randomized Analysis Set
The All Randomized Analysis Set includes all participants who were enrolled (informed consent 
signed) and randomized into the study. This is the primary analysis set for listings.
3.1.2.
All Enrolled Analysis Set
The All Enrolled Analysis Set includes all participants who were screened and enrolled in the 
study. The All Enrolled Analysis Set will be used for listings if it differs from the All 
Randomized Analysis Set.
3.1.3.
Full Analysis Set
The Full Analysis Set (FAS) includes all participants who were randomized to BLV and took at 
least 1 dose of BLV or randomized to the delayed treatment group. This is the primary analysis 
set for efficacy analyses.


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3.1.4.
Per-Protocol Analysis Set
The Per-Protocol (PP) Analysis Set was defined as all participants in the FAS for whom no 
protocol deviations were judged to have an impact on the analysis of the primary efficacy 
endpoint of combined response (PP 48W Analysis Set) or on the secondary efficacy endpoint of 
sustained virological response at follow-up Week 48, SVR48 (PP 192W Analysis Set). The PP 
Analysis Set is the secondary analysis set for efficacy analyses.
There are 3 different PP Analysis Sets that have been defined for the study:
• The PP 24W Analysis Set (defined prior to the Week 24 interim analysis) and not used 
for any of the analyses described in this Week 192 SAP
• The PP 48W Analysis Set (defined for the Week 48 primary efficacy analysis)
• The PP 192W Analysis Set (defined for the Week 192 analysis specifically for the 
SVR48 endpoint)
The decision as to whether a particular protocol deviation is considered as reason for exclusion 
of the participant from the PP Analysis Set (for the relevant analysis timepoint) should be made 
at the data review meeting for each analysis and documented in each corresponding data review 
meeting report (ie, clean file report). Additionally, participants with monitor-approved 
Bulevirtide/Hepcludex/Myrcludex rescue therapy recorded on the CM eCRF with a start date on 
or prior to the FU-Week 48 HDV RNA collection date will be excluded from the PP Week 192 
Analysis Set. “Monitor-approved” is defined as no PD related to BLV rescue therapy.
For the Week 192 analysis, efficacy analyses using the PP 48W Analysis Set will be repeated 
for: primary efficacy endpoint of combined response at Week 48; key secondary endpoint of 
undetectable HDV RNA at Week 48; and the secondary endpoints of ALT normalization and 
virologic response at Week 48 using the updated Week 192 database. In addition, the secondary 
efficacy endpoint SVR48 will be analyzed using the PP 192W Analysis Set.
3.1.5.
Safety Analysis Set
The Safety Analysis Set includes all participants who were randomized into the study and took at 
least 1 dose of BLV, or who were randomized to the delayed treatment group. This is the 
primary analysis set for safety analyses (with the exception of safety displays summarizing only 
post-treatment period data).
3.1.6.
Post-Treatment Safety Analysis Set
The Post-Treatment Safety Analysis Set includes participants in the Safety Analysis Set who 
have at least 1 non-missing study assessment (eg, AE onset date, CM start date, laboratory 
collection, vital sign assessment, ECG assessment, physical exam, pregnancy, or death) 
performed after last BLV dose. This is the primary analysis set for safety displays during only 
the post-treatment period; and post-treatment potential liver-related clinical events.


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3.1.7.
Anti-drug Antibody Analysis Set
The Anti-drug Antibody (ADA) Analysis Set includes all participants who took at least 1 dose of 
BLV and had at least 1 non-missing ADA data. This is the primary analysis set for the 
immunogenicity analyses.
3.1.8.
Pharmacokinetic Analysis Set
The Pharmacokinetic (PK) Analysis Set includes all randomized participants who took at least 
1 dose of BLV and had at least 1 non-missing concentration value reported by the PK laboratory. 
This is the primary analysis set for the PK analyses. 
3.2.
Participant Grouping
For analyses based on the All Randomized Analysis Set and FAS, participants will be grouped 
according to the treatment to which they were randomized. For analyses based on the PP 
Analysis Set, Safety Analysis Set, ADA Analysis Set, and PK Analysis Set, participants will be 
grouped according to the actual treatment received. Analyses based on the Post-Treatment Safety 
Analysis Set will be based on the treatment received during the on-treatment period. The actual 
treatment received will differ from the randomized treatment only when their actual treatment 
differs from randomized treatment for the entire treatment duration.
Potential Liver-Related Clinical Events, AEs, and Laboratory Toxicity Grading summaries will 
use the following groupings to summarize data by treatment group and treatment period.
Group A
• Delayed Treatment [DT] (Baseline up to Week 48): includes AEs with onset date on or 
after randomization date and prior to the first dose of BLV. The last laboratory value 
with a collection date on or prior to the randomization date is the baseline value; 
postbaseline laboratory collections (DT group) will be those with laboratory collection 
dates after randomization date and prior to the first dose date of BLV. For participants 
who prematurely discontinue from study prior to Week 48, events will be included up to 
early discontinuation from study if not receiving BLV (N = 51)
• DT to BLV 10 mg (Overall BLV treatment period): includes AEs with an onset date/time 
on or after the first dose date/time of BLV and up to the last dose date of BLV. The last 
laboratory value with collection date/time on or prior to first BLV dose date/time is 
assigned to the baseline laboratory value (ie, baseline is reset); postbaseline 
“on-treatment” laboratory collections after first BLV dose date/time and up to last dose 
date of BLV will be included. (N = 50, 1 participant from DT group terminated early 
before Week 48 visit). 
• DT to BLV 10 mg (Post-treatment period): includes AEs with an onset date after the last 
dose date of BLV and laboratory values with a collection date after the last dose date of 
BLV.


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Groups B and C
• Group B or C (BLV treatment period [Baseline up to Week 48]): event meets criteria for 
overall BLV treatment period (see next bullet) and AE onset is prior to Week 48 visit 
(laboratory collection is at or prior to Week 48) or participant discontinued study drug at 
or prior to Week 48. 
• Group B or C (Overall BLV treatment period): includes AEs with onset date/time on or 
after first dose date/time of BLV and up to last dose of BLV. The last laboratory value 
with collection date/time on or prior to BLV first dose date/time will be the baseline 
value; laboratory values with date/time of collection after first dose date/time of BLV 
and collection date up to last dose date of BLV) will be “on-treatment” values.
• Group B or C (Post-treatment period): includes AEs with an onset date after the last dose 
date of BLV, and laboratory values collected after the last dose date of BLV.
In the above descriptions, when both date and time are used in the comparison to determine 
period and at least one of the times is not available, then only the dates will be compared.
On-treatment and post-treatment data will be summarized on 2 separate tables for AEs, potential 
liver-related clinical events and laboratory toxicity grading. On-treatment displays will present 
data up to Week 48 (for comparison to control [DT group] through Week 48); and for all data 
collected while on BLV treatment (Weeks 0-144 for Groups B and C; Weeks 48-144 for DT to 
BLV 10 mg group for those dosed per protocol). On-treatment data will be summarized for the 
Safety Analysis Set; post-treatment data will be summarized for the Post-Treatment Safety 
Analysis Set.
Cumulative summaries displayed by visit will use the analysis visit windows as specified in 
Section 3.8.2 of the SAP to assign data to analysis visits. For the DT group, baseline will be the 
last value on or prior to randomization. For DT to BLV 10 mg group, baseline will be re-set as 
the last non-missing value on or prior to first dose of BLV (the re-baseline liver stiffness is the 
available value at Week 48).
3.3.
Strata and Covariates
Participants eligible for the study were randomly assigned to treatment groups via an electronic 
randomization system in a 1:1:1 ratio using a stratified randomization schedule. Stratification 
was based on the following variables:
•
Cirrhosis status at randomization (presence vs. absence)
Efficacy endpoints will be evaluated using stratification factors as covariates for analyses, as 
specified in Section 6.


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3.4.
Examination of Participant Subgroups
The primary efficacy endpoint combined response at Week 48 (and components [ALT 
normalization and virologic response]); all secondary endpoints (undetectable HDV RNA at 
Week 48, SVR24, SVR48, and liver stiffness by visit); by visit displays of categorical endpoints 
combined response, ALT normalization, and HBV DNA category (< LLOQ target not 
detected,< LLOQ target detected, and ≥ LLOQ); and continuous displays of ALT (U/L), HBV 
DNA (log10 IU/mL) and HBsAg (log10 IU/mL) and their respective changes from baseline will 
be examined using the following 2 subgroups:
•
Cirrhosis status at randomization (presence vs. absence)
•
Concomitant HBV treatment (Yes vs. No)
Categorical endpoints HDV RNA decrease ≥ 2 log10 IU/mL, undetectable HDV RNA, and 
virologic response by visit; and continuous endpoint HDV RNA (log10 IU/mL) and change from 
baseline by visit will be displayed by cirrhosis status at randomization.
Treatment-emergent adverse events (TEAEs) while on treatment up to Week 48 will be 
examined using the ADA incidence by Week 48 (positive vs. negative). Treatment-emergent 
AEs while on treatment up to Week 144 will be examined using the ADA incidence by Week 
144 (positive vs. negative). The geometric mean (95% CI) of BLV plasma concentration, and 
selected efficacy endpoints (complete response, ALT normalization, virologic response, and 
undetectable HDV RNA) will be examined by treatment group, visit, and ADA incidence at 
Week 144 (positive vs. negative). 
3.5.
Multiple Comparisons
One interim analysis at Week 24 and one primary analysis at Week 48 were conducted to 
compare the efficacy of BLV 10 mg versus delayed treatment and BLV 2 mg versus delayed 
treatment using the primary efficacy endpoint. To account for the repeated analysis of response 
(interim analysis at Week 24 and primary analysis at Week 48) the nominal two-sided 
significance level of 0.05 was split between the time points with 0.01 for Week 24 and 0.04 for 
Week 48. At each time point, the BLV dose was compared to DT group in terms of a hierarchical 
testing procedure starting with the higher dose (BLV 10 mg) at the respective adjusted two-sided 
significance levels.
Multiple group comparisons for the primary endpoint and a key secondary endpoint were 
handled with a hierarchical testing procedure. Details are described in Sections 6.2.1 and 6.3.1.
All other analyses will be considered explorative and no adjustment for multiple testing will be 
performed.


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3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified.
The handling of missing or incomplete dates for AEs is described in Appendix 3, and for prior 
and concomitant medications in Section 7.5. Imputation rules adopted in the efficacy analyses 
are specified in Section 6.
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis, unless 
otherwise specified.
3.7.
Data Handling Conventions and Transformations
In general, age in years at the time when informed consent was signed will be used for analyses 
and presented in listings. For DT to BLV 10 mg group, re-baseline age in years at Week 48 visit 
will be used for the analyses.
For virology laboratory data, pharmacokinetics data, molecular analysis data, and gene 
expression analysis data, the following rules will be applied:
•
Values below the lower limit of quantification (< LLOQ) with specification of target not 
detected (ie, < limit of detection [LOD]) will be imputed as 0.
•
Values < LLOQ (without specification of target not detected) will be imputed as half of the 
LLOQ value, if LLOQ does not equal the LOD.
•
Values < LLOQ (without specification of target not detected) will be imputed as 0, if LLOQ 
equals LOD (ie, HBV DNA by MLM).
•
Values above the upper limit of quantification (ULOQ) will be imputed as the ULOQ.
•
Non-measurable data will be considered as missing data.
For log10 transformed data, the following rules will be applied:
•
Untransformable value of 0 will be imputed as 0 if LOD > 1.
•
Untransformable value of 0 will be imputed as log10(LOD/2) if LOD < 1.
The LLOQ, ULOQ and LOD for virology are specified in the Table 3-1.


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Table 3-1.
Virology LLOQ and LOD
Parameters
Lab Institutes
LLOQ
LOD
HDV RNA
University Hospital Frankfurt (data 
transferred through MLM)
50 IU/mL
6 IU/mL
HBV DNA
University Hospital Frankfurt (data 
transferred through MLM)
10 IU/mL
10 IU/mL
HBV DNA
Invitro
100 IU/mL
20 IU/mL
HBsAg
University Hospital Frankfurt (data 
transferred through MLM)
not applicable
0.05 IU/mL
Safety laboratory data that are continuous in nature but less than the LLOQ or above the ULOQ 
(reported in the form of “< xx.xx” or “> xx.xx”) will be imputed as one half of LLOQ, or as the 
same as ULOQ to calculate summary statistics.
3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day will be calculated from the randomization date for DT group or from the first dosing 
date of BLV for Group B/C and for DT to BLV 10 mg group and derived as follows: 
•
For postdose study days: Assessment Date – First Dosing Date (or randomization date for DT 
group) + 1
•
For days prior to the first dose: Assessment Date – First Dosing Date (or randomization date 
for DT group)
Therefore, Study Day 1 is the day of randomization for DT group or the day of the first dose of 
BLV administration for Group B/C and DT to BLV 10 mg group.
3.8.2.
Analysis Visit Windows
The nominal visit as recorded on the CRF will be used when data are summarized by visit. 
However, when the nominal visit was made outside the analysis visit window, the value will not 
be included in analysis.


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Table 3-2.
Analysis Visit Windows for by Visit Assessments for Group A [DT] 
Group (for Quality of Life Only) and Groups B/C
Visit Window Study Day
Analysis Visit
Target Study 
Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 4
29
2
59
Week X*
X × 7+1
X × 7+1-30
X × 7+1+30
Follow-up Week X (Group A [DT]$/ B/C)
(144+X)×7+1
(144+X)×7+1-30
(144+X)×7+1+30
* For Group A BLV treated participants, the upper limit at Week 48 for DT group is First Dose Date of BLV – Study Day 1 + 1.
$ Follow-Up visits for Group A (DT) group are only applicable for Quality of Life Assessments.
Table 3-3.
Analysis Visit Windows Through Week 48 for Group A [DT group]
Visit Window Study Day
Analysis Visit
Target Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 4
29
2
59
Week X
X × 7+1
X × 7+1-30
X × 7+1+30
Week 48*
337
307
First Dose Date of 
BLV – Study Day 1 + 1 
(or 367 for participants 
not treated with BLV)
* Liver stiffness at Week 48 is the available value from Week 48 visit. 
Not applicable for Quality of Life.
Table 3-4.
Analysis Visit Windows for by Visit Assessments for Group A [DT to 
BLV 10 mg group]
Visit Window Study Day
Analysis Visit
Target on-BLV 
Study Day
Lower Limit
Upper Limit
Baseline on BLV*
1
(none)
1
Week 4 on BLV
29
2
59
Week X on BLV
X × 7+1
X × 7+1-30
X × 7+1+30
Follow-up Week X
(96+X)×7+1
(96+X)×7+1-30
(96+X)×7+1+30
* Liver stiffness baseline on BLV is the available value from Week 48 visit; last available value on or prior to first dose of BLV 
otherwise.
Not applicable for Quality of Life.
The measurement at end of treatment (EOT) is defined as the record collected at the visit within 
(last dose date of BLV ± 7 days) for groups A (DT to BLV 10 mg), B, and C.


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The data collected at unscheduled visits (including ET visits) will be used in the following ways:
•
An unscheduled visit on or prior to randomization for DT group or on or prior to the first 
dose of BLV may be included in the calculation of the baseline value, if applicable.
•
Unscheduled visits after randomization and up to first BLV dose (or up to last dose for ET 
prior to Week 48) for DT group or after the first dose of BLV and up to last dose of BLV will 
be included in determining the maximum postbaseline toxicity grade while on treatment.
•
Unscheduled visits after the first dose of BLV will be included in the determination of the 
value at EOT.
•
Unscheduled visits after the last dose of BLV will be included when determining the maximum 
postbaseline toxicity grade during the post-treatment period.
•
A record from an unscheduled visit will be assigned to a visit when there is no available data 
in the corresponding analysis visit window. If multiple measurements from unscheduled 
visits exist, the selection rules specified in Section 3.8.3 will be followed.
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value.
If multiple valid, non-missing measurements exist in an analysis window, records will be chosen 
based on the following rules if a single value is needed:
•
For baseline, the last non-missing value on or prior to the randomization date for the DT 
group, or on or prior to the first dosing date for BLV for all other groups will be selected, 
unless specified differently. 
•
For postbaseline values, records from scheduled visits or an ET visit will be selected. If there 
is no available scheduled visit or ET record, the data from unscheduled visits will be selected 
as described below.
The record closest to the target day for that visit will be selected.
If there are 2 records that are equidistant from the target day, the later record will be 
selected.


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4.
PARTICIPANT DISPOSITION
4.1.
Participant Enrollment and Disposition
A summary of participant enrollment will be provided by treatment group and overall for each 
region. The summary will present the number and percentage of participants enrolled. For each 
column, the denominator for the percentage calculation will be the total number of participants 
analyzed for that column.
A similar enrollment table will be provided by randomization stratum. The denominator for the 
percentage of participants in the randomization stratum will be the total number of enrolled 
participants.
A summary of participant disposition will be provided by treatment group and overall. This 
summary will present the number of participants screened, the number of participants who met 
all eligibility criteria but were not randomized with the reasons participants were not 
randomized, the number of participants randomized, the number of participants randomized but 
not dosed, and the number of participants in each of the categories listed below:
•
Safety Analysis Set 
•
Post-Treatment Safety Analysis Set
•
Full Analysis Set
•
Per-Protocol Week 48 Analysis Set
•
Per-Protocol Week 192 Analysis Set
•
Completed Week 24
•
Completed Week 48
•
Completed Week 96
•
Completed Week 144
•
Completed Week 192
•
Continuing study after Week 192
•
Did not complete the study with reasons for premature discontinuation of study
The number and percentage of participants discontinued from the study by Week 48, by 
Week 144, and for the study up to the Week 192 data cutoff will be presented along with the 
reasons for premature discontinuation. The denominator for the percentage calculation will be 
the total number of participants in the Safety Analysis Set corresponding to that column. 


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The following by-participant listings will be provided by participant ID number in ascending 
order to support the above summary tables:
•
Reasons for premature study discontinuation
•
Reasons for screen failure (will be provided by screening ID number in ascending order)
4.2.
Extent of Study Drug Exposure and Compliance
The sponsor will capture, clean, and validate the missing doses that are not documented in the 
participant diary (hereafter referred to as “sponsor identified missed doses”) in an excel file 
(included in the clean file report as an appendix).
4.2.1.
Study Drug Exposure
The total duration of BLV study drug exposure in weeks will be computed as (last dose date of 
BLV – first dose date of BLV + 1)/7 regardless of any temporary interruptions and will keep 
2 decimal places (ie, 4.56 weeks).
The total dose of BLV (in mg) study drug administered will be computed as the sum of all doses 
administered (as reported in the participant diary, which takes participant reported missed doses 
into consideration) minus sponsor identified missed doses (the number of days without dosing 
times the planned daily dose for BLV).
The dose intensity (in mg/week) will be computed as the total dose administered divided by the 
total duration of exposure.
4.2.2.
Study Drug Compliance
The compliance rate of the full regimen will be computed as the ratio of the total dose 
administered to the expected full regimen dose and expressed as a percentage. The expected full 
regimen dose for BLV is defined as 96 weeks of planned daily dosage (10 mg) for participants in 
DT to BLV 10 mg group, and 144 weeks of planned daily dosage (2 mg or 10 mg) for 
participants in Groups B and Group C.
The total number of missed doses will be computed as the expected total number of doses minus 
the number of doses administered (as reported in the participant diary), plus the number of 
additional sponsor identified missed doses. If this results in a negative number, the total number 
of missed doses will be set to the number of sponsor identified missed doses, or zero if there 
were no sponsor identified missed doses.
The expected total number of BLV study drug doses will be defined as:
Minimum of (last on-treatment visit, or study day 1006 [ie, study day 1006 = 144×7-2 per 
protocol visit window]) – first dose date + 1 
The proportion of missed doses will be computed as the ratio of the total number of missed doses 
to the expected total number of doses and expressed as a percentage.


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4.2.3.
Summaries of Study Drug Exposure and Compliance
Descriptive statistics for following parameters will be presented by treatment group (Group B, 
Group C, DT to BLV 10 mg) for BLV study drug.
•
Total duration of exposure (weeks)
•
Total dose administered (mg)
•
Dose intensity (mg/week)
•
Compliance rate (%)
•
Participants with ≥ 1 missed dose
•
Total number of missed doses
•
Percentage of missed doses (%)
In addition, the by-participant listings of BLV administration and accountability will be 
provided. No formal statistical testing is planned.
4.3.
Protocol Deviations 
Participants who did not meet the eligibility criteria for study entry but enrolled in the study will 
be summarized regardless of whether they were exempted by the sponsor or not. The summary 
will present the number and percentage of participants who did not meet at least 1 eligibility 
criterion and the number of participants who did not meet specific criteria by treatment group 
and overall based on the All Randomized Analysis Set. A by-participant listing will be provided 
for those participants who did not meet at least 1 eligibility (inclusion or exclusion) criterion. 
The listing will present the eligibility criterion (or criteria if more than 1 deviation) that 
participants did not meet and related comments, if collected.
Protocol deviations occurring after participants entered the study are documented during routine 
monitoring. The number and percentage of participants with important protocol deviations by 
deviation reason will be summarized by treatment group for the All Randomized Analysis Set. A 
by-participant listing will be provided for those participants with important protocol deviation.
4.4.
Assessment of COVID-19 Impact
This study was ongoing during the novel coronavirus (COVID-19) pandemic which had an 
impact on the study conduct. This section describes how special situations due to COVID-19 will 
be handled in the analysis.


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


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
Participant demographic and baseline characteristics variables will be summarized by treatment 
group (eg, DT group, BLV 2 mg group, BLV 10 mg group, and DT to BLV 10 mg group), and 
total, using descriptive statistics for continuous variables, and number and percentage of 
participants for categorical variables, where the total number is the sum of the DT group, BLV 
2 mg group, and BLV 10 mg group. The summary of demographic and baseline characteristics 
data will be provided for the FAS, PP 48W, and PP 192W Analysis Sets, for the following:
•
Age (years)
•
Sex (male, female)
•
Race (Asian, Black or African American, White)
•
Height (cm)
•
Body weight (kg)
•
Body mass index (BMI, kg/m2)
•
BMI category (<30 kg/m², ≥30 kg/m²)
If the Safety Analysis Set differs from the FAS, or there are participants whose actual treatment 
differs from randomized treatment for the whole treatment period, this summary will be provided 
for the Safety Analysis Set as well.
A by-participant demographic and baseline characteristics listing, including the informed consent 
date will be provided. No formal statistical testing is planned.
5.2.
Other Baseline Characteristics
Participants’ other baseline characteristics variables will be summarized by treatment group, and 
total using descriptive statistics for continuous variables, and number and percentage of 
participants for categorical variables. The summary of other baseline characteristics data will be 
provided for the FAS, PP 48W, and PP 192W Analysis Sets for the following:
•
Cirrhosis status at randomization (Presence, Absence)
•
Child–Pugh score for cirrhotic participants
•
Child–Pugh class for cirrhotic participants


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


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•
Baseline gamma glutamyl transferase (GGT) (U/L)
•
Baseline platelet count (×109/L)
•
Baseline total bilirubin (μmol/L)
•
Baseline total bile salts (μmol/L)
•
Concomitant Oral HBV medication (Yes/No)
For DT to BLV 10 mg, unless otherwise specified, a baseline value will be defined as the last 
measurement obtained on or prior to the first dose of BLV [at Week 48 visit]. Baseline liver 
stiffness is the available measurement from the Week 48 visit.
In summary tables of demographic and baseline characteristics, the original baseline values at 
randomization will be used for the DT to BLV 10 mg group for the following variables: 
•
Sex (male, female)
•
Race (Asian, Black or African American, White)
•
Height (cm)
•
Cirrhosis status at randomization (Presence, Absence)
•
Child–Pugh score for cirrhotic participants
•
Child–Pugh class for cirrhotic participants
•
Abdominal ultrasound (abnormal clinically significant [CS], abnormal not clinically 
significant [NCS], normal)
•
Serum alpha-fetoprotein (AFP; IU/mL)
•
Prior PEG-IFNα (prior medication preferred name contains the word ‘interferon’) (yes, no)
•
HIV antibody (positive, negative, missing)
•
HCV antibody (positive, negative, missing)
•
HDV antibody (positive, negative, missing)
•
HBeAg (positive, negative, missing)
•
HBeAg antibody (positive, negative, missing)
•
Qualitative HBV DNA at screening (positive, negative, missing)


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•
HDV genotype
•
HBV genotype
Estimated on-study creatinine clearance will be calculated by the Cockcroft-Gault method: 
creatinine clearance = [(140 – age (yrs)) × weight (kg) × (0.85 if female)] /(0.814 × creatinine 
(μmol/L)), where weight is total body mass in kilograms. 
If the Safety Analysis Set differs from the Full Analysis Set, or there are participants whose 
actual treatment differs from randomized treatment for the whole treatment duration, this 
summary will be provided for Safety Analysis Set as well.
A by-participant listing of other baseline characteristics will be provided. No formal statistical 
testing is planned.
5.3.
Substance Use
Participant substance use will be summarized by treatment group, and overall using number and 
percentage of participants. The summary will be provided for the FAS, PP 48W, and PP 192W 
Analysis Sets, for the following:
•
Alcohol breath test at screening (Positive, Negative)
•
Alcohol breath test at baseline (Positive, Negative)
•
Alcohol consumption status (Current, Former, Never) 
•
Smoking status (Current, Former, Never)
•
Urine drug test at screening (Positive, Negative)
•
Drug abuse status (Current, Former, Never)
5.4.
Medical History
Medical history collected at screening will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) v26.1.
Medical history will be summarized for the Safety Analysis Set by system organ class (SOC), 
preferred term (PT), treatment group, and overall. Participants who reported 2 or more medical 
history terms that are coded to the same SOC and/or PT will be counted only once by the unique 
coded term in the summary. No formal statistical testing is planned. 
A by-participant listing of medical history will be provided.


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6.
EFFICACY ANALYSES
6.1.
General Considerations
The primary analysis set for efficacy analyses will be the FAS, defined in Section 3.1.2.
Derivation of Multi-component Endpoints
For the derivation of multi-component endpoints including combined response and virological 
response, the following steps will be used unless otherwise specified:
•
Step 1: assign individual components to analysis visit windows specified in Section 3.8.2.
•
Step 2: impute missing data for individual component(s)
•
Step 3: derive the multi-component endpoint using each individual component (or the 
imputed value from step 2 above, if the individual component is missing)
Missing Data Imputation
Below are the descriptions for the imputation methods that will be used in the efficacy analyses:
•
Missing Equals Failure (MEF): For binary response endpoints, a missing value will be 
imputed as nonresponder. 
─For analyses of combined response at Week 24 and 48 (primary endpoint); 
undetectable HDV RNA at Week 24 and Week 48 (key secondary endpoint), SVR24, 
and SVR48 (secondary endpoint) using FAS, MEF will be adopted when missing was 
not related to COVID-19. 
─MEF adopted for sensitivity analyses of primary and key secondary endpoints.
─In addition, MEF will be adopted for all analyses of binary endpoints for the 
secondary and 
 endpoints using FAS.
•
Last observation carrying forward (LOCF): Missing value will be imputed using the last 
observation (including observation from unscheduled visit). For all analyses (except the 
sensitivity analysis) of the primary efficacy endpoint and undetectable HDV RNA at 
Week 24 and Week 48 using FAS, LOCF will be used when missing was related to 
COVID-19.
•
Next observation carrying backward (NOCB): Missing value will be imputed using the next 
observation (including observation from unscheduled visit). For secondary efficacy endpoints 
of SVR24 and SVR48 using FAS, NOCB will be used when a missing value was related to 
COVID-19.
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•
Observed Case (OC): Missing values remain missing. The OC will be used for analyses of 
continuous endpoints, for SVR24 (using FAS), and analyses using the PP 48W and PP 192W 
Analysis Sets. By visit displays up to Week 192 for the following efficacy endpoints will be 
displayed using OC for the FAS: combined response, HDV RNA Undetectable, ALT 
normalization, virologic response, ≥ 2 log10 IU/mL decrease from baseline in HDV RNA, 
HBV DNA category, liver stiffness, and quality of life.
6.2.
Primary Efficacy Endpoints
The primary efficacy endpoint is combined response at Week 48. Combined response is defined 
as fulfilling both of the following 2 conditions simultaneously: 
•
Undetectable (< LLOQ, target not detected) HDV RNA or decrease in HDV RNA by 
≥ 2 log10 IU/mL from baseline 
•
ALT normalization
6.2.1.
Primary Analysis of the Primary Efficacy Endpoint
Two 2-sided Fisher’s exact 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
where pO, pM2mg, and pM10mg are the expected response rate for delayed treatment, BLV 2 mg and 
BLV 10 mg, respectively. In terms of a hierarchical testing procedure, the second null hypothesis 
will not be rejected if the first null hypothesis could not be rejected. These hypotheses were 
tested at the Week 24 interim analysis and at the Week 48 primary analysis. To account for the 
repeated analysis, the nominal two-sided significance level of 0.05 will be split between these 
two time points with 0.01 for Week 24 and 0.04 for Week 48.
The primary analysis of combined response at Week 24 is the estimated rate difference between 
BLV and delayed treatment group with 99% exact unconditional CI for the difference based on 
the score statistic. The p-value from a 2 two-sided Fisher’s exact test will also be provided. There 
is a statistically significant difference at Week 24 if p < 0.01. In addition, for each group, the 
response rate with Clopper-Pearson 95% CIs will be presented.
The primary analysis of combined response at Week 48 is the estimated rate difference between 
BLV and delayed treatment group with 96% exact unconditional confidence interval (CI) for the 
difference based on the score statistic. The p-value from a 2 two-sided Fisher’s exact test will 
also be provided. There is a statistically significant difference at Week 48 if p < 0.04. The 
comparison of BLV 2 mg versus delayed treatment is considered significant only if the 
comparison of BLV 10 mg versus delayed treatment is significant. In addition, for each group, 
the response rate with Clopper-Pearson 95% CIs will be presented.
The primary analysis will be based on the FAS.


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6.2.2.
Sensitivity Analysis of the Primary Efficacy Endpoint
The same analysis as specified in Section 6.2.1 will be repeated using the data for which missing 
values were imputed as failure regardless of whether it was related to COVID-19 (Section 6.1).
6.2.3.
Per-protocol Analysis of the Primary Efficacy Endpoint
The same analysis as specified in Section 6.2.1 will be repeated using the PP 48W Analysis Set 
based on actual treatment on the observed cases without imputing missing values, as a supportive 
analysis.
6.2.4.
Subgroup Analysis of the Primary Efficacy Endpoint
With an expected low number of responders in the delayed treatment group, the primary efficacy 
analysis will not be stratified by cirrhosis or other covariables. Descriptive analyses of combined 
response will be presented by subgroups for efficacy endpoints as defined in Section 3.4.
6.3.
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
•
Undetectable HDV RNA at Week 48 (key secondary efficacy endpoint)
•
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)
•
Change from baseline in liver stiffness as measured by elastography at Weeks 48, 96, 144, 
192, and 240
The change from baseline in liver stiffness at Week 240 will be analyzed in the final CSR.
6.3.1.
Analysis of Secondary Efficacy Endpoints
Undetectable HDV RNA at Week 48 (key secondary endpoint)
The proportion of participants with undetectable HDV RNA at Week 48 is the key secondary 
endpoint and will be used to test differences between the BLV doses and hence evaluate the dose 
response relationship. 
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H03: rM2mg = rM10mg vs. H13: rM2mg ≠ rM10mg
where rM2mg, rM10mg are the expected rates of participants with undetectable HDV RNA at 
Week 48 for BLV 2 mg and BLV 10 mg, respectively.
This test will only be performed if the two null-hypotheses for the primary variable (H01 and H02 
in 6.2.1) have both been rejected. As for the primary analysis, the above hypothesis will also be 
tested at Week 24 and hence the nominal two-sided significance level of 0.05 will be split 
between the time points with 0.01 for Week 24 and 0.04 for Week 48, respectively. 
The estimated rate differences between BLV 10 mg and BLV 2 mg with exact unconditional CI 
based on score statistic (99% CI for Week 24 and 96% CI for Week 48), and the p-value from a 
Fisher’s exact test will be provided using FAS and PP 48W Analysis Set. The Clopper-Pearson 
95% CIs on the undetectable HDV RNA rate in each group will also be presented. The same 
summary will be repeated by subgroups for efficacy endpoints as defined in Section 3.4.
ALT Normalization at Week 48
The proportion of participants with ALT normalization at Week 48 will be compared between 
BLV 2 mg and the delayed treatment group and BLV 10 mg and the delayed treatment group 
using a two-sided Fisher’s exact test. Nominal p-values without multiple comparison adjustment 
and 95% exact unconditional confidence intervals based on score statistic for the proportion 
differences will be provided. The same analysis will be performed at Week 24 and at Week 48, 
using FAS and using PP 48W Analysis Set. In addition, for each group, the Clopper-Pearson 
95% CIs on the response rate will also be presented. The same summary will be repeated by 
subgroups for efficacy endpoints as defined in Section 3.4.
SVR24 and SVR48
Response rate for SVR24 and SVR48 will be displayed and compared between the BLV 2 mg 
and [DT to BLV 10 mg group] and between the BLV 2 mg group and BLV 10 mg group using a 
two-sided Fisher’s exact test. Nominal p-values without multiple comparison adjustment and 
95% exact unconditional confidence intervals based on score statistic for the proportion 
differences will be provided for the SVR rates. For each group, the Clopper-Pearson 95% CI on 
the SVR rates will also be presented. Analysis will be performed for the FAS using NOCB for 
COVID-related missing values and MEF otherwise, for both SVR24 and SVR48. An analysis for 
the PP 192W Analysis Set using OC for SVR48; and FAS using OC for SVR24 will also be 
performed.
Analysis for FAS (NOCB for COVID-related missing values, and MEF otherwise) for SVR24 
and SVR48, PP 192W Analysis Set using OC for SVR48, and FAS using OC for SVR24 will be 
repeated for the subgroups defined in Section 3.4.
Results of SVR24 (Responder, Nonresponder) versus SVR48 (Responder, Nonresponder) will be 
displayed by treatment group (DT to BLV 10 mg, BLV 2 mg, and BLV 10 mg) for participants 
with a non-missing value at both timepoints to explore whether the outcomes at the 2 timepoints 
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Change from Baseline in Liver Stiffness at Week 487 Week 967 Week 1447 and Week 192 
For the change from baseline in liver stiffness at Week 48, an ANCOVA model will be used to 
compare the least squares (LS) means between BL V 2 mg and the delayed ti·eatment group, and 
BL V 10 mg and the delayed ti·eatment group using FAS and PP 48W Analysis Set The model 
includes ti·eatment, region, presence of cinhosis and baseline liver stiffness as a covariate. 
Nominal p-values without multiple comparison adjustment and the 95% CI for the LS mean 
difference between each BL V group and the delayed ti·eatment group will be provided. In 
addition, for each h'eatment group, the LS mean will be provided. 
For the change from baseline in liver stiffness at Week 96, Week 144, and Week 192, a 
mixed-effects model for repeated measurements (MMRM) will be used to evaluate ti·eatment 
effect using FAS. The model includes ti·eatment (BLV 2 mg, BLV 10 mg, and DT to BLV 10 mg 
group), region, presence of cinhosis, visit, and ti·eatment by visit interaction as fixed effects, and 
baseline liver stiffness (the baseline for DT to BLV 10 mg group is the reset baseline) as 
covariable. An lmsti11ctured variance-covariance man-ix will be used. The Kenward-Roger 
method will be used to estimate the degrees of freedom. Resti·icted maximum likelihoods 
(REML) will be used to fit the model. Missing change values will not be othe1w ise imputed 
using MMRM. For each ti·eatment group, the LS mean with 95% CI at Week 96 and FU-48 (for 
DT to BLV 10 mg group, Group Band Group C) and at Week 144 (for Group Band Group C 
only) will be presented respectively. In addition, the difference in LS means and the 95% CI for 
the LS mean difference between BL V 2 mg ( Group B) and BL V 10 mg ( Group C) at each visit 
will be provided. 
Descriptive statistics of liver stiffness at each visit, as well as the change from baseline, will be 
provided by ti·eatment group. The summaiy will be repeated by subgroups for efficacy endpoints 
defined in Section 3 .4 using FAS. The plots of mean ± SD of change from baseline in liver 
stiffness over time, as well as by subgroup of cinhosis status, will be presented. 
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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
Clinical and laboratory adverse events (AEs) will be coded using the MedDRA v26.1. System 
organ class (SOC), high-level group term (HLGT), high-level term (HLT), preferred term (PT), 
and lower-level term (LLT) will be provided in the AE dataset.
7.1.1.
Adverse Event Severity
Adverse events are graded as Grade 1, 2, 3, 4, or 5 according to the Common Terminology 
Criteria for Adverse Events (CTCAE, Version 5.0). Events for which a CTCAE term cannot be 
found will be assigned a severity grade according to the classification of AEs specified in the 
study protocol. The severity grade of events for which the investigator did not record severity 
will be categorized as “missing” for tabular summaries and data listings. The “missing” category 
will be listed last in summary presentation.
7.1.2.
Relationship of Adverse Events to Study Drug
The related AEs for each study drug are those for which the investigator selected “Reasonable 
possibility” on the AE eCRF to the question of causality. Relatedness will always default to the 
investigator’s choice, not that of the medical monitor. Events for which the investigator did not 
record relationship to study drug will be considered related to study drug for summary purposes. 
However, by-participant data listings will show the relationship as missing.
7.1.3.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs meet the 
definitions of SAEs that were specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with the SAEs captured and stored in the Gilead global safety 
database before data finalization.
For SAEs with multiple reports (initial reports and one or more follow-up reports), only the last 
report will be included in the summary tables and listings.
7.1.4.
Treatment-Emergent Adverse Events
7.1.4.1.
Definition of Treatment-Emergent Adverse Events
For the DT group, treatment-emergent adverse events (TEAEs) are defined as the following:
•
Any AEs with an onset date on or after randomization date and before BLV start date
•
Any AEs with an onset date on or after the randomization date and prior to the Week 48 visit 
date, or up to study discontinuation date if the participant discontinued the study before the 
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For DT to BLV 10 mg, BLV 2 mg and BLV 10 mg groups, TEAEs are defined as 1 or both of 
the following:
•
Any AEs with an onset on or after study drug start and no later than 30 days after permanent 
discontinuation of study drug
•
Any AEs leading to premature discontinuation of study drug 
For delayed treatment participants who switched to BLV 10 mg, TEAEs with onset prior to the 
first dose of BLV will be allocated to the DT group. TEAEs with onset on or after the first dose 
of BLV will be allocated to the DT to BLV 10 mg group.
For BLV 2 mg and BLV 10 mg groups, TEAEs with onset prior to the Week 48 visit will be 
allocated to the baseline to Week 48 period.
7.1.4.2.
Definition of Post Treatment Adverse Events
For DT to BLV 10 mg, BLV 2 mg and BLV 10 mg groups, post-treatment AEs are defined as:
•
Any AE with an onset after the last dose of BLV study drug 
7.1.4.3.
Incomplete Dates
If the onset or end date of an AE is fully or partially unknown, the incomplete date will be 
imputed before analysis according to the rules in Appendix 3.
7.1.5.
Summaries of Treatment-Emergent Adverse Events and Deaths (On-
Treatment Period)
Treatment-emergent AEs while on treatment will be summarized based on the Safety Analysis 
Set. The AEs will be allocated to “on-treatment time periods” based on AE onset, randomization 
date (DT group only), Week 48 visit date, and the start and end of BLV dosing (see Section 3.2).
•
TEAEs up to Week 48 (DT, BLV 2 mg, BLV 10 mg groups) 
•
TEAEs up to Week 144 (BLV 2 mg and BLV 10 mg groups)
•
TEAEs Week 48 (first BLV dose) up to Week 144 (DT to BLV 10 mg group)
7.1.5.1.
Summaries of AE incidence in Combined Severity Grade Subsets (On-Treatment 
Period)
A brief, high-level summary of the number and percentage of participants who experienced at 
least 1 TEAE while on treatment in the categories described below will be provided by treatment 
group and “on-treatment time period”. All AEs with outcome of death with an onset while on 
treatment will also be included in this summary.


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The number and percentage of participants who experienced at least 1 TEAE while on treatment 
during the “on-treatment” periods described above will be provided and summarized by SOC, 
PT, and treatment group for the AE categories described below:
•
TEAEs
•
TEAEs with Grade 3 or higher 
•
TEAEs with Grade 2 or higher
•
TE treatment-related AEs
•
TE treatment-related AEs with Grade 3 or higher 
•
TE treatment-related AEs with Grade 2 or higher
•
TE SAEs
•
TE treatment-related SAEs 
•
TEAEs leading to premature discontinuation of study drug
•
TEAEs leading to death (ie, outcome of death)
Multiple events will be counted only once per participant in each summary. Adverse events will 
be summarized and listed first in alphabetic order of SOC, and then by PT in descending order of 
BLV 2 mg frequency (baseline up to Week 144 period) within each SOC. For summaries by 
severity grade, the most severe grade will be used for those AEs that occurred more than once in 
an individual participant and treatment period. 
In addition to the above summary tables, all TEAEs, TEAEs with Grade 3 or higher, TEAEs 
occurring in ≥ 10% of participants in any treatment group, TE SAEs, AEs leading to premature 
discontinuation of BLV, TE treatment-related AEs, and TE treatment-related SAEs will be 
summarized by PT only, in descending order of BLV 2 mg frequency (baseline up to Week 144 
period).
In addition data listings that include events reported throughout the duration of the study will be 
provided for the following:
•
All AEs, indicating whether the event is treatment-emergent
•
All SAEs
•
All Deaths
•
All AEs with severity of Grade 3 or higher


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•
All AEs with severity of Grade 2 or higher
•
All AEs leading to premature discontinuation of study drug 
Adverse events with an onset or resolution date after last dose of BLV study drug will be flagged 
with the symbol ‘~’ and the number of days post last dose of BLV will be presented for the 
column “Days” in the listing.
7.1.6.
Additional Analysis of Adverse Events (On-Treatment Period)
7.1.6.1.
Hepatic Adverse Events
Hepatic AEs potentially indicative of hepatitis flares will be identified using MedDRA v26.1 
search terms. The number and percentage of participants who experienced any TE hepatic AE 
while on treatment will be summarized by PT, treatment group, and “on-treatment period”. 
The by-participant listing of hepatic AEs will also be provided and will include events reported 
throughout the duration of the study. Hepatic AEs with an onset or resolution date after last dose 
of BLV study drug will be flagged with the symbol ‘~’ and the number of days post last dose of 
BLV will be presented for “Days” column in the listing.
7.1.6.2.
Subgroup Analyses of Treatment-Emergent Adverse Events
Treatment-emergent AEs while on treatment by anti-drug antibody (ADA) incidence at Week 48 
will be provided by PT and treatment group: 
•
For DT, Group B and Group C, TEAEs (while on treatment for Groups B and C) from 
baseline up to Week 48 will be summarized by treatment and ADA incidence at Week 48. 
Treatment-emergent AEs while on treatment by anti-drug antibody (ADA) incidence at 
Week 144 will be provided by PT and treatment group: 
•
For Group B and Group C, TEAEs while on treatment from baseline up to Week 144 will be 
summarized by treatment and ADA incidence. 
•
For DT to BLV 10 mg, TEAEs while on treatment from BLV first dose (ie, Week 48) up to 
Week 144 will be summarized by ADA incidence. The ADA incidence will be derived using 
ADA data prior to the first dose of BLV at the Week 48 visit as baseline and ADA data after 
participants receive BLV as postbaseline assessments.
7.1.7.
Summaries of Adverse Events (Post-Treatment Period)
Posttreatment AEs will be summarized for the Post-Treatment Safety Analysis Set for the 
treatment groups BLV 2 mg, BLV 10 mg, and DT to BLV 10 mg.


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7.1.7.1.
Summaries of Posttreatment AEs by Preferred Term
The number and percentage of participants who experienced at least 1 post-treatment AE will be 
summarized by PT, and treatment group for the AE categories described below:
•
AEs in the post-treatment period
•
AEs with Grade 3 or higher in the post-treatment period 
•
SAEs in the post-treatment period
•
AEs leading to death (ie, outcome of death) in the post-treatment period
•
AEs that occurred in ≥ 5% of Participants in Any Treatment Group during the post-treatment 
period
Multiple events with the same PT will be counted only once per participant in each summary. 
Posttreatment AEs will be summarized by PT in descending order of BLV 2 mg frequency and 
then alphabetically by PT for those AEs with the same BLV 2 mg frequency. For summaries by 
severity grade, the most severe grade will be used for those AEs that occurred more than once in 
an individual participant during the study. 
7.1.8.
Additional Analysis of Adverse Events (Post-Treatment Period)
7.1.8.1.
Hepatic Adverse Events
A post-treatment summary of hepatic AEs potentially indicative of hepatitis flare (identified 
using MedDRA v26.1 search terms) will be displayed for BLV 2 mg, BLV 10 mg, and DT to 
BLV 10 mg groups. 
7.1.8.2.
Adverse Events Reported After Administration of Commercial BLV
Adverse events with an onset date on or after the start date of commercial BLV drug (identified 
by Bulevirtide/Hepcludex/Myrcludex recorded on the concomitant medication [CM] eCRF) in 
the post-treatment period will be listed.
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. All available data at the time of the database snapshot will 
be included for participants who were ongoing at the time of an interim analysis. When values 
are below the LOQ, they will be listed as such, and the imputed value will be used for the 
purpose of calculating summary statistics as specified in Section 3.7. 
Separate by-participant listings for laboratory test results throughout the duration of the study 
will be provided by participant ID number and visit in chronological order for hematology, 
coagulogram, serum chemistry, total bile salts, and urinalysis. Values falling outside of the 
relevant reference range and/or having a severity grade of 1 or higher on the CTCAE severity 
grade will be flagged in the data listings, as appropriate. No formal statistical testing is planned.


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7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics of baseline values, values at each postbaseline visit (including 
post-treatment visits through Follow-Up Week 48 [Study Week 192]), and change from baseline 
at each postbaseline visit will be provided on a single table for the Safety Analysis Set by 
treatment group for the following laboratory tests. White blood cell differential results from 
manual assay will not be included as they are not considered valid.
•
Hematology 
Haematocrit (%)
Haemoglobin (g/dL)
Platelet Count (×109/L)
Reticulocytes (‰)
Red Blood Cells (×1012/L)
White Blood Cells (×109/L)
Absolute Neutrophils (×109/L)
Relative Neutrophils (%)
Absolute Eosinophils (×109/L)
Relative Eosinophils (%)
Absolute Basophils (×109/L)
Relative Basophils (%)
Absolute Monocytes (×109/L)
Relative Monocytes (%)
Absolute Lymphocytes (×109/L)
Relative Lymphocytes (%)
•
Total Bile Salts (μmol/L)


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•
Coagulogram
Prothrombin Time (%)
Activated Partial Thromboplastin Time (aPTT) (sec)
International Normalized Ratio (INR)
•
Chemistry
Albumin (g/L) 
ALP (U/L)
AST (U/L) 
Total Bilirubin (μmol/L) 
Direct Bilirubin (μmol/L) 
C-Reactive Protein (mg/L)
Chloride (mmol/L) 
Total Cholesterol (mmol/L) 
Creatinine (μmol/L) 
GGT (U/L) 
Glucose (mmol/L) 
Lipase (U/L) 
Total Amylase (U/L) 
Pancreatic Amylase (U/L)
Phosphate (mmol/L) 
Potassium (mmol/L) 
Total Protein (g/L) 
Sodium (mmol/L) 
Urea (mmol/L) 
Vitamin D (ng/mL)


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•
Urinalysis
pH
Specific Gravity (g/L)
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
first dose of BLV or on or prior to randomization for the DT group. Change from baseline to a 
postbaseline visit will be defined as the visit value minus the baseline value. The mean, median, 
Q1, Q3, minimum, and maximum values will be displayed to the reported number of digits; SD 
values will be displayed to the reported number of digits plus 1.
Median (Q1, Q3) of the observed values for these laboratory tests will be plotted for the Safety 
Analysis Set using a line plot by treatment group and visit.
For laboratory data collected at follow-up visits during the post-treatment period, the change 
from EOT at each post-treatment visit will also be included in the change from baseline tables 
(described above) for the following laboratory tests: platelets, white blood cell (WBC), absolute 
and relative eosinophils, total bile salts, total bilirubin, direct bilirubin, albumin, GGT, 
Vitamin D, AST, total amylase, pancreatic amylase, INR, and creatinine. 
7.2.2.
Summaries of Qualitative Laboratory Results
The summary of clinical assessment of laboratory variables (abnormal high CS, abnormal high 
NCS, normal, abnormal low NCS, abnormal low CS) will be provided by visit (including 
post-treatment visits through Follow-Up Week 48 [Study Week 192]) and treatment group for 
laboratory tests listed in Section 7.2.1 as well as for urinalysis of protein, glucose, bilirubin, 
urobilinogen, ketones, erythrocytes, leukocytes, and nitrites.
7.2.3.
Shifts Relative to the Baseline Value
Shift tables will be presented by showing changes in results from baseline value (abnormal high 
CS, abnormal high NCS, normal, abnormal low NCS, abnormal low CS) to Weeks 48, 96, 144, 
and FU-48 (ie, Study Week 192) for laboratory tests listed in Section 7.2.1 and 7.2.2. The 
number and percentage of participants in each cross-classification group of the shift table will be 
presented. Participants with a missing value at baseline or at the postbaseline visit will not be 
included in the denominator for percentage calculation at the visit.
7.2.4.
Graded Laboratory Values
The CTCAE Version 5.0 will be used to assign toxicity grades (0 to 4) to laboratory results for 
analysis. Grade 0 includes all values that do not meet the criteria for an abnormality of at least 
Grade 1. For laboratory tests with criteria for both increased and decreased levels, analyses for 
each direction (ie, increased, decreased) will be presented separately. 


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7.2.4.1.
Treatment-Emergent Laboratory Abnormalities (On-Treatment Period)
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline for postbaseline values up to BLV first dose or ET for DT group; 
or up to last BLV dose date + 30 days for other groups. Baseline value is the last laboratory value 
collected on or prior to randomization for DT group and last value collected on or prior to first 
BLV dose for other groups. If the relevant baseline laboratory value is missing, any abnormality 
of at least Grade 1 observed within the time frame specified above will be considered treatment 
emergent.
The summary of TE laboratory abnormalities in the on-treatment period will be provided for:
•
TE laboratory abnormalities up to Week 48 (DT, BLV 2 mg, BLV 10 mg groups) 
•
TE laboratory abnormalities up to Week 144 (BLV 2 mg and BLV 10 mg groups)
•
TE laboratory abnormalities from Week 48 (first BLV dose) up to Week 144 (DT to BLV 
10 mg group)
TE lab abnormalities will be allocated to “on-treatment time periods” based on laboratory 
collection date, randomization date (DT group only), Week 48 visit date, and the start and end of 
BLV dosing (see Section 3.2).
7.2.4.2.
Summaries of Laboratory Abnormalities (On-Treatment Period)
The following summaries (number and percentage of participants) for TE laboratory 
abnormalities while on treatment (up to Week 48 and up to Week 144) will be presented: 
•
Graded laboratory abnormalities
•
Grade 3 or 4 laboratory abnormalities
For all summaries of laboratory abnormalities while on treatment, the denominator is the number 
of participants with non-missing postbaseline values during the relevant treatment period. 
Participants will be categorized according to the most severe postbaseline abnormality grade for 
a given lab test during the treatment period.
A by-participant listing of treatment-emergent laboratory abnormalities while on treatment will 
be provided by participant ID number and visit in chronological order. This listing will include 
all test results that were collected throughout the study for the lab test of interest, with all 
applicable severity grades or abnormal flags (highest grade from randomization up to Week 48 
for DT group, and while on treatment during the “on-treatment” period for all other groups) 
displayed. A similar by-participant listing of treatment-emergent Grade 3 or 4 laboratory 
abnormalities while on treatment will also be provided.


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7.2.4.3.
Summaries of Laboratory Abnormalities (Post-Treatment Period)
The number and percentage of participants categorized by the most severe post-treatment 
toxicity grade collected during the post-treatment follow-up period will be summarized by 
treatment group for each laboratory parameter (including hyper and hypo directions with 
toxicity-grading [when applicable]) and overall (for all laboratory tests at the participant level) 
for all lab tests with toxicity grading. Denominator for percentage calculation will be the number 
of participants with a non-missing value in the post-treatment period.
A listing will include test results collected throughout the study for the laboratory test with at 
least 1 Grade 3 or 4 toxicity grade during the post-treatment period. Laboratory collection dates 
after last dose of BLV study drug will be flagged with the symbol ‘~’ for the number of days 
post last dose of BLV in the “Days” column for that date in the listing. All applicable severity 
grades and/or abnormal flags will be presented in the listing with the highest severity for a 
laboratory test and participant during the post-treatment period flagged.
7.2.5.
Liver-related Laboratory Evaluations
7.2.5.1.
Potential Drug Induced Liver Injury (DILI) While on Treatment
The participants who meet any one of the following criteria for potential drug induced liver 
injury (DILI) will be summarized by treatment group and on-treatment period, and the 
corresponding listing will be provided:
•
Criteria 1: ALT and/or AST > 3×ULN and total bilirubin > 2×ULN
•
Criteria 2: ALT > 5×ULN
•
Criteria 3: Total bilirubin > 2×ULN
Events will be allocated to “on-treatment periods” based on the laboratory collection date, 
randomization date (DT group only), Week 48 visit date, and the start and end of BLV dosing 
(see Section 3.2).
7.2.5.2.
Posttreatment ALT > 5 x ULN and ALT > 10 x ULN
The number and percentage of participants with posttreatment ALT values meeting the criteria 
below will be displayed by treatment group for the Post-treatment Safety Analysis Set:
•
ALT > 5 x ULN
•
ALT > 10 x ULN
The denominator for percentage calculation will be the number of participants in the treatment 
group with at least 1 post-treatment ALT value collected. A supporting listing of participants 
meeting criteria will be created.


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7.3.
Body Weight and Vital Signs
Descriptive statistics will be provided by treatment group and visit (including post-treatment 
visits through Follow-Up Week 48 [Study Week 192]) for participants in the Safety Analysis Set 
for body weight, and vital signs (systolic and diastolic blood pressures [mmHg], respiratory rate 
[breaths/min] and body temperature [C]) as follows:
•
Baseline value
•
Values at each postbaseline visit
•
Change from baseline at each postbaseline visit
A baseline value will be defined as the last available value collected on or prior to the date/time 
of the first dose of BLV study drug for the DT to BLV 10 mg, BLV 2 mg, and BLV 10 mg 
groups, and the last value on or prior to randomization for the DT group. Change from baseline 
to a postbaseline visit will be defined as the postbaseline value minus the baseline value. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No formal statistical testing is planned.
A by-participant listing of vital signs will be provided by participant ID number and visit in 
chronological order. Body weight will be included in the vital signs listing, if space permits. If 
not, they will be provided separately.
7.4.
Physical Examination
For each type of local reaction at injection site, the number and percentage of participants with at 
least one instance reported as an AE will be summarized by severity and treatment, and the 
maximum severity grade of the reaction type will be presented. In addition, a by-participant 
listing will be provided for local reaction at injection site.
7.5.
Prior, Concomitant, and Post-Treatment Medications
Medications collected at screening and during the study will be coded using the World Health 
Organization (WHO) Drug dictionary.
7.5.1.
Prior, Concomitant, and Post-Treatment Medications
Prior medications are defined as medications stopped prior to the first dose of BLV (for 
Groups B, C, and DT to BLV 10 mg group) or prior to randomization date for the DT group. For 
Group B, C, and DT to BLV 10 mg group, concomitant medications are defined as ongoing 
medications or medications stopped on or after the first dose of BLV, excluding medications 
started after the last dose of BLV. For the DT group, concomitant medications are defined as 
ongoing medications or medications stopped on or after the date of randomization, excluding 
medications started on or after the first dose of BLV. Post-treatment medications are defined as 
medications that start after the last dose of BLV.


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If the medication start or stop date is partially unknown, the incomplete date will be imputed 
according to the rules in the Table 7-1. If a medication cannot be classified using the reported 
and/or imputed start and end dates, it will be considered as concomitant medication. The original 
reported dates will be presented in data listings.
Table 7-1
Imputed Partial Medication Dates
Scenario
Imputed Start Date
Imputed End Date
Unknown year
Missing
Missing
Unknown month
01 January
31 December
Unknown day
First day of month
Last day of month
7.5.2.
Summaries of Non-Study Drug Medications
Prior medications, concomitant medications, and post-treatment medications will be summarized 
by preferred name using the number and percentage of participants for each treatment group and 
overall. A participant reporting the same medication more than once will be counted only once 
when calculating the number and percentage of participants who received that medication. The 
summary will be ordered by preferred term in order of descending overall frequency. For drugs 
with the same frequency, sorting will be done alphabetically.
Prior and concomitant summaries will be based on the Safety Analysis Set; post-treatment 
summaries will be based on the Post-Treatment Safety Analysis Set. No formal statistical testing 
is planned. In addition, a by-participant listing will be provided.
7.5.3.
HBV Medications
HBV medications are defined as oral medications with preferred names containing any of the 
following terms: tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, tenofovir 
disoproxil, entecavir, adefovir, adefovir dipivoxil, lamivudine, telbivudine.
The following HBV medications summaries will be provided by preferred name using the 
number and percentage of participants for each treatment group and overall; in addition, the 
corresponding listings will be generated:
•
Participants with concomitant HBV medications
•
Participants with HBV medications started in the post-treatment period (based on the 
Post-Treatment Safety Analysis Set)
•
HBV medications started before baseline and ongoing during treatment: participants with any 
HBV medication started prior to the first dose of BLV or before randomization for Group A 
DT group, and any concomitant HBV medication (same as or different from the previous 
one[s]) ongoing on/after the first dose of BLV (randomization for the DT group)


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•
Participants with prior HBV medications (stopped before baseline): participants with all 
HBV medications stopped before the first dose of BLV or before randomization for the 
DT group
•
HBV medications started on-treatment: participants with all HBV medications started 
on/after the first dose of BLV (randomization for the DT group) and on/before the last dose 
of BLV (before the first dose of BLV or until ET before Week 48 visit for the DT group)
Summaries will be based on the Safety Analysis Set (except where specifically noted otherwise). 
No formal statistical testing is planned.
7.5.4.
Commercial BLV
A listing of participants who started commercial BLV drug (Bulevirtide/Hepcludex/Myrcludex 
recorded on the concomitant medication [CM] eCRF) will be provided. The first and last dose 
date of BLV study drug and the number of days post last dose for start and end date (when 
applicable) of administration of commercial BLV drug will be included in the listing.
7.6.
Electrocardiogram Results
7.6.1.
Investigator Electrocardiogram Assessment
The investigator’s assessment of electrocardiogram (ECG) results (normal, abnormal NCS, 
abnormal CS, or missing) will be tabulated for the Safety Analysis Set at each visit (including 
post-treatment visits through Follow-Up Week 48 [Study Week 192]) by treatment group. In 
addition, a shift table of the ECG assessment at each visit compared with baseline values will be 
presented by treatment group. A baseline value will be defined as the last available value 
collected on or prior to the date/time of the first dose of BLV study drug for the DT to BLV 
10 mg, BLV 2 mg, and BLV 10 mg groups, and the last value on or prior to randomization for 
the DT group. The number and percentage of participants in each cross-classification group of 
the shift table will be presented. Participants with a missing value at baseline or postbaseline will 
not be included in the denominator for percentage calculation.
A by-participant listing for ECG assessment results will be provided by participant ID number 
and visit in chronological order.
7.6.2.
Other Electrocardiogram Assessment
Descriptive statistics will be provided by visit (including post-treatment visits through 
Follow-Up Week 48 [Study Week 192]) and treatment group for ECG measurements and change 
from baseline including RR interval (msec), PQ interval (msec), QRS interval (msec), QT 
interval (msec), QT interval corrected for heart rate (QTc, Bazett) (msec), and heart rate 
(beats/min).
In addition, the number and percentage of participants with QTc values in each category below 
will be summarized by visit and treatment group:


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•
< 451 msec
•
451 to 480 msec
•
481 to 500 msec
•
> 500 msec 
The number and percentage of participants with QTc change from baseline values in each 
category below will be summarized by visit and treatment group:
•
> 30 msec
•
> 60 msec
Participants with a value at the visit will be included in the denominator for percentage 
calculation (all participants had a baseline value). In addition, a by-participant listing for ECG 
measurements will be provided. No formal statistical testing is planned.
7.7.
Other Safety Measures
A data listing will be provided for participants who become pregnant during the study.


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8.
IMMUNOGENICITY ANALYSES
8.1.
ADA Incidence and Prevalence
The evaluable population for ADA prevalence is participants with at least one non-missing ADA 
data at any visit, including the baseline. The evaluable population for ADA incidence is 
participants with at least one non-missing ADA data at postbaseline visits.
•
ADA prevalence: participants with positive ADA at any visit including the baseline will be 
considered ADA positive. Otherwise, participants will be considered ADA negative.
•
ADA incidence: defined in Table 8-1
Table 8-1.
Definition of ADA Incidence
Baseline ADA
Postbaseline ADA
ADA Incidence
Negative/Missing
Positive (any visit)
Positive
Positive/Negative/Missing 
Negative (all visits)
Negative
Positive
Positive (any visit)
Negative
The number and percentage of ADA prevalence and incidence at Weeks 48, 144, and 168 will be 
summarized by treatment group. The corresponding listing will also be provided.


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9.
PHARMACOKINETIC (PK) ANALYSES
9.1.
PK Sample Collection
For participants treated with BLV, blood samples for analysis of BLV concentration will be 
collected at all treatment visits. The sampling will be done 60 ±15 minutes after BLV injection.
9.2.
PK Analyses 
Descriptive statistics (including geometric mean and arithmetic coefficients of variation [%CV]) 
of BLV plasma concentrations will be presented by treatment group and visit. In addition, the 
geometric mean (95% CI) of BLV plasma concentration will be plotted by treatment group and 
visit using a line plot. Descriptive statistics and a line plot of the geometric mean (95% CI) of 
BLV plasma concentration will also be presented by treatment group, visit, and ADA incidence 
by Week 144 (positive, negative).
The by-participant listing of PK sampling details and PK concentrations will be provided.


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MYR301
Statistical Analysis Plan – Week 192 
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05 February 2024
GILEAD CONFIDENTIAL INFORMATION
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10.
OTHER EVALUATIONS
The analyses of variables from other evaluations will be conducted using the FAS. 
10.1.
HBeAg
HBeAg status and HBeAg antibody status will be summarized by visit and treatment group for 
participants who are positive for HBeAg at screening.
10.2.
Liver Biopsy - Molecular Analysis and Gene Expression
Descriptive statistics were presented by visit and treatment group on log10 transformed data for 
the following parameters (including the change from baseline) at Week 48 primary analysis and 
results were described in the interim Week 48 CSR dated 13 July 2022. In addition, the 
by-participant listings were provided.
Molecular analysis:
•
Relative expression level of HDV RNA
•
Relative expression level HBV RNA (S region)
•
Relative expression level of total HBV RNA (X region)
•
Relative expression level of pregenomic HBV RNA
•
HBV DNA (S region; copies/cell)
•
Total HBV DNA (X region; copies/cell)
Molecular analysis using immunofluorescence staining:
•
HDAg, % of positive hepatocytes
Gene expression:
•
Relative expression level of NTCP mRNA
•
Relative expression level of CYP7A1 mRNA
•
Relative expression level of CXCL10 mRNA
•
Relative expression level of ISG15 mRNA
•
Relative expression level of MX1 mRNA
•
Relative expression level of OAS mRNA


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MYR301
Statistical Analysis Plan – Week 192 
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05 February 2024
GILEAD CONFIDENTIAL INFORMATION
Page 55 of 65
•
Relative expression level of HLA-E mRNA
•
Relative expression level of TAP1 mRNA
•
Relative expression level of USP18 mRNA
•
Relative expression level of CXCL11 mRNA
•
Relative expression level of CXCL9 mRNA
•
Relative expression level of CXCR3 mRNA
•
Relative expression level of CCL5 mRNA
•
Relative expression level of CXCL8 mRNA
•
Relative expression level of IL18 mRNA
•
Relative expression level of TGFB1 mRNA
For the following parameters only the by-participant listings were provided:
•
Molecular analysis: DNA content (ng/μL), RNA content (ng/μL), Beta globin (copies), 
cccDNA (copies/cell).
•
Gene expression: GAPDH CT, RPL30CT, SERPINA1 mRNA CT


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MYR301
Statistical Analysis Plan – Week 192 
Version 1.0
05 February 2024
GILEAD CONFIDENTIAL INFORMATION
Page 56 of 65
11.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.


Bulevirtide (BLV)
MYR301
Statistical Analysis Plan – Week 192 
Version 1.0
05 February 2024
GILEAD CONFIDENTIAL INFORMATION
Page 57 of 65
12.
APPENDICES
Appendix 1 Sample SAS Code
The following statement will be used to construct the confidence interval for the binomial 
proportions described in Section 6:
proc freq data = final;
table trtp*aval/riskdiff (cl=exact) fisher alpha=0.0x;
exact riskdiff;
where trtp = "Arm X" | trtp = "Arm Y";
run;
For combined reponse and undetectable HDV RNA, alpha=0.01 at Week 24 and alpha=0.04 at 
Week 48. Otherwise, alpha=0.05.
proc freq data = final;
by trtp;
table aval/bnomial;
exact binomial;
run;
The following statement will be used to construct ANCOVA described in Section 6:
proc mixed data = final; 
class usubjid trtp region;
model chg = base region strata trtp /ddfm=kr;
lsmeans trtp /diff cl alpha=0.05;
run;
The following statement will be used to construct MMRM model described in Section 6:
proc mixed data = final;
class usubjid trtp avisit region strata;
model chg = base region strata trtp avisit trtp*avisit/ddfm = kr;
repeated avisit/subject=usubjid type=un;
lsmeans trtp*avisit/diff cl;
run;


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MYR301
Statistical Analysis Plan – Week 192 
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05 February 2024
GILEAD CONFIDENTIAL INFORMATION
Page 58 of 65
Appendix 2 Schedule of Assessments
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


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MYR301
Statistical Analysis Plan – Week 192 
Version 1.0
05 February 2024
GILEAD CONFIDENTIAL INFORMATION
Page 59 of 65
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
Randomization 9 
X
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
Quality of life questionnaires (EQ-
5D, FSS, HQLQ™)
X
X (W24, 
W40 only)
X
X (W72, W96 
only)
X
X (W192 only)
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


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MYR301
Statistical Analysis Plan – Week 192 
Version 1.0
05 February 2024
GILEAD CONFIDENTIAL INFORMATION
Page 60 of 65
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
Biochemistry (abbreviated panel) 15
X (W4, W8, 
W16, W32, 
W40 only)
X (W52, W56, 
W64, W80, W88, 
W108, W132 
only)
X
X
Coagulogram 16
X
X 6
X (W8, 
W24, W40 
only)
X
X (W64, W80, 
W96, W108, 
W120, W132 
only)
X
X (W168, W192, 
and W216 only)
X
Total blood bile salts
X
X
X
X
X
X
X
X
Alpha-fetoprotein test
X
Vitamin D
X
X (W24 
only)
X
X (W72, W96, 
W120 only)
X
X (W168 and 
W192 only)
X
HBV DNA for pts. not receiving 
nucleoside/nucleotide analogues 
X
Serum alpha-2-macroglobulin
X
X
X (W96 only)
X
X (W168 and 
W192 only)
X
ANALYSIS PERFORMED IN CENTRAL VIROLOGY LABORATORY/SAMPLES TO BE SENT TO CENTRAL LABORATORY AT ONCE
HDV RNA
X
ANALYSIS PERFORMED IN CENTRAL VIROLOGY LABORATORY/SAMPLES TO BE STORED AT SITE
HDV genotyping
X
HDV RNA 
X
X
X
X
X
X
X
X
HBV DNA (HBV genotyping at 
first positive HBV DNA) 
X
X
X
X
X
X
X
X
HBsAg 
X
X
X
X
X
X
X
X


Bulevirtide (BLV)
MYR301
Statistical Analysis Plan – Week 192 
Version 1.0
05 February 2024
GILEAD CONFIDENTIAL INFORMATION
Page 61 of 65
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
HBsAg antibodies 17
X
X (W24 
only)
X
X (W96 only)
X
X (W168 only)
X
HBeAg and HBeAg antibodies 18
X
X
X (W96 only)
X
X
ANALYSIS PERFORMED IN CENTRAL LABORATORY/SAMPLES TO BE STORED AT SITE
Immunogenicity (bulevirtide 
antibodies) 19
X
X (W16, 
W24 only)
X
X (W64, W72, 
W96, W120 
only)
X
X (W168)
X
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 the protocol.
2.
Signed and dated informed consent must be obtained before any procedure specific to the 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 


Bulevirtide (BL V) 
MYR301 
Statistical Analysis Plan - Week 192 
Version 1.0 
vim! hepatitis should be recorded. Prior therapy for other diseases is collected for therapies that patient receives cw1·ently and therapies that were discontinued within 
3 months before Screening. 
5. 
A complete physical examination is performed at Screening (SCR), Randomization (VI), 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, respirato1y, cardiovascular, gastrointestinal including hepatobilia1y 
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. 
AimA: sta1tingfromW48. 
8. 
Vital signs include body temperature, hea1t rate, and blood pressure. 
9. 
Patients eligible for the study are randomized after completion of all procedures scheduled for Screening and Day I ( except study dmg adininistration, Patient Dia1y 
dispensing and assessment of adverse events, sample collection for pha1macokinetics) and confinuation of pa1ticipant's eligibility. 
I 0. Patients should be instmcted NOT to adininister study dmg at home at days of visits to study sites. At these days study dmg is adininistered at study site in accordance with 
schedule of events for assessment of irnmunogenicity and pha1macokinetics of the study dmg. 
11. Only for women of childbearing potential. 
12. Urinalysis is not needed at V2 (W4), V9 (W52), and FU 3 (WI68), and FU 3.1 (WI80). 
13. Hematology includes hemoglobin, hematocrit, reticulocytes, RBC, platelet count, WBC with differential (absolute counts and percentage for neutrophils, eosinophils, 
basophils, monocytes, and lymphocytes). 
14. Pa1ticipants must attend study sites after fasting for at least 9 hours (water and concomitant medications are pennitted) for the pwpose of conducting the biochemistiy. Full 
biochem.istiy includes total protein, album.in, ALT [this sample will be used to obtain ALT results for efficacy assessment as described in Section 6.5.4], AST, GGT, 
P-amylase, alkaline phosphatase, lipase, total bilimbin, direct bilimbin, total cholesterol, creatinine, w·ea, glucose, potassiwu, sodiwu, chloride, phosphoms, and CRP. 
15. Pa1ticipants must attend study sites after fasting for at least 9 hours (water and concomitant medications are pennitted) for the pwpose of conducting the biochemistiy. 
Abbreviated biochemistry includes:includes album.in, ALT [this sample will be used to obtain ALT results for efficacy assessment as described in Section 6.5.4], AST, GGT, 
total bilimbin, direct bilimbin, creatinine, lipase, P-amylase, CRP. 
16. Coagulogram includes prothrombin time, international no1malized ratio, and activated partial thromboplastin time. 
17. Collection of anti-HBsAg samples at designated time points; testing only ifHBsAg becomes undetectable. 
18. Collection and testing ofHBeAg and HBeAg antibodies only if patient is HBeAg positive at SCR. 
19. Samples for irnmunogenicity assessment should be taken before adininisti·ation of the study dmg, dtuing first 48 weeks irnmunogenicity samples are taken only for Aims B 
andC. 
20. Blood samples for deteffilillation ofNTCP polymo1phism are collected at Day I for all the patients. NTCP polymo1phism will be performed in central laborato1y as detailed 
in Section 6.4.4 of the protocol. 
21. Dedicated samples for phenotypic assay are collected only at Day I. For other resistance tests (HBV genome sequencing and HDV genome sequencing) and phenotypic assay 
at the other time points back-up virology samples are used. Full resistance tests are performed as detailed in Section 6.4.4 of the protocol. 
22. Dtuing first 48 weeks pha1macokinetics samples are taken only for Aims B and C. One sample at each visit I hour ± 15 minutes post bulevirtide dose. 
23. At Screening liver biopsy is performed after confirmation of eligibility. If a liver biopsy was pe1fon11ed within I year prior to Screening, and a patient can provide biopsy 
records and appropriate biopsy specimens, the available specimens can be used for the baseline evaluation and biopsy at Screening is not required. Othe1w ise, liver biopsy at 
screening is pe1fo1med if feasible provided that patient is considered to be eligible after the review of all eligibility criteria. 
24. Liver biopsy should be pe1fo1med within± 7 days from the date of the visit for patients who do not have medical conti·aindications for the procedtu·e. If baseline liver biopsy 
samples are not available (were not provided to centi·al laboratory or were considered as non-evaluable by centi·al laborato1y) subsequent liver biopsy should not be 
e1fo1med. 
25. 
05 February 2024 
GILEAD CONFIDENTIAL INFORMATION 
Page 62 of65 


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MYR301
Statistical Analysis Plan – Week 192 
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05 February 2024
GILEAD CONFIDENTIAL INFORMATION
Page 63 of 65
Appendix 3. Imputation of incomplete AE start or end date
1
For Group B and Group C
1.1
to impute partial AE date if year and month are available:
Imputed start date
Imputed end date
If AE year/month same as 1st dose year/month
Same as 1st dose date or AE end 
date whichever comes first.
Last of the month
If AE year/month before 1st dose year/month
First of the month
Last of the month
If AE year/month after 1st dose year/month
First of the month
Last of the month
1.2
to impute partial AE date if only year is available:
Imputed start month/date
Imputed end 
month/date
If AE year same as 1st dose year
Same as 1st dose month/date or 
AE end month/date whichever 
comes first
December 31
If AE year before 1st dose year
January 1
December 31
If AE year after 1st dose year
January 1
December 31
1.3
to impute partial AE start date if neither year nor month is available:
Imputed AE start year/month/date
If AE end date is before 1st dose date 
AE end date
If AE end date is at/after 1st dose date 
Same as 1st dose date
1.4
to impute partial AE end date if neither year nor month is available:
Impute the missing AE end date using the last visit date in database for this participant, or AE 
start date, whichever comes last.


Bulevirtide (BLV)
MYR301
Statistical Analysis Plan – Week 192 
Version 1.0
05 February 2024
GILEAD CONFIDENTIAL INFORMATION
Page 64 of 65
2
For Arm A (i.e., delayed treatment)
2.1
to impute partial AE date if year and month are available:
Imputed start date
Imputed end date
If AE year/month before randomization year/month
First of the month
Last of the month
If AE year/month same as randomization year/month
Same as randomization date or AE end 
date whichever comes first.
Last of the month
If AE year/month after randomization year/month but 
before 1st BLV dose year/month 
First of the month
Last of the month
If AE year/month at 1st BLV dose year/month
1) if Relationship to bulevirtide=’not 
applicable (bulevirtide not 
administred)’, then first of the month
2) if Relationship to bulevirtide not 
equal to ’not applicable (bulevirtide not 
administred)’, then same as 1st BLV 
dose date or AE end date whichever 
comes first.
Last of the month
If AE year/month after 1st BLV dose year/month
First of the month
Last of the month
2.2
to impute partial AE date if only year is available:
Imputed start month/date
Imputed end 
month/date
If AE year before randomization year
January 1
December 31
If AE year same as randomization year and 
before 1st BLV dose year (randomization 
year < 1st BLV year)
Same as randomization month/date or AE end 
month/date whichever comes first
December 31
If AE year same as 1st BLV dose year 
(randomization year = 1st BLV year)
1) if Relationship to bulevirtide=’not applicable 
(bulevirtide not administred)’, then same as 
randomization month/date or AE end month/date 
whichever comes first.
2) if Relationship to bulevirtide not equal to ’not 
applicable (bulevirtide not administred)’, then same as 1st 
BLV dose month/date or AE end month/date whichever 
comes first.
December 31
If AE year same as 1st BLV dose year 
(randomization year < 1st BLV year)
1) if Relationship to bulevirtide=’not applicable 
(bulevirtide not administred)’, then January 1.
2) if Relationship to bulevirtide not equal to ’not 
applicable (bulevirtide not administred)’, then same as 1st 
BLV dose month/date or AE end month/date whichever 
comes first.
December 31
If AE year after 1st BLV dose year
January 1
December 31


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MYR301
Statistical Analysis Plan – Week 192 
Version 1.0
05 February 2024
GILEAD CONFIDENTIAL INFORMATION
Page 65 of 65
2.3
to impute partial AE start date if neither year nor month is available:
Imputed AE start year/month/date
If AE end date is before randomization date 
AE end date.
If AE end date is at/after randomization date but 
before 1st BLV dose date 
Same as randomization date
If AE end date is at/after 1st BLV dose date 
if Relationship to bulevirtide=’not applicable (bulevirtide 
not administered)’, then same as Randomization date.
2) if Relationship to bulevirtide not equal to ’not applicable 
(bulevirtide not administered)’, then same as 1st BLV dose 
date.
2.4
to impute partial AE end date if neither year nor month is available:
Impute the missing AE end date using the last visit date in database for this participant, or AE 
start date, whichever comes last.


MYR301_ W192_SAP_v1.0
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Biostatistics eSigned
Clinical Development
eSigned
PPD
PPD
PPD
PPD-

SAP_001.pdf: 




Statistical Analysis Plan
LINK Medical Study ID:
MYR001
MYR301 Statistical Analysis Plan Final 3.0 - 2021-08-20, Template used: -
Page 3 of 44
LINK Medical Study ID: 
MYR001
Table of Content
1
Acronyms and Abbreviations used in the Document........................................................................... 6
2
Introduction............................................................................................................................................... 8
3
Study Objectives ...................................................................................................................................... 8
3.1
Primary Objective.......................................................................................................................... 8
3.1.1
Primary Variables....................................................................................................................... 8
3.2
Secondary Objectives ................................................................................................................... 8
3.2.1
Secondary Efficacy Variables .................................................................................................... 8
3.2.3
Safety Variables ......................................................................................................................... 9
3.2.5
Pharmacokinetic variables ......................................................................................................... 9
3.2.6
Other Variables .......................................................................................................................... 9
4
Study Design........................................................................................................................................... 10
5
Study Population .................................................................................................................................... 10
5.1
Sample Size ................................................................................................................................ 11
6
Assessments .......................................................................................................................................... 11
6.1
Impact of COVID-19 on Assessments and Study Procedures ................................................... 11
6.2
Efficacy assessments.................................................................................................................. 11
6.2.1
Virology .................................................................................................................................... 11
6.2.2
ALT........................................................................................................................................... 11
6.2.3
Transient Elastometry .............................................................................................................. 11
6.2.4
Liver Biopsy.............................................................................................................................. 12
6.2.5
Serum Alpha-2-macroglobulin ................................................................................................. 12
6.2.6
Liver Related Clinical Event ..................................................................................................... 12
6.3
Safety assessments .................................................................................................................... 13
6.3.1
Adverse Events ........................................................................................................................ 13
6.3.2
Physical Examination............................................................................................................... 14
6.3.3
Vital Signs ................................................................................................................................ 14
6.3.4
Electrocardiogram.................................................................................................................... 14
6 3 5
Safety Laboratory Assessments
14
6.5
Pharmacokinetic assessments.................................................................................................... 15
6.6
Other Assessments..................................................................................................................... 15
6.6.2
NTCP Polymorphism and Resistance Tests............................................................................ 15
6.6.3
Demographics and Anthropometrics........................................................................................ 15
6.6.4
Substance Use......................................................................................................................... 15
6.6.5
Abdominal Ultrasound.............................................................................................................. 16
6.6.6
Urine Pregnancy Test .............................................................................................................. 16
6.6.7
Serum Alpha-fetoprotein .......................................................................................................... 16
6.6.8
Serology Test ........................................................................................................................... 16
6.6.9
Medical History......................................................................................................................... 16
6.6.10
Prior and Concomitant Medication........................................................................................... 16
7
Method of Analysis................................................................................................................................. 16
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7.1
General........................................................................................................................................ 16
7.1.1
Presentation of Results............................................................................................................ 16
7.1.2
Baseline ................................................................................................................................... 17
7.1.3
Analysis Relative Day .............................................................................................................. 17
7.1.4
Analysis Visit ............................................................................................................................ 17
7.1.4.1
Unscheduled visits ............................................................................................................................... 18
7.1.5
Handling of Missing Data ......................................................................................................... 18
7.1.5.1
Imputation of values based on limits of detection and quantification....................................................18
7
7.1.6
Planned Analyses .................................................................................................................... 19
7.1.6.1
Notes on the interim analysis at week 24............................................................................................. 19
7.1.7
Multiplicity................................................................................................................................. 19
7.1.8
Subgroups................................................................................................................................ 19
7.1.9
Impact of COVID-19 on Statistical Analysis............................................................................. 20
7.2
Analysis Sets............................................................................................................................... 20
7.2.1
Randomised set ....................................................................................................................... 20
7.2.2
Full analysis set........................................................................................................................ 20
7.2.3
Per-protocol set........................................................................................................................ 20
7.2.4
Major protocol deviations leading to exclusion from the PP set .............................................. 20
7.2.5
Safety Analysis Set .................................................................................................................. 21
7.3
Disposition of Subjects................................................................................................................ 21
7.4
Protocol Deviations ..................................................................................................................... 21
7.5
Demographics and Baseline Characteristics .............................................................................. 22
7.6
Medical History and Concurrent Diseases.................................................................................. 22
7.7
Prior and Concomitant Medication.............................................................................................. 22
7.8
Efficacy Evaluation...................................................................................................................... 23
7.8.1
Primary Efficacy Variable......................................................................................................... 23
7.8.2
Secondary Efficacy Variables .................................................................................................. 24
7.8.2.1
Undetectable HDV RNA at Week 48 (key secondary variable)............................................................ 24
7.8.2.2
ALT normalization at Week 48............................................................................................................. 25
7.8.2.3
Undetectable HDV RNA Week 24 and Week 48 after scheduled end of treatment (sustained 
virological response) ............................................................................................................................................... 25
7.8.2.4
Change from baseline in liver stiffness (kPa)....................................................................................... 25
7.9
Safety Evaluation ........................................................................................................................ 28
7.9.1
Extent of Exposure................................................................................................................... 28
7.9.2
Adverse Events ........................................................................................................................ 29
7.9.3
Laboratory ................................................................................................................................ 30
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7.9.4
Physical Examination............................................................................................................... 31
7.9.5
Vital Signs ................................................................................................................................ 31
7.9.6
Electrocardiogram .................................................................................................................... 31
7.11
Pharmacokinetic Evaluation........................................................................................................ 32
7.12
Evaluation of Other Variables ..................................................................................................... 32
7 12 1
NTCP polymorphism
32
7.12.3
HBeAg...................................................................................................................................... 32
7.12.4
Liver Biopsy.............................................................................................................................. 32
7.13
Changes to Planned Analysis ..................................................................................................... 33
7.13.1
Definition of the Per-Protocol Analysis..................................................................................... 33
7.13.2
ALT samples ............................................................................................................................ 33
8
Derived Variables ................................................................................................................................... 33
8.1
Disposition of Subjects................................................................................................................ 33
8.2
Demographics and Baseline Characteristics .............................................................................. 33
8.2.1
Age........................................................................................................................................... 33
8.2.2
Body Mass Index...................................................................................................................... 34
8.2.3
Previous IFN therapy ............................................................................................................... 34
8.2.4
Prior and concomitant HBV medication ................................................................................... 34
8.3
Change from Baseline................................................................................................................. 34
8.4
Exposure and Compliance .......................................................................................................... 34
8.5
Efficacy variables ........................................................................................................................ 36
8.5.1
Undetectable HDV RNA........................................................................................................... 36
8.5.2
Combined response (primary efficacy variable) ...................................................................... 36
8.5.3
Histological findings ................................................................................................................. 36
8.6
Safety variables........................................................................................................................... 36
8.6.1
Treatment Emergent Adverse Event........................................................................................ 36
8.6.2
Physical examination ............................................................................................................... 36
9
References .............................................................................................................................................. 37
10
Signoff ..................................................................................................................................................... 38
Appendix 1: Schedule of assessments....................................................................................................... 39
Appendix 2: Liver related clinical events.................................................................................................... 44
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1
Acronyms and Abbreviations used in the Document
Abbreviation
Explanation
ADA
Anti-drug antibodies
AE
Adverse Event
AFP
Serum alpha fetoprotein
ALT
Alanine transferase
AST
Aspartate transferase
ATC
Anatomical Therapeutic Chemical [classification system]
BMI
Body mass index
CHD
Chronic hepatitis delta 
COVID-19
Coronavirus disease 2019
CI
Confidence interval
CRF
Case report form
CRP
C-reactive protein
CS
Clinically Significant
CTCAE
Common Terminology Criteria for Adverse Events
DDP
Data display plan
DNA
Deoxyribonucleic acid
DRM
Data Review Meeting
ECG
Electrocardiogram
eCRF
Electronic case report form
EOS
End of study
EQ-5D
EuroQol 5-Dimentions
FAS
Full analysis set
FSS
Fatigue Severity Scale
GGT
Gamma glutamyl transferase
HBeAg
Hepatitis B virus e-antigen
HBsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B virus
HIV
Human immunodeficiency virus
HDV
Hepatitis delta (D) virus
HQLQ™
Hepatitis Quality of Life Questionnaire™
IAP
Interim Analysis Plan
IC50
half maximal inhibitory concentration
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IMP
Investigational medicinal product
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Abbreviation
Explanation
INR
International normalised ratio
kPa
Kilopascal
LOD
Limit of detection
LLoQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MEF
Missing Equals Failure
MMRM
Mixed-effects model for repeated measures
NCS
Not Clinically Significant
NTCP
Sodium taurocholate co-transporting polypeptide 
PCR
Polymerase chain reaction 
PK
Pharmacokinetic
PP
Per-protocol
RBC
Red blood cell count
REML
Restricted maximum likelihood 
RNA
Ribonucleic acid
SAE
Serious adverse event 
SAP
Statistical analysis plan
ULOQ
Upper limit of quantification
VAS
Visual Analogue Scale
WBC
White blood cell count
WT
wild type
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2
Introduction
The Statistical Analysis Plan (SAP) is a complementary document to the Clinical Study Protocol and includes 
a more technical and detailed elaboration of the principal features of the proposed statistical analysis and 
presentations, and the way in which anticipated analysis problems will be handled.
If the SAP suggests changes to the principal features stated in the protocol, these should also be 
documented in a protocol amendment. Otherwise, it will suffice to record the changes in the SAP.
A separate virology analysis plan will be prepared by the sponsor to provide details of the analysis of NTCP 
polymorphism and resistance testing (phenotyping assay and genome sequencing) data.
3
Study Objectives
3.1
Primary Objective
To evaluate the efficacy of bulevirtide administered subcutaneously 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.
3.1.1
Primary Variables
The primary variable is the combined response at week 48. 
Combined response is defined as fulfilment of two conditions simultaneously: 
-
Undetectable HDV RNA (HDV RNA < LOD) or decrease in HDV RNA by ≥ 2 log10 IU/ml from 
baseline; 
-
ALT normalization.
3.2
Secondary Objectives
The secondary objectives are:
x
To evaluate optimal treatment duration;
x
To assess the safety of bulevirtide.
The exploratory objectives are:
x
To investigate the immunogenicity of bulevirtide;
x
To investigate influence of bulevirtide on quality of life;
x
HBV/HDV genotyping;
x
Resistance testing.
3.2.1
Secondary Efficacy Variables
The secondary efficacy variables are:
x
Undetectable HDV RNA at week 48;
x
ALT normalization at week 48; 
x
Undetectable HDV RNA 24 weeks after scheduled end of treatment (sustained virological response); 
x
Undetectable HDV RNA 48 weeks after scheduled end of treatment (sustained virological response);
x
Change from baseline in liver stiffness as measured by elastography at week 48, 96, 144, 192 and 
240.
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3.2.3
Safety Variables
The safety variables are:
x
Adverse events (treatment emergent);
x
Changes in vital signs; 
x
Changes in PR, QRS, QT, QT-interval corrected for heart rate (QTc, Bazett), and heart rate based 
on assessments of electrocardiogram;
x
Changes in laboratory tests (haematology, coagulogram, biochemistry, blood bile salts, vitamin D).
3.2.4
Immunogenicity Variables
Appearance and concentration of bulevirtide antibodies
3.2.5
Pharmacokinetic variables
Plasma concentration of bulevirtide. 
Sampling is done 1 hour ± 15 min post bulevirtide injection. During first 48 weeks pharmacokinetics samples 
will be collected only for Arms B and C (not from the delayed treatment group).
3.2.6
Other Variables
x
HDV/HBV genotyping;
x
NTCP polymorphism (only in non-responders and patients with virological breakthrough);
x
Resistance testing (HBV genotypic assay with focus on the HBV envelope, Phenotypic resistance 
assay and HDV genotypic assay);
x
HBeAg and HBeAg antibodies status at all postbaseline assessments (for patients with positive 
HBeAg at SCR)
x
Other parameters in liver biopsy samples.
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4
Study Design
This is a randomized, open-label, parallel group, multicenter Phase III study that will evaluate the efficacy 
and safety of bulevirtide in subjects with chronic hepatitis delta (CHD) who have no adequate treatment 
options. 
This study will be conducted at approximately 24 sites across approximately 5 countries globally which may 
include Germany, Russia, Italy, Georgia and USA. A total of 150 subjects will be randomized. 
Subjects will be assessed for eligibility to enter the study during a 4-week Screening period. Eligible subjects 
will be randomized at Visit 1 in a 1:1:1 ratio with stratification for the presence of liver cirrhosis (no/yes) to 
receive delayed treatment with bulevirtide 10 mg/day after an observational period of 48 weeks (arm A), 
immediate treatment with bulevirtide 2 mg/day (arm B) or immediate treatment with bulevirtide 10 mg/day 
(arm C) for 144 weeks. 
At week 48, CHD patients from the delayed treatment group (arm A) will be switched to bulevirtide 10 
mg/day for 96 weeks. 
The total duration of treatment period is 144 weeks. After completion of the treatment period, subjects will be 
followed for additional 96 weeks. For all subjects the total amount of time to complete the study will be 240-
244 weeks (inclusive of the Screening, Treatment, and Follow-Up Periods).
A scheme of the study design is presented in Figure 1. The schedule of events to be conducted during the 
144-week Treatment Period and the safety Follow-Up Period is presented in Table 1. Treatment and all 
study procedures will be performed on an outpatient basis.
5
Study Population
This study plans to randomize a total of 150 adult male and female patients (18-65 years) with chronic HDV 
infection and elevated ALT at Screening.
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5.1
Sample Size
To account for the repeated analysis of response (interim at 24 weeks and main analysis at 48 weeks) the 
nominal two-sided significance level of 0.05 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. 
The expected response rates at 48 weeks for the bulevirtide 2mg and 10mg doses are 45% or greater. The 
conservative expectation for the delayed treatment response rates is 8% or less. These assumptions are 
based on results from preceding phase 2 study (MYR 202). 
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.
6
Assessments
A schedule of assessments from the protocol is presented in Appendix 1: Schedule of assessments.
6.1
Impact of COVID-19 on Assessments and Study Procedures
Due to the ongoing coronavirus disease 2019 (COVID-19) pandemic, extraordinary measures may need to 
be implemented and trial management may need to be adjusted due to unavoidable circumstances, e.g. self-
isolation/quarantine of trial participants, limited access to public places (including hospitals) and/or public 
transportation as well as health care professionals being committed to critical tasks.
This can have an impact on the study procedures and subjects’ attendance of scheduled study visits.
If it is not possible for subjects to visit the sites, blood and urine sampling for efficacy and safety analysis,
and ECG assessments may be performed out of the site, and study medication may be delivered to the 
subject.
All protocol deviations related to COVID-19 will be classified as “COVID-19 related”.
6.2
Efficacy assessments
6.2.1
Virology
Blood samples for virology tests will be collected according to the schedule of assessments and analysed by 
the central virology laboratory. The following virology tests will be performed
x
HDV RNA by a quantitative PCR;
x
HBV DNA by a quantitative PCR;
x
HBsAg level by a quantitative immunoassay;
x
HBeAg and HBeAg antibodies (only if patient is HBeAg positive at Screening);
x
HBsAg antibodies.
6.2.2
ALT
The ALT test results from the safety blood samples for clinical chemistry testing will be used for efficacy 
analyses.
6.2.3
Transient Elastometry
Transient elastography to assess hepatic fibrosis staging will be performed using FibroScan at Screening,
Week 48, 96, 144, 192 and 240. 
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6.2.4
Liver Biopsy
Liver biopsy samples will be collected at Screening and Week 48. If there are available appropriate biopsy 
specimens from within 1 year prior to Screening, these can be used for the baseline evaluation, and biopsy 
at Screening is not required.
The histological activity index (HAI), also known as the Knodell score, is an additive score calculated as the 
sum of the semi-quantitative scores for four individual features: periportal and/or bridging necrosis, 
hepatocyte degeneration and/or focal necrosis, portal inflammation, and fibrosis. In clinical trials, the first 
three categories are often totalled to give a necro-inflammatory score (0–18), while the fibrosis score (0–4) is 
reported separately.
The Knodell fibrosis score stages fibrosis in a 5-tier system (with stage 2 eliminated to overstate the 
difference between mild and severe disease):
0.
No fibrosis
1.
Fibrous portal expansion
3.
Bridging fibrosis
4.
Cirrhosis.
The Ishak fibrosis score is part of the Ishak score, a modified form of the HAI, and has 7 stages:
0.
No fibrosis
1.
Fibrous expansion of some portal areas, with or without short fibrous septa
2.
Fibrous expansion of most portal areas, with or without short fibrous septa
3.
Fibrous expansion of most portal areas with occasional portal to portal bridging
4.
Fibrous expansion of portal areas with marked bridging (portal to portal as well as portal to central)
5.
Marked bridging (portal–portal and/or portal–central) with occasional nodules (incomplete cirrhosis)
6.
Cirrhosis, probable or definite
The METAVIR scoring system is used to assess the extent of inflammation and fibrosis by histopathological 
evaluation in a liver biopsy. It comprises two scores, the fibrosis stage representing the amount of fibrosis or 
scarring, and the activity grade indicating the degree of inflammation:
x
Fibrosis stage:
F0: No fibrosis
F1: Portal fibrosis without septa
F2: Portal fibrosis with few septa
F3: Numerous septa without cirrhosis
F4: Cirrhosis
x
Activity grade:
A0: No activity
A1: Mild activity
A2: Moderate activity
A3: Severe activity
A4:
The analysis of the liver biopsy samples also includes molecular analysis of HDV RNA, HBV RNA and DNA, 
and HDAg, and analysis of gene expression of CXCL10, NTCP, CYP7A1, ISG15, MX1, OAS, HLA-E, TAP1, 
and USP18.
6.2.5
Serum Alpha-2-macroglobulin
Blood samples for testing for the serum fibrosis marker, alpha-2-macroglobulin, will be collected at Day 1, 
Weeks 48, 96,144,168 and the last follow-up visit and analysed by central laboratory.
6.2.6
Liver Related Clinical Event
Liver related clinical events are reported as adverse events, see section 6.3.1.
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6.2.7
Quality of life questionnaires
Quality of life will be assessed at Baseline and Weeks 24, 40, 48, 72, 96, 144, 192 and 240 using 3 different 
instruments:
x
EuroQol 5-Dimentions (EQ-5D).
Quality of Life will be assessed using the EQ-5D-3L. The European Quality of Life – 5 Dimensions 
Questionnaire (EQ-5D-3L) is a standardised instrument for use as a measure of health outcome developed 
by the EuroQol Group. It comprises the 5 dimensions: mobility, self-care, usual activities, pain/discomfort 
and anxiety/depression. Each dimension has 3 levels, Level 1-3 (no problems, some problems and
extreme problems).
In addition, a Visual Analogue Scale (VAS) will be used. The patient will score his/her “own health state 
today” on a scale from 0 to 100 mm, where 0 mm is the worst imaginable health state and 100 mm is the 
best imaginable health state. EQ VAS is an integer score, hence the eCRF allows integer values only. 
However, there are known cases where the source data include decimals for the EQ VAS score. Such 
non-integer scores are rounded to the nearest integer upon data entry into the eCRF.
x
Fatigue Severity Scale (FSS) 
Disabling fatigue will be assessed using the FSS. The patients will answer nine items by scoring on a 
seven-point scale where 1 = strongly disagree and 7 = strongly agree.
x
The Hepatitis Quality of Life Questionnaire™ (HQLQ™) 
The HQLQ is a two-part survey assessing the functional health and well-being of the subject. It 
comprises the 36 questions from the second version of the Short Form 36 Health Survey (SF-36v2) 
questionnaire as well as 15 additional questions that measure other generic health concepts. The SF-
36v2 items are organised into eight scales: physical functioning (PF), role limitations due to physical 
health (role physical, RP), bodily pain (BP), general health perceptions (GH), vitality (VT), social 
functioning (SF), role limitations due to emotional problems (role emotional, RE), and general mental 
health (MH). In addition, two summary measures are also constructed: the physical component summary 
(PCS) and the mental component summary (MCS). The additional questions are organised into four 
scales: health distress (HD), positive wellbeing (PWB), hepatitis-specific limitations (HLIM), and hepa-
titis-specific health distress (HHD). The scale scores and summary measures will be computed by 
Optum® and provided as external files.
6.3
Safety assessments
6.3.1
Adverse Events
The reporting period for serious adverse events starts after informed consent has been obtained and ends at 
the end of study visit.
The reporting period for non-serious adverse events starts with the initiation of study treatment and ends at
the end of study visit. Non-serious events occurring during the screening period which are judged to be 
related to study procedures should also be reported.
The severity of adverse events will be assessed according to the NCI-CTCAE (version 5.0), and the highest 
observed severity grade for each event will be reported. Events for which a CTCAE term cannot be found will 
be assigned a severity grade according to the definitions in section 7.2.1. of the clinical study protocol. For 
each event, the highest severity grade observed will be reported.
Local reactions at the injection sites and the following liver related clinical events are considered as adverse 
events of special interest:
x
Cirrhosis development.
x
Development or worsening of jaundice.
x
Development or worsening of coagulopathy.
x
Development or worsening of ascites.
x
Development or worsening of hepatic encephalopathy.
x
Bleeding from oesophageal varices.
x
Hepatocellular carcinoma development.
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x
Liver transplantation.
x
Liver related hospitalisation: number of hospitalisations and duration of each period of hospitalisation.
x
Liver related death.
A list of dictionary terms used to identify these liver related clinical events is given in Appendix 2.
6.3.2
Physical Examination
A complete physical examination will be performed at Screening, Randomisation (Visit 1), and Weeks 24, 48,
96 and 144 including assessments of the following body systems: 
x
general appearance; 
x
skin; 
x
head, eyes, ears, nose and throat; 
x
lymph nodes; 
x
respiratory; 
x
cardiovascular; 
x
gastrointestinal, 
x
musculoskeletal; 
x
endocrine; 
x
nervous systems; 
x
urogenital
At all other visits, a symptom directed physical examination is performed.
At each visit during the treatment phase, and at the first follow-up visit, an assessment of local reactions at the 
injection sites will be made, and the severity grade of four pre-specified types of reactions (pain; tenderness; 
erythema/redness; induration/swelling) will be reported. The severity grade will be reported according to the 
criteria for clinical abnormalities defined in Table A of the FDA Guidance for Industry ‘Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials’.
6.3.3
Vital Signs
Measurements of blood pressure, heart rate, respiratory rate and body temperature will be performed at all 
visits.
6.3.4
Electrocardiogram
A 12-lead electrocardiogram (ECG) will be recorded at Screening, and at Weeks 8, 24, 48, 72, 96, 120, and 
144,192 and 240. Assessments of heart rate, QRS, RR, PQ, QT and QTc intervals, using Bazett’s formula 
for the correction for heart rate, will be made, as well as a general assessment of whether the ECG results 
were normal or abnormal and the clinical significance of abnormal results.
6.3.5
Safety Laboratory Assessments
Samples for haematology, biochemistry, coagulogram, vitamin D, total blood bile salts and urinalysis will be 
analysed by the central laboratory.
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6.5
Pharmacokinetic assessments
Bulevirtide concentration will be measured throughout the study to investigate the possible bulevirtide 
accumulation in plasma. Analysis will be done by central laboratory.
Blood sample for estimation of drug concentration will be collected at Randomization/Baseline visit and all 
Treatment visits after the start of bulevirtide therapy. Sampling should be done 1 hour ± 15 min post 
bulevirtide injection. During first 48 weeks pharmacokinetics samples will be collected only for arms B and C.
6.6
Other Assessments
6.6.2
NTCP Polymorphism and Resistance Tests
Samples for determination of NTCP polymorphism will be collected at Day 1. Polymorphism will be 
performed by central laboratory for subjects for whom results of HDV RNA indicate lack of response or viral 
breakthrough.
Blood samples for phenotypic assay will be collected at Day 1 for all the patients. Baseline phenotypic assay 
will be performed for at least 10% of the Day 1 samples, in order to determine an EC50 (half maximal 
effective concentration) threshold at baseline. The five first patients from each arm after randomisation will
be included into the analysis, based on their baseline HDV RNA titer which is supposed to be at least 1 000 
IU/ml.
For other resistance tests (e.g. HBV genome sequencing and HDV genome sequencing) and phenotypic
assay at the other timepoints, back-up virology samples are used. Resistance testing is performed in central 
laboratory.
Full resistance testing will be performed in patients for whom results of HDV RNA testing in central laboratory 
indicate lack of response or viral breakthrough.
Lack of response is achieved if one of the two following conditions are met:
a)
No decline in HDV RNA values at any time during treatment.
b)
A decline in HDV RNA of less than ͳ ଵ଴IU/mL after 6 months (24 weeks) of treatment.
Viral breakthrough is achieved if one of the two following conditions are met:
a)
Two consecutive detectable HDV RNA values (≥LOD) if the HDV RNA value was previously undetect-
able (<LOD) at two or more consecutive time points.
b)
A confirmed increase in HDV RNA of ൒ʹ ଵ଴IU/mL from the nadir on two consecutive visits under 
treatment and/or until the end of treatment, assuming the nadir was previously at least ͳ ଵ଴IU/mL 
below the HDV RNA baseline value at two consecutive visits1
For more details on the assessments of NTCP polymorphism and resistance tests, see section 6.4.4 of the 
clinical study protocol.
6.6.3
Demographics and Anthropometrics
Demographic data (date of birth, sex and race) will be collected at Screening.
Body weight will be measured at every visit, and height will be measured at Screening.
6.6.4
Substance Use
An assessment of substance use (smoking/alcohol/drugs) will be done at screening. Information about the 
status (non-user, former user, current user) and the frequency of use will be collected.
1 The second condition is met by subjects having an increase of at least 2 log10 from nadir (smallest value) 
at two or more consecutive visits after having had values at least 1 log10 below baseline at two consecutive 
visits.
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In addition, the alcohol levels in exhaled oxygen will be measured at Screening and Randomisation, and a 
urine drug test (amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, opiates, 
and tricyclic antidepressants) will be performed at Screening.
6.6.5
Abdominal Ultrasound
Abdominal ultrasound will be done at Screening.
6.6.6
Urine Pregnancy Test
Required for women of childbearing potential. Pregnancy test will be performed at Screening and during the 
study.
6.6.7
Serum Alpha-fetoprotein
Serum alpha-fetoprotein will be measured for all subjects at Screening.
6.6.8
Serology Test
Samples for serology tests will be collected at Screening and analysed by central laboratory. The following 
tests will be performed:
x
HIV antibodies.
x
HCV antibodies.
x
HDV antibodies.
x
HBeAg and HBeAg antibodies.
x
HBV DNA (for patients not receiving the treatment with nucleoside/nucleotide analogue for chronic 
HBV infection)
In case of positive test result for HCV antibodies, a qualitative test of HCV RNA must be done; the subject 
can be enrolled into the study if the latter is negative
6.6.9
Medical History
The following information will be collected:
x
Information about diseases, conditions and surgeries related to the liver (collected for a lifelong 
period);
x
Information about other diseases, conditions and surgeries (collected if occurred within 5 years 
before screening or regardless of the time if they are considered to be relevant by Investigator).
6.6.10
Prior and Concomitant Medication
The following information will be collected:
x
All previous treatment for viral hepatitis;
x
Prior therapy for other diseases for therapies that patient receives currently and therapies that were 
discontinued within 3 months before Screening;
x
Concomitant medication.
7
Method of Analysis
7.1
General
All statistical analyses will be performed in accordance with the ICH E9 guideline for Statistical Principles for 
Clinical Trials (1), using SAS® (Version 9.4 or higher, SAS Institute Inc., Cary, NC, USA).
7.1.1
Presentation of Results
All results will be presented by treatment group and in total, unless stated otherwise. 
It will be clearly stated which unit applies to each presented variable.
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Continuous data will be summarised using descriptive statistics, and the following parameters will be 
reported:
x
number of subjects with evaluable observations and missing observations
x
arithmetic mean and standard deviation
x
median and IQR
x
first and third quartiles
x
minimum and maximum.
Categorical data will be presented using absolute frequency and percentage. When the absolute frequency 
is zero, the percentage will not be presented. Unless stated otherwise, the denominator for percentage 
calculations will be the total number of subjects in the applicable analysis set, including subjects with missing 
data. For variables with missing values, the number and percentage of subjects with missing values will be 
presented.
Significance tests will be two-sided and performed at the 5% significance level, unless stated otherwise. 
When reporting the results of significance tests, p-values will be presented.
All confidence intervals will be two-sided with a nominal confidence of 95% for within groups and if not stated 
otherwise. 
Data will be presented using an appropriate number of decimal places, to ensure that undue precision is not 
implied (e.g. the number of decimals should not exceed the accuracy of the measuring instrument). Raw 
data will be presented with the same number of decimals as collected, and derived data with an appropriate 
number of decimals based on general practice, mathematical rationale or scientific rationale.
Minimum and maximum values will be presented with the same number of decimals as the analysed variable 
and the other descriptive statistics will be presented with one decimal more. Percentages and proportions 
will be presented with one decimal. Odds ratios and hazard ratios will be presented with 3 decimals, and 
small and large values will be presented as ‘<0.001’ and ‘>999.999’ respectively. Confidence interval bounds 
will be presented with the same number of decimals as the corresponding point estimate, and p-values will 
be presented with 4 decimals or as ‘<.0001’.
Mock tables and graphs are presented in the Data Display Plan (DDP), which is a supplementary document 
to this analysis plan. Individual subject data listings will be presented according to the ICH E3 guideline for 
Structure and Content of Clinical Study Reports (2), unless stated otherwise.
7.1.2
Baseline
The baseline value for a parameter is defined as the last non-missing value before the first dose of the 
investigational medicinal product (IMP) for bulevirtide 2 and 10 mg and last value before or at randomization 
for the delayed treatment.
7.1.3
Analysis Relative Day
The analysis relative day for an assessment/value is defined as the time in days from the date of 
randomization to the date of the assessment. The date of randomization is considered as day 1, and earlier 
dates will correspond to a negative day.
7.1.4
Analysis Visit
An analysis visit is defined as a categorical variable used to classify values within an analysis variable into 
temporal or conceptual groups used for analyses.
In this study, the analysis visits will correspond to the regular study visits and will be named as ‘Week X’ for 
all post-baseline visits. However, for sustained response the analysis visits during the follow-up phase will be 
named ‘Y weeks post-treatment’. 
A separate analysis visit named ‘Baseline’ will be added for the baseline values.
Data reported at an ‘Early discontinuation’ visit in the eCRF at the same date as or within the specified visit 
window of a regular study visit will be associated with the analysis visit corresponding to that regular study 
visit.
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For the analysis of primary and secondary efficacy variables, time windows will be defined for some visits, for 
selection of data for specific analyses. Further details on this are provided in section 7.8.
7.1.4.1
Unscheduled visits
Unless stated otherwise, data from unscheduled visits will be presented in data listings only and not included 
in analysis or summary tables.
Data reported at unscheduled visits during the screening period should be considered when identifying base-
line values for parameters.
If a retest has been performed at an unscheduled visit because a value could not be obtained at the original 
visit (i.e., the value is missing at the original visit), the retest value should be mapped to the corresponding 
analysis visit if the date of assessment is within 30 days from the planned timepoint for the original visit and 
occurs before the next scheduled visit.
7.1.5
Handling of Missing Data
In general, imputations of missing data will be made only for analyses of efficacy variable on the FAS (unless 
stated otherwise).
Details on the handling of missing data for efficacy variables are provided in sections 7.8.1 (primary), 7.8.2
(secondary), and 
In analyses using a mixed-effects model for repeated measures (MMRM), missing values are handled by 
means of built-in maximum-likelihood based methods in the SAS® procedure used for the analysis, under 
the 'missing at random' assumption.
Further for values outside of limits of detection and quantification, Quality of Life and Safety laboratory test 
results details are provided in the subsections below (7.1.5.1, 7.1.5.2 and 7.1.5.3).
Data listings will include the observed values. For derived variables, values based on imputed data might be 
presented in listings
7.1.5.1
Imputation of values based on limits of detection and quantification
The following rules will be applied (for the PP set as well):
x
Values below the limit of detection (LOD) will be imputed as zero.
x
Values below the lower limit of quantification (LLOQ) will be imputed as half the LLOQ value, unless 
the LLOQ is the same as the LOD, in which case the LOD rule takes precedence.
x
Values above the upper limit of quantification (ULOQ), will be imputed as the ULOQ value.
x
'Non-measurable' data will be considered as missing data.
For log-10 transformed data, the following rules will be applied:
x
Missing values due to untransformed values of zero will be imputed as zero if LOD > 1.
x
Missing values due to untransformed values of zero will be imputed as log10(LOD/2) if LOD <1.
7.1.5.3
Safety Laboratory Test Results
For safety laboratory test results, the following rules will be applied:
x
Values reported as below the LLOQ, will be imputed as half the LLOQ value.
x
Values reported as above the ULOQ, will be imputed as the ULOQ value
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7.1.6
Planned Analyses
There will be five planned analysis in this study at following times:
1.
When all patients completed visit at Week 24 or had discontinued the study (interim analysis);
2.
When all patients completed visit at Week 48 or had discontinued the study (main primary endpoint 
analysis);
3.
When all patients completed visit at Week 96 or had discontinued the study (week 96 analysis);
4.
When all patients completed visit at Week 144 or had discontinued the study (end-of treatment 
analysis). 
5.
When all patients completed visit at week 240 or had discontinued the study (final analysis: analysis 
of all collected data of the study).
Since this is an open label study, no separate interim analysis plans will be written. Thus, this SAP applies to 
all planned analyses above. The planned analyses will be performed on the current state of the data at the 
specific cut-off time for each of the planned analyses.
The planned analyses 1-4 above will be based on available data up to the date of the last assessment 
associated with the visit at Week 24/48/96/144 (or the date of withdrawal for subjects who withdrew before 
that visit).
However, for study medication diary records, concomitant medications and Adverse Events, records/events 
with date up to but not including the date of the visit for the planned analysis will be included.
7.1.6.1
Notes on the interim analysis at week 24.
The third version of the clinical study protocol included changes requiring updates to the eCRF. Due to the 
uncertainty of whether these updates will have been implemented in time for the first interim analysis, the 
first interim analysis will be based on the previous version of the clinical study protocol (version 2.0, 2019-02-
01).
This means that the following will not be included in the first interim analysis:
x
Liver related hospitalisation (other liver related clinical events will be included).
In addition, the following data are not expected to be available for the first interim analysis:
x
NTCP polymorphism;
x
Resistance testing.
7.1.7
Multiplicity
An interim analysis will be performed on the primary endpoint at Week 24. To account for the repeated 
analysis and maintain the nominal two-sided significance level of 0.05 this level will be split among the 
interim (Week 24) and main analysis (Week 48), with allocating 0.01 to interim and 0.04 to main analysis.
Multiple group comparisons for the primary endpoint and the inclusion of a main secondary endpoint will be 
handled with a hierarchical testing procedure. Details are described in Section 7.8.1 and 7.8.2.
All other analyses will be considered explorative and no adjustment for multiple testing will be performed.
7.1.8
Subgroups
The following subgroups will be defined:
x
Based on presence of cirrhosis (stratification factor):
o
Subjects with cirrhosis;
o
Subjects without cirrhosis.
x
Based on anti-drug-antibodies (ADA):
o
ADA positive subjects;
o
ADA negative subjects.
x
Based on HBeAg:
o
Subjects who were HBeAg positive at Screening;
o
Subjects who were HBeAg negative at Screening.
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The following two regions will be defined:
x
Russia 
x
Germany/Italy/Sweden
The definition of regions is preliminary and will be reviewed during the clean file meeting; any changes to the 
above definitions will be documented in the clean file report.
7.1.9
Impact of COVID-19 on Statistical Analysis
All subjects completing the study will have been in the study during the COVID-19 pandemic and might have 
data affected by the pandemic.
The potential impact of the pandemic is taken into account in the analysis of the primary and the key 
secondary efficacy variables as described in section 7.8.1. No such analyses are planned for the other 
secondary 
 efficacy variables.
At the time of each interim analysis and the main analysis, the current status of the COVID-19 pandemic 
should be taken into consideration, and relevant additional sensitivity analyses may be defined
7.2
Analysis Sets
The decision on the classification of subjects to each analysis set will be taken at the data review meeting 
(DRM) and documented in the DRM report together with the reasons for excluding subjects from analysis 
sets
7.2.1
Randomised set
The randomised set is defined as all enrolled and randomised patients. Any analyses of the randomised set 
will be based on the planned treatment (i.e. subjects will be analysed ‘as randomised’).
7.2.2
Full analysis set
The full analysis set (FAS) is defined as all patients either randomised to delayed treatment arm or 
randomized to bulevirtide and received bulevirtide at least once after randomization.
Analysis of the full analysis set will be based on the planned treatment (i.e. subjects will be analysed ‘as 
randomised’).
7.2.3
Per-protocol set
The per-protocol set (PP) is defined as all subjects of the full analysis set for whom no protocol deviation 
judged as having an impact on the primary efficacy analysis was reported or identified.
The decision as to which protocol deviations should be considered as reason for exclusion from the per-
protocol analysis set should be made at the Week 48 DRM (for main primary endpoint analysis) and 
documented in the DRM report.
At the interim at Week 24, a separate PP 24W will be used. The PP 24W set is defined as all subjects of the 
full analysis set for whom no protocol deviation judged as having an impact on the interim primary efficacy 
analysis at Week 24 was reported or identified. The decision as to which protocol deviations should be 
considered as reason for exclusion from the PP 24W set should be made at the Week 24 DRM and
documented in the DRM report.
Hence there will be two PP sets in the study:
-
The PP 24W set (defined for the 24W interim analysis)
-
The PP set (defined for the primary efficacy analysis)
Analysis on the per-protocol analysis sets will be based on the actual treatment (i.e. subjects will be 
analysed ‘as treated’).
7.2.4
Major protocol deviations leading to exclusion from the PP set
The following deviation is considered as major deviation leading to exclusion from PP set:
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x
Assessment missing or performed outside of ±14 days from the planned visit for the primary efficacy 
variable (Week 48).
Additional major deviations leading to exclusion from the PP set will be documented in the clean file report.
7.2.5
Safety Analysis Set
All patients randomized to delayed treatment arm or randomized to bulevirtide and received bulevirtide at 
least once after randomization.
Analysis on the safety population will be based on the actual treatment (i.e. subjects will be analysed ‘as 
treated’).
7.3
Disposition of Subjects
The following will be presented, by country, study site, and in total:
x
Number of screened subjects, in total across all treatment groups.
x
Number of screening failures, in total across all treatment groups.
x
Number of randomised subjects, by treatment group and in total.
Based on the number of randomised subjects, the following will also be presented by country, study site and 
in total, broken down by treatment group and in total across all treatment groups:
x
Number and percentage of subjects who did not receive any dose of IMP.
x
Number and percentage of subjects who received at least one dose of IMP.
x
Number and percentage of subjects who completed the study. [Final/Follow up period]
x
Number and percentage of subjects who completed Week 24/48/96/144. [Respective planned analysis]
x
Number and percentage of subjects who withdrew prematurely from the study.
x
Number and percentage of subjects in each of the analysis sets
In addition, a frequency table on the primary reason for premature withdrawal from the study will be 
presented by treatment group and in total. Percentages for this table will be based on the number of 
prematurely withdrawn subjects.
The number of subjects attending each study visit will also be summarised.
7.4
Protocol Deviations
The number and percentage of randomised subjects (by treatment arm) with at least one major protocol 
deviation leading to exclusion from an analysis set will be presented.
An overview tables of all protocol deviations during first 48 weeks will be presented by treatment group for 
the randomised analysis set, including the number and percentage of subjects with at least one, and the total 
number, of the following:
x
Any protocol deviation, in total and by grade (minor/major).
x
Any protocol deviation not related to COVID-19, in total and by grade.
x
Any protocol deviation related to COVID-19, in total and by grade.
In addition, the incidence of major protocol deviations during first 48 weeks, and the incidence of major
protocol deviations related to COVID-19, will be summarised by category and type of deviation. For each 
category and type, the total number of deviations as well as the number and percentage of subjects with at 
least one deviation in that category or type will be presented
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7.5
Demographics and Baseline Characteristics
Summary statistics and frequencies on demographic data will be presented for the FAS datasets and PP set 
(PP 24w set for the 24w Interim).
The following data (collected at Screening and/or Randomisation) will be summarised:
x
Demographics: age, sex, and race;
x
Baseline anthropometrics: height, body weight, body mass index (BMI) and BMI categories ('<30 
kg/m²' and '≥30 kg/m²');
x
Cirrhosis status, and Child–Pugh score and class for cirrhotic subjects;
x
Substance use: Smoking status, alcohol consumption status, drug abuse status, alcohol breath test, 
and urine drug test;
x
Abdominal ultrasound;
x
Serum alpha fetoprotein (AFP) test [IU/mL];
x
Serology test results: HIV antibodies, HCV antibodies, HDV antibodies, HBeAg and HBeAg antibodies, 
and HBV DNA;
x
HDV and HBV2 genotyping;
x
Baseline HDV RNA and HBV DNA levels (log-10 transformed values);
x
Baseline HBsAg levels (log-10 transformed values);
x
Baseline ALT levels;
x
Baseline liver stiffness;
x
Previous IFN therapy (number and % of subjects).
For HDV and HBV genotyping, only the main genotypes will be summarised in tables; if available, data on
sub-genotypes will be presented in listings only.
7.6
Medical History and Concurrent Diseases
Medical history and concurrent diseases will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA).
For each system organ class and preferred term, the number and percentage of subjects with at least one 
condition in that system organ class or preferred term, and the number of events, will be presented. Medical 
history and concurrent diseases will be presented in separate tables, based on the safety analysis set.
Medical history is defined as events stopped prior to baseline. Concurrent diseases are defined as ongoing 
events and events stopped on or after baseline. If the start and/or stop date is partially unknown, the 
following imputation rules will be used for the purpose of classifying the events:
Imputed start date
Imputed end date
Unknown year
Missing
Missing
Unknown month
1 January
31 December
Unknown day
First of month
Last of month
If it is not possible to classify the condition based on the reported and/or imputed start and end dates, it will 
be considered as concurrent. In data listings, the dates will be presented as reported.
7.7
Prior and Concomitant Medication
Medications will be coded according to the World Health Organization (WHO) Drug Dictionary and 
summarized by therapeutic subgroup (ATC level 2) and preferred name.
For each therapeutic subgroup and preferred name, the number and percentage of subjects who used at 
least one medication of that therapeutic subgroup or preferred name will be presented. Prior and 
concomitant medications will be summarized in separate tables, based on the safety analysis set.
2 HBV genotyping is performed at the first occasion of positive HBV DNA result, which can be post-baseline.
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In addition, use of prior and concomitant HBV medications will be summarised in a similar way (in 2 separate 
tables), by preferred name. For definition of HBV medication, see section 8.2.4.If a reported medication 
cannot be coded with a preferred name, the lowest available higher-level dictionary term will be used instead 
in the summary tables. If a medication cannot be coded on a lower level than the therapeutic subgroup or the 
anatomical main group (ATC level 1), that medication will be presented as ‘Not codable’ under that 
therapeutic subgroup/anatomical main group.
Prior medication is defined as medication stopped prior to baseline. Concomitant medication is defined as 
ongoing medication or medication stopped on or after baseline. If the start and/or stop date is partially 
unknown, the following imputation rules will be used for the purpose of classifying the medication:
Imputed start date
Imputed end date
Unknown year
Missing
Missing
Unknown month
1 January
31 December
Unknown day
First of month
Last of month
If it is not possible to classify a medication based on the reported and/or imputed start and end dates, it will 
be considered as concomitant. In data listings, the dates will be presented as reported.
7.8
Efficacy Evaluation
All analyses of efficacy variables will be performed using the full analysis set and the per-protocol (PP) set.
FAS will be used as main analysis and will be repeated using the PP set as supportive analysis. If the size of 
the randomised analysis set differs from the size of the full analysis set by more than 10%, the analysis of 
the primary efficacy variable will also be performed on the randomised analysis set.
In addition to the statistical hypothesis testing described in the subsections below, all descriptive summaries 
of efficacy data (primary, secondary 
will also be presented for the subgroups based on 
presence of cirrhosis for both the full analysis set and the per-protocol analysis set.
7.8.1
Primary Efficacy Variable
Combined response at Week 48
Combined response is defined as fulfilling both of below criteria:
1.
Undetectable HDV RNA (HDV RNA < LOD) or decrease in HDV RNA by ≥ 2 log10 IU/ml from 
baseline;
2.
ALT normalization.
Patients with missing assessment in HDV RNA or ALT on Week 24 or Week 48 respectively will be handled 
as non-responder using the MEF approach regardless of the reason for absence (see also paragraph 7.1.5 
handling of missing data).
The proportions of subjects with combined response at Week 48 for each of bulevirtide 2 mg and bulevirtide 
10 mg will be compared with the control group of delayed treatment. Fisher’s exact test will be used to test 
the following two null hypotheses:
H01: pO = pM10mg vs. 
H11: pO ≠ pM10mg
and
H02: pO = pM2mg vs. 
H12: pO ≠ pM2mg
where pO, pM2mg and pM10mg are the expected response rate for delayed treatment arm, bulevirtide 2 mg and 
bulevirtide 10 mg, respectively.
The overall significance level will be 0.05. However, the above hypotheses will also be tested at Week 24,
and hence the nominal two-sided significance level will be split among the time points with 0.01 for Week 24
and 0.04 for Week 48.
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In terms of a hierarchical testing procedure the second null hypothesis (H02 above) will not be rejected if the 
first null hypothesis (H01) could not be rejected.
The frequencies, proportions of subjects with combined response at Week 48 will be presented by treatment 
group along with the p-values and confidence intervals for the comparison versus group A. Exact 
unconditional 96%-confidence intervals based on scores for the proportion differences will be presented, For 
the within group proportions, Clopper-Pearson 95%-confidence will be calculated.
The hypotheses specified above will be tested at the interim analysis at Week 24 with a significance level of 
0.01 using the same methods. Exact unconditional 99%-confidence intervals based on scores for the 
proportion differences will be presented, For the within group proportions, Clopper-Pearson 95%-confidence 
will be calculated.
Due to the expected low number of responders under delayed treatment the analysis will not be stratified by 
cirrhosis or other covariables. However, as described above all descriptive analyses of efficacy will also be 
presented by presence of cirrhosis.
For the main and interim analysis of combined response on the FAS, the handling of time window deviations 
and imputation of missing values depends on whether the deviation is related to COVID-19, and the 
following rules will be applied:
x
Deviations not related to COVID-19: Assessments made outside of the time window defined by ±30 
days from the planned time point will be considered as missing. Missing values will be imputed using 
the missing equals failure approach (i.e., subjects with a missing value will be considered as non-
responders).
x
Deviations related to COVID-19: If, due to COVID-19, the assessment is not performed at the planned 
visit, or if the entire visit is missing, the assessment will be considered as missing. Missing values will 
be imputed using the last observation carrying forward (LOCF) approach. If there is no previous non-
missing post-baseline value that can be carried forward, the missing equals failure approach will be 
applied.
A sensitivity analysis will be performed on the FAS, where assessments made outside of the time window 
defined by ±30 days from the planned time point will be considered as missing, regardless of whether the 
time deviation is related to COVID-19. Missing values will be imputed using the missing equals failure 
approach.
The analysis on the PP sets will be performed on the observed cases without replacement of missing values.
7.8.2
Secondary Efficacy Variables
For the secondary efficacy variables except the key secondary variable, assessments made outside of the 
time window defined by ±30 days from the planned time point will be considered as missing, regardless of 
whether the time deviation is related to COVID-19. For FAS analysis of binary variables, missing values will 
be imputed using the missing equals failure approach. No imputations of missing values will be made for PP 
analysis or for the non-binary secondary efficacy variables
For the key secondary variable the same two steps approach as described for the primary endpoint will be 
applied.
7.8.2.1
Undetectable HDV RNA at Week 48 (key secondary variable)
For the proportion of patients with Undetectable HDV RNA at Week 48 a comparison between bulevirtide 
2 mg and 10 mg will be performed. A two-sided Fisher’s exact test will be used to test the following 
hypothesis:
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.
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This test will only be performed if the two null-hypotheses for the primary variable (H01 and H02 above) both 
have been rejected. 
As for the primary analysis, the above hypotheses will also be tested at the interim analysis at Week 24 and 
hence the nominal two-sided significance level of 0.05 will be split among the time points with 0.01 for Week 
24 and 0.04 for Week 48 respectively.
Exact unconditional confidence intervals based on scores for the proportion differences will be presented, 
with corresponding confidence levels of 99% for Week 24 and 96% for Week 48.
For the within group proportions, Clopper-Pearson 95%-confidence will be calculated.
All further analyses including the subsequent planned analyses as described in Section 7.1.6 will be 
considered explorative.
7.8.2.2
ALT normalization at Week 48
The proportions of subjects with ALT normalisation at Week 48 for each of bulevirtide 2 mg and bulevirtide 
10 mg will be compared with the control group of delayed treatment using Fisher’s exact test. Exact 
unconditional confidence intervals based on scores for the proportion differences will be presented, with 
corresponding confidence levels of 95%.
For the within group proportions, Clopper-Pearson 95%-confidence will be calculated.
7.8.2.3
Undetectable HDV RNA Week 24 and Week 48 after scheduled end of treatment (sustained 
virological response)
Undetectable HDV RNA at week 168 and 192 (i.e.  24 and 48 weeks after scheduled end of treatment) will 
be analysed in the same way as for ALT normalization.
7.8.2.4
Change from baseline in liver stiffness (kPa)
Change from baseline in liver stiffness (as measured by elastography) will be analysed using mixed-effects 
model for repeated measures (MMRM). 
Change from baseline in liver stiffness will be the dependent variable, where data for all post-baseline 
analysis visits will be used. The model will include treatment, region, presence of cirrhosis, visit and 
treatment-by-visit interaction as fixed-effect factors, and baseline liver stiffness as covariate. Restricted 
maximum likelihood (REML) will be used. Within-patient variation will be modeled as random effect with 
unstructured covariance structure. Confidence intervals will be based on estimated means (least square 
means) and corresponding t-statistics.
The Kenward-Roger approximation will be used to estimate the denominator degrees of freedom. If the 
model 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.
SAS procedure PROC MIXED will be used for analysis.
This analysis will be performed at the Week 96 and subsequent analyses. As the first post-baseline 
measurement for liver-stiffness is done at Week 48 the main analysis at Week 48 is without repeated 
measures. For this analysis the model will hence be reduced by removing the factors for visit and visit-
treatment interaction and omitting the features for a repeated measurement model.
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7.9
Safety Evaluation
All evaluations of safety data will be performed on the safety analysis set.
7.9.1
Extent of Exposure
Exposure will be presented at each interim, i.e. at week 24, 48, 96 and 144..
Exposure to bulevirtide will be presented for each of the groups (delayed treatment, bulevirtide 2mg and 
10mg) separately and in total. 
However, to account for duration of exposure the following will be presented 
-Exposure
The delayed treatment group will be included in the presentation after week 48 (from Interim 2 to Final 
analysis).
Summary statistics will be presented for:
-
treatment duration (weeks);
-
total dose (mg);
-
dose intensity (mg/week);
-
compliance (%);
In addition, summary statistics for the number and proportion of missed doses will also be presented.
To account for duration of exposure, there will be separate presentations for the treatment phase up to Week 
48 and the treatment phase after Week 48.
-
Exposure at Week 24, Week 48, 96 and 144 (for Arm B and C only)
-
Exposure after Week 48 to 96, after Week 48 to 144 (for all treatment groups)
For definition of exposure and compliance see section 8.4.
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7.9.2
Adverse Events
Adverse events will be coded according to MedDRA.
The analysis will focus on the treatment-emergent AEs (TEAE), defined as AEs which started or worsened 
after randomization (delayed treatment group) or after start of treatment (bulevirtide groups).
For serious adverse events with multiple reports (initial reports and one or more follow-up reports), only the 
record associated with the last report for the event will be considered for the summary tables.
To account for duration of exposure, the following will be presented:  
x
TEAEs within first 48 weeks for all groups using the protocol definition
x
TEAEs during treatment period for Arm B and C only
x
TEAEs after Week 48 – Week 144 for all groups with a modified TEAE definition:
AEs which started or worsened after start of treatment for all treatment groups, including delayed 
treatment.
x
TEAEs during study period (treatment and follow-up) for Arm B and C only.
x
TEAEs after Week 48 (treatment and follow-up) for all groups with a modified TEAE definition:
AEs which started or worsened after start of treatment for all treatment groups, including delayed 
treatment.
The following will also be presented:
x
TEAEs started after the end of treatment (FU period)
An overview of all TEAEs will be presented, including the number and percentage of subjects with at least 
one, and the total number, of the following:
1.
TEAEs;
2.
Serious TEAEs;
3.
TEAEs leading to withdrawal of the study medication or dose reduction;
4.
Fatal TEAEs;
5.
TEAEs, broken down by severity;
6.
TEAEs, broken down by causality to bulevirtide (Reasonable possibility, No reasonable possibility 
and Not applicable)
7.
TEAEs, broken down by causality to study procedure (Yes, No)
The incidence of TEAEs will be presented by system organ class and preferred term. For each system organ 
class and preferred term, the total number of TEAEs as well as the number and percentage of subjects with 
at least one TEAEs in that system organ class or preferred term will be presented. The incidence of serious 
TEAEs will be presented in the same way. AEs will also be presented in this way for the subgroup of ADA 
positive subjects and the subgroup of ADA negative subjects.
Separate tables for the incidence of TEAEs broken down by severity using the NCI-CTCAE grades used in 
the eCRF (Mild, Moderate, Severe, Life-threatening/ disabling and death)
and the incidence of TEAEs broken down by causality assessment (Reasonable possibility, No reasonable 
possibility) will also be presented by system organ class and preferred term.
There will also be tables on the most frequently reported TEAEs, on system organ class level and on 
preferred term level. The decision on the frequency cut-off for these tables will be taken during the analysis 
of the TEAE data in consultation with the author of the clinical study report and could be influenced by 
factors such as the overall number of TEAEs, study design, and the nature of the indication. The frequency 
cut-off will be mentioned in a table note.
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7.9.3
Laboratory
Summary statistics on the test results and change from baseline, and shift tables on the categorisation of 
values in relation to the normal range, will be presented by visit for the parameters below.
For laboratory parameters with qualitative results for some subjects and quantitative results for other 
subjects, the quantitative (numeric) test results will be categorised as ‘positive’ to allow frequency tables to 
be presented for such parameters as well.
Qualitative test results equal to one or more plus signs (‘+’, ‘++’, etc.) will be standardised as ‘Positive’.
Haematology:
x
White blood cell (WBC, Leukocytes) count
x
White Blood Cell (Leukocytes) differentials, absolute [10^9/L] and relative [%] for: basophils, 
eosinophils, lymphocytes, monocytes, neutrophils; 
x
Haematocrit [%], 
x
Haemoglobin [g/dL], 
x
Platelets [10^9/L],
x
Red blood cell (RBC) count, 
x
Reticulocytes (absolute10^9/L and relative ‰); 
Biochemistry:
x
Albumin [g/L],
x
Alkaline phosphatase [U/L],
x
Aminotransferase (ALT) [U/L],
x
Aspartate aminotransferase (AST) [U/L],
x
Total bilirubin [umol/L], 
x
Direct bilirubin [umol/L],
x
C-reactive protein (CRP) [mg/L];
x
Chloride [mmol/L],
x
Total cholesterol [mmol/L], 
x
Creatinine [umol/L], 
x
Gamma glutamyl transferase (GGT) [U/L],
x
Glucose [mmol/L], 
x
Lipase [U/L],
x
Pancreatic amylase [U/L],
x
Phosphate [mmol/L],
x
Potassium [mmol/L], 
x
Total protein [g/L],
x
Sodium [mmol/L],
x
Urea [mmol/L];
Blood bile salts
x
total bile salts [umol/L];
Coagulogram:
x
Prothrombin time [%];
x
Activated partial thromboplastin time [aPTT] [sec];
x
International normalised ratio (INR).
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Urinalysis:
x
pH
x
Specific gravity 
x
Protein 
x
Glucose 
x
Bilirubin 
x
Urobilinogen 
x
Ketones 
x
Erythrocytes 
x
Leukocytes 
x
Nitrites 
Vitamin D (ng/mL)
7.9.4
Physical Examination
Physical examination data will be summarised by visit (Baseline, week 24, week 48, week 96, and week 144) 
for each of the examined body systems below as the number and percentage of subjects with normal/
abnormal findings. 
1.
General appearance 
2.
Skin
3.
Head – Eyes – Ears – Nose - Throat,
4.
Lymph nodes
5.
Respiratory system
6.
Cardiovascular system
7.
Gastrointestinal system
8.
Musculoskeletal system
9.
Endocrine system
10. Nervous system
11. Urogenital system
The shift from baseline will also be presented.
For each type of local site reaction, the number and percentage of subjects for whom that type of reaction 
was reported at at least one visit will be presented, broken down by maximum severity grade of the reaction
7.9.5
Vital Signs
Summary statistics for below vital sign parameters will be presented by visit. 
1.
body weight 
2.
BMI
3.
heart rate
4.
respiration rate
5.
body temperature
6.
blood pressure (systolic and diastolic)
For post-baseline visits, the change from baseline will also be summarised.
7.9.6
Electrocardiogram
A frequency table on the overall evaluation (assessment of normality) of electrocardiogram (ECG) will be 
presented by visit. For post-baseline visits, the shift from baseline will also be presented.
For all quantitative ECG parameters, summary statistics will be presented by visit. Summary statistics for the 
change from baseline will also be presented.
For QTc, cut-off values of 30 and 60 ms will be considered for the change from baseline, and for each cut-off 
value the number and percentage of subjects who experienced a change from baseline greater than the cut-
off value will be presented by visit.
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In addition, the number and percentage of subjects within each of the following categories based on the QTc 
values (<451 ms, 451–480 ms, 481–500 ms or >500 ms) will be presented by visit.
7.11
Pharmacokinetic Evaluation
All analyses and summaries of PK data will use the safety analysis set.
Bulevirtide plasma concentrations, summary statistics (including the geometric mean, and the arithmetic and 
geometric coefficients of variation [CV%]) will be presented by visit. 
As the delayed treatment group (Arm A) does not start treatment until week 48, PK before and after week 48 
will be presented separately as follows:
a)
Plasma concentrations of bulevirtide during first 48 weeks for Arm B and C only;
b)
Plasma concentrations after 48 weeks for all groups.
7.12
Evaluation of Other Variables
The presentation of other variables will be performed on the full analysis set.
7.12.1
NTCP polymorphism
Analysis details for NTCP polymorphism will be described in virology analysis plan and virology study report.
7.12.3
HBeAg
HBeAg status and HBeAg antibodies status at baseline and Weeks 48, 96 and 144 will be summarised 
descriptively by visit, for subjects with positive HBeAg status at Screening
7.12.4
Liver Biopsy
Descriptive statistics for the following molecular analysis and gene expression parameters will be presented 
based on log-10 transformed data, including the change from baseline for the transformed data:
x
Molecular analysis:
o
relative expression level of HDV RNA;
o
relative expression level of HDV RNA (S region);
o
relative expression level of total HBV RNA (X region);
o
relative expression level of pregenomic HBV RNA;
o
HBV DNA (S region) [copies/cell];
o
total HBV DNA (X region) [copies/cell];
o
HBsAg.
x
Molecular analysis using immunofluorescence staining:
o
HDAg, % of positive hepatocytes.
x
Gene expression:
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o
relative expression level of NTCP mRNA;
o
relative expression level of CYP7A1 mRNA;
o
relative expression level of CXCL10 mRNA;
o
relative expression level of ISG15 mRNA;
o
relative expression level of MX1 mRNA;
o
relative expression level of OAS mRNA;
o
relative expression level of HLA-E mRNA;
o
relative expression level of TAP1 mRNA;
o
relative expression level of USP18 mRNA;
o
relative expression level of CXCL11 mRNA;
o
relative expression level of CXCL9 mRNA;
o
relative expression level of CXCR3 mRNA;
o
relative expression level of CCL5 mRNA;
o
relative expression level of CXCL8 mRNA;
o
relative expression level of IL18 mRNA;
o
relative expression level of TGFB1 mRNA.
Data will be summarised only for subjects with available data at both visits.
The following parameters will be presented in listings only:
x
Molecular analysis: DNA content [ng/μL], RNA content [ng/μL], Beta globin [copies], cccDNA [copies/
cell].
x
Gene expression: GAPDH CT, RPL30CT, SERPINA1 mRNA CT.
7.13
Changes to Planned Analysis
7.13.1
Definition of the Per-Protocol Analysis
According to the clinical study protocol, the per-protocol analysis set was defined as “all patients of the FAS 
without any major protocol deviations”.
However, in the SAP this was modified to the following:
The per-protocol set (PP) is defined as all subjects of the full analysis set for whom no protocol deviation 
judged as having an impact on the primary efficacy analysis was reported or identified.
7.13.2
ALT samples
According to the protocol, different samples were to be taken for the efficacy and safety evaluations of ALT. 
However, during the trial, it was discovered that the frozen samples (to be used for efficacy) were not stable 
at –20°C and could not be used. Thus, the ALT test results from the samples for the safety evaluation will be 
used for the efficacy analyses as well
8
Derived Variables
8.1
Disposition of Subjects
A screening failure is defined as a screened but not randomised subject.
8.2
Demographics and Baseline Characteristics
8.2.1
Age
Age will be computed as the integer part of the time in years between the date of birth and the date the 
written informed consent was signed, using the SAS function yrdif() with the basis parameter set to ‘age’. For 
subjects for whom only the year of birth is collected, age will be computed as the difference between the 
year the informed consent was signed and the year of birth.
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8.2.2
Body Mass Index
BMI will be computed as the body weight in kg divided by the squared height in metres.
8.2.3
Previous IFN therapy
A dichotomous variable indicating whether previous IFN therapy was used will be derived. Previous IFN 
therapy is defined as prior medication for which the preferred name includes the word ‘interferon’.
8.2.4
Prior and concomitant HBV medication
A dichotomous variable indicating HBV medications will be derived. A medication is considered as HBV 
medication if CMDECOD includes any of the following terms: tenofovir, tenofovir alafenamide, tenofovir 
disoproxil fumarate, entecavir, adefovir, lamivudine, telbivudine (regardless of capitalisation).
8.3
Change from Baseline
Change from baseline will be computed as the difference between a post-baseline value and the cor-
responding baseline value.
8.4
Exposure and Compliance
Duration of exposure in weeks, computed as the time in days from the date of the first dose to the date of the 
last dose plus 1 day, divided by 7 days/week.
The bulevirtide treatment duration at week x (in weeks) will be computed based on the dates of the first and 
last injections up to week x.
Total dose of bulevirtide at week x (in mg) will be computed as the sum of all injected doses of bulevirtide up 
to week x.
The bulevirtide dose intensity at week x (in mg/week) will be computed as the cumulative dose of bulevirtide 
at week x divided by the duration of exposure to bulevirtide at week x.
Compliance with bulevirtide treatment (in %) at week x will be computed as the ratio of the cumulative dose 
of bulevirtide to the planned total dose at week x of bulevirtide (planned daily dose multiplied by X×7 days) 
multiplied by 100.
For Delayed treatment, presented at Week 96 and Week 144, the planned total dose at week X of bulevirtide
is calculated as planned daily dose multiplied by (X-48)×7 day.
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Hence, at week 24, 48, 96 and 144 the following will be calculated:
Week 
x
Bulevirtide 
treatment duration 
at week x (weeks) 
Total dose of 
bulevirtide at 
week x (mg) 
Bulevirtide dose 
intensity at week x 
(mg/week) 
Compliance with 
bulevirtide treatment (%) 
at week x 
week 
24
first dose to dose at 
week 24 (or last dose 
before w24)
the sum of all injected 
doses of bulevirtide 
up to week 24
total dose of bulevirtide 
at week 24 divided by 
the duration of 
bulevirtide at week 24
Bulivirtide groups:
the planned total dose at week 
24 of bulevirtide (planned daily 
dose multiplied by 24×7 days) 
multiplied by 100.
week 
48
first dose to dose at 
week 48 (or last dose 
before w48)
the sum of all injected 
doses of bulevirtide 
up to week 48
total dose of bulevirtide 
at week 48 divided by 
the duration of 
bulevirtide at week 48
Bulivirtide groups:
the planned total dose at week 
48 of bulevirtide (planned daily 
dose multiplied by 48×7 days) 
multiplied by 100.
week 
96
first dose to dose at 
week 96 (or last dose 
before w96)
the sum of all injected 
doses of bulevirtide 
up to week 96
total dose of bulevirtide 
at week 96 divided by 
the duration of 
bulevirtide at week 96
Bulivirtide groups:
the planned total dose at week 
96 of bulevirtide (planned daily 
dose multiplied by 96×7 days) 
multiplied by 100.
Delayed treatment:
the planned total dose at week 
96 of bulevirtide (planned daily 
dose multiplied by 48×7 days) 
multiplied by 100.
week 
144
first dose to last dose 
at w144 (or last dose 
before w144)
the sum of all injected 
doses of bulevirtide 
up to week 144
total dose of bulevirtide 
at week 144 divided by 
the duration of 
bulevirtide at week 144
Bulivirtide groups:
the planned total dose at week 
144 of bulevirtide (planned 
daily dose multiplied by 144×7 
days) multiplied by 100.
Delayed treatment:
the planned total dose at week 
144 of bulevirtide (planned 
daily dose multiplied by 96×7 
days) multiplied by 100.
The number of missed doses at Week X will be computed as the expected number of doses Week X minus 
the number of administered doses at Week X. The expected number of bulevirtide doses will be computed 
as the date of Week X (or the date of premature withdrawal from the study, whichever comes first) minus the 
date of randomisation. 
The proportion of missed doses will be computed as the ratio of the number of missed doses to the expected 
number of doses and expressed as a percentage.
For Delayed treatment, presented at Week 96 and Week 144, the expected number of bulevirtide doses will 
be computed as the date of Week X (or the date of premature withdrawal from the study, whichever comes 
first) minus the date of Week 48.
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8.5
Efficacy variables
8.5.1
Undetectable HDV RNA 
Undetectable HDV RNA is defined as HDV RNA value <LOD.
8.5.2
Combined response (primary efficacy variable)
Combined response is defined as fulfilment of both of the following two conditions simultaneously:
1.
Undetectable HDV RNA (HDV RNA < LOD) or decrease in HDV RNA by ≥ 2 log10 IU/ml from 
baseline;
2.
ALT normalisation.
8.5.3
Histological findings
The change from baseline will be categorised as improvement (decrease of at least 1 point), no change or 
worsening (increase of at least 1 point) for each of the following parameters: HAI, Knodell fibrosis score, 
Ishak fibrosis score, METAVIR fibrosis stage and METAVIR activity grade.
 
8.6
Safety variables
8.6.1
Treatment Emergent Adverse Event
Two definitions of Treatment Emergent Adverse Event (TEAE) are used in this study:
TEAE (as in the protocol):
AEs which started or worsened after randomization (delayed treatment group) or after start of treatment 
(bulevirtide groups). 
Modified TEAE definition:
AEs which started or worsened start of treatment for all treatment groups, including delayed treatment.
8.6.2
Physical examination
The analysis parameters will be dichotomous variables categorising the examination results as 'Normal' or 
'Abnormal NCS' or 'Abnormal CS' (findings not reported as normal, Not Clinically Significant or Clinically 
Significant). For examinations reported as not done, the analysis value will be missing.
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9
References
1. ICH Harmonised Tripartite Guideline for Statistical Principles for Clinical Trials E9. 1998.
2. ICH Harmonised Tripartite Guideline for Structure and Content of Clinical Trial Reports E3. 1995.
3. Clinical Study Protocol MYR 301, Version 2.0 dated 01-Feb-2019. 
4. Optum, HQLQv2 Scoring Guidelines for Certified Scoring. 2016.
5. EuroQol EQ-5D-3L User Guide Version 6.0. 2018.
6. FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials. September 2007.
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Appendix 2: Liver related clinical events
For each of the pre-specified liver related clinical events (except hospitalisation and death), the applicable 
MedDRA preferred terms are listed below:
x
Cirrhosis development:
o
Biliary cirrhosis
o
Cardiac cirrhosis
o
Cirrhosis alcoholic
o
Cryptogenic cirrhosis
o
Hepatic cirrhosis
o
Lupoid hepatic cirrhosis
o
Pseudocirrhosis
x
Development or worsening of jaundice:
o
Jaundice
o
Jaundice acholuric
o
Jaundice cholestatic
o
Jaundice extrahepatic obstructive
o
Jaundice hepatocellular
x
Development or worsening of coagulopathy:
o
Coagulopathy
x
Development or worsening of ascites:
o
Ascites
o
Bacterascites
o
Biliary ascites
o
Haemorrhagic ascites
o
Malignant ascites
x
Development or worsening of hepatic encephalopathy:
o
Hepatic encephalopathy
o
Minimal hepatic encephalopathy
x
Bleeding from oesophageal varices:
o
Oesophageal varices haemorrhage
o
Varices oesophageal
x
Hepatocellular carcinoma development:
o
Hepatic cancer
o
Hepatocellular carcinoma
o
Liver carcinoma ruptured
o
Mixed hepatocellular cholangiocarcinoma
x
Liver transplantation:
o
Complications of transplanted liver
o
Liver and pancreas transplant rejection
o
Liver transplant
o
Liver transplant failure
o
Liver transplant rejection
o
Renal and liver transplant
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