Clinical trial NCT02888106
Conditions: Chronic Viral Hepatitis B With Delta-agent
Sponsor: Hepatera Ltd.
Start date: 2016-04-01; Completion date: 2020-10-30
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Randomised, Comparative, Parallel-Arm Study to Assess Efficacy and Safety of Myrcludex B in Combination with Peginterferon Alfa-2a Versus Peginterferon Alfa-2a Alone in Patients with Chronic Viral Hepatitis B with Delta-agent

Detailed description:
This is a multicenter, open-label, randomised, comparative, active-controlled parallel-arm phase II study.

The study will be conducted in Russia. The aim of this study is to explore the safety and efficacy of treatment with Myrcludex B used as a monotherapy and in combination with PEG-IFNα and Tenofovir compared to monotherapy with PEG-IFNα in patients with chronic viral hepatitis B with delta-agent, based on the achievement of undetectable viral load at the end of the follow-up period 6 months (24 weeks) after the end of treatment. The study is also aimed at investigating immunogenicity of Myrcludex B and the drug pharmacokinetics when used in combination with PEG IFN alfa-2a and with Tenofovir.

It is planned to screen 110 patients, and 90 patients will be randomised in equal numbers into six treatment arms.

* Arm A (n=15): PEG IFN alfa-2a 180 µg for 48 weeks
* Arm B (n=15): Myrcludex B 2 mg + PEG IFN alfa-2a 180 µg for 48 weeks
* Arm C (n=15): Myrcludex B 5 mg + PEG IFN alfa-2a 180 µg for 48 weeks
* Arm D (n=15): Myrcludex B 2 mg for 48 weeks
* Arm E (n=15): Myrcludex B 10 mg (10 mg once a day)+ PEG IFN alfa-2a 180 µg for 48 weeks
* Arm F (n=15): Myrcludex B 10 mg (5 mg twice a day)+ Tenofovir for 48 weeks

Arms: arm 1: PEG IFN alfa-2a 180 µg for 48 weeks arm 2: Myrcludex B 2 mg + PEG IFN alfa-2a 180 µg for 48 weeks arm 3: Myrcludex B 5 mg + PEG IFN alfa-2a 180 µg for 48 weeks arm 4: Myrcludex B 2 mg for 48 weeks arm 5: Myrcludex B 10 mg (10 mg once a day) + PEG-IFN alfa-2a 180 μg during 48 weeks arm 6: Myrcludex B 10 mg (5 mg twice a day) + Tenofovir during 48 weeks
Interventions: intervention 1: Myrcludex B intervention 2: PEG IFN alfa-2a intervention 3: Tenofovir
Intervention descriptions: intervention 1: Lyophilised powder for solution for subcutaneous injection intervention 2: solution for subcutaneous injection, once per week intervention 3: Film-coated tablets, 300 mg, per os, once daily

Protocol documents:
Prot_000.pdf: 
Hepatera LLC 
PROTOCOL No. MYR 203 
Final version 7.0  
dd. September 24, 2019 
Translation into English,  
dd. October 10, 2019 
 
 
CONFIDENTIAL 
Page 1 of 88 
 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Study title: 
A Multicenter, Open-label, Randomized, Comparative, parallel-arm phase 
II study to Assess efficacy and safety of Myrcludex B in combination with 
Peginterferon alfa-2a versus Peginterferon alfa-2a alone in patients with 
chronic viral hepatitis B with delta-agent 
 
 
Sponsor: 
Hepatera LLC, 12/19 b.1 Verkhnyaya Radischevskaya str., 109240 
Moscow, Russia 
 
 
Protocol Number: 
MYR 203 
 
 
Protocol version and date: 
Final version 7.0 dated September 24, 2019 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, especially the unpublished data, is the property of Hepatera 
LLC., and is provided to you as an investigator, potential investigator, or consultant, for consideration by 
you, your personnel, and the relevant Expert Council of the organization/Independent Ethics Committee 
under the terms of confidentiality. The information is for use only within the scope of the approved clinical 
study specified in this protocol. The information cannot be disclosed without the prior written consent of 
Hepatera LLC, except for the cases necessary to obtain informed consent from persons who the study drug 
will be indicated to. 


Hepatera LLC 
PROTOCOL No. MYR 203 
Final version 7.0  
dd. September 24, 2019 
Translation into English,  
dd. October 10, 2019 
 
 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ................................................................................................................ 2 
LIST OF TABLES .......................................................................................................................... 7 
LIST OF FIGURES ........................................................................................................................ 7 
GENERAL INFORMATION ....................................................................................................... 10 
LIST OF ABBREVIATIONS ....................................................................................................... 12 
SYNOPSIS .................................................................................................................................... 13 
1 
INTRODUCTION ............................................................................................................. 23 
1.1 
CHRONIC VIRAL HEPATITIS B WITH DELTA AGENT ........................................... 23 
1.2 
Study drug Myrcludex B .................................................................................................... 25 
1.2.1 
General Information ................................................................................................... 25 
1.2.2 
Preclinical Study Results ............................................................................................ 26 
1.2.3 
Clinical Study Results ................................................................................................. 27 
1.3 
Study Justification .............................................................................................................. 33 
1.3.1 
Overall Study Design and Plan .................................................................................. 33 
1.3.2 
Study population ......................................................................................................... 35 
1.3.3 
Justification of the administration route, dose, dosage regimen and treatment duration
 
 .................................................................................................................................... 35 
1.3.4 
Brief description of known and potential risks and benefits for study subjects.......... 35 
1.4 
Regulatory documents........................................................................................................ 35 
2 
OBJECTIVES AND ENDPOINTS OF THE STUDY ..................................................... 37 
2.1 
Study objective ................................................................................................................... 37 
2.2 
Study objectives ................................................................................................................. 37 
2.3 
Study Endpoints ................................................................................................................. 37 
2.4 
Investigated pharmacokinetic parameters .......................................................................... 38 
3 
STUDY DESIGN AND PLAN ......................................................................................... 39 
3.1 
Study design and plan ........................................................................................................ 39 
3.2 
Randomization ................................................................................................................... 40 
3.3 
Blinding procedure ............................................................................................................. 40 
3.4 
Schedule of study procedures and stages ........................................................................... 40 


Hepatera LLC 
PROTOCOL No. MYR 203 
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dd. October 10, 2019 
 
 
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3.4.1 
Informed consent ........................................................................................................ 40 
3.4.2 
Screening period (Day-28 – Day-1) ........................................................................... 40 
3.4.3 
Treatment period(Week 1 – Week 48) ........................................................................ 41 
3.4.4 
Follow-up period (Week 49 –Week 72) ...................................................................... 48 
3.5 
Acceptable window periods for planned visits and procedures ......................................... 49 
3.6 
Limitations of the study ..................................................................................................... 49 
4 
PATIENT SELECTION AND DROP-OUT..................................................................... 51 
4.1 
Patient selection ................................................................................................................. 51 
4.2 
Inclusion Criteria................................................................................................................ 51 
4.3 
Exclusion criteria ............................................................................................................... 51 
4.4 
Enrollment of patients who are unable to give informed consent to participate in the study 
 
 
 ............................................................................................................................................ 52 
4.5 
Exclusion criteria ............................................................................................................... 52 
4.6 
Premature Termination of the Study .................................................................................. 53 
5 
TREATMENTS ................................................................................................................ 54 
5.1 
General Information ........................................................................................................... 54 
5.1.1 
Drug Myrcludex B ...................................................................................................... 54 
5.1.2 
Peginterferon alfa-2a (PEG-IFN alfa-2a) .................................................................. 54 
5.1.3 
Tenofovir ..................................................................................................................... 54 
5.2 
Packaging, labeling, storage conditions and drug accountability ...................................... 55 
5.3 
Administration route, dose, dosage regimen ...................................................................... 56 
5.3.1 
Myrcludex B ................................................................................................................ 56 
5.3.1.1 Doses, dosage regimen ............................................................................................... 57 
5.3.1.2 Measures to be taken when the dose of the study drug Myrcludex B is missed ......... 57 
5.3.1.3 Adjustment of the dose of Myrcludex B ...................................................................... 58 
5.3.2 
Peginterferon alfa-2a (PEG-IFN alfa-2a) .................................................................. 58 
5.3.2.1 Doses and dosage regimen ......................................................................................... 59 
5.3.2.2 Adjustment of the dose of peginterferon alfa-2a ......................................................... 59 
5.3.2.3 Rules for dose adjustment, delayed injection and dose delay .................................... 60 
5.3.3 
Tenofovir ..................................................................................................................... 61 
5.3.4 
Dose adjustment of Myrcludex B and peginterferon alfa-2a with increased ALT and AST 
activity  .................................................................................................................................... 61 
5.3.5 
Missing one or more drug doses in connection with the development of adverse events
 
 .................................................................................................................................... 61 


Hepatera LLC 
PROTOCOL No. MYR 203 
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dd. October 10, 2019 
 
 
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5.3.6 
Rules for preparation and performance of self-injections Myrcludex B + Peginterferon 
alfa 2a  .................................................................................................................................... 61 
5.3.7 
Rules of Tenofovir self-taking ..................................................................................... 63 
5.4 
Concomitant treatment ....................................................................................................... 63 
6 
STUDY PROCEDURES .................................................................................................. 64 
6.1 
Collection of data on demographic and other baseline characteristics .............................. 64 
6.1.1 
Demographic data ...................................................................................................... 64 
6.1.2 
Medical history ........................................................................................................... 64 
6.1.3 
Collection of data on previous and concomitant treatment........................................ 64 
6.1.4 
Measurement of the body height, weight .................................................................... 64 
6.1.5 
Urine pregnancy test ................................................................................................... 64 
6.1.6 
Urine drug screening .................................................................................................. 64 
6.1.7 
Alcohol-breath test ...................................................................................................... 64 
6.1.8 
Alpha-fetoprotein blood test ....................................................................................... 64 
6.1.9 
Serologic assay ........................................................................................................... 64 
6.2 
Efficacy evaluation ............................................................................................................ 65 
6.2.1 
Fibroscan .................................................................................................................... 65 
6.2.2 
Liver biopsy ................................................................................................................ 65 
6.2.3 
Abdominal ultrasound ................................................................................................ 65 
6.2.4 
HBV and HDV genotyping, resistance assay and analysis of NTCP polymorphism . 67 
6.3 
Safety Evaluation ............................................................................................................... 67 
6.3.1 
Physical examination .................................................................................................. 67 
6.3.2 
Ophthalmological examination .................................................................................. 68 
6.3.3 
Evaluation of vital signs ............................................................................................. 68 
6.3.4 
Electrocardiography ................................................................................................... 68 
6.3.5 
Hematology ................................................................................................................. 68 
6.3.6 
Blood chemistry .......................................................................................................... 69 
6.3.7 
Coagulogram .............................................................................................................. 69 
6.3.8 
Urinalysis .................................................................................................................... 69 
6.3.9 
Total bile acids ........................................................................................................... 70 
6.3.10 Blood test for TSH, T4 ................................................................................................ 70 
6.4 
Pharmacokinetics Evaluation ............................................................................................. 70 
6.5 
Immunogenicity ................................................................................................................. 71 
6.6 
Patient Diary ...................................................................................................................... 71 
6.7 
Justification of the selected study parameters .................................................................... 71 


Hepatera LLC 
PROTOCOL No. MYR 203 
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Translation into English,  
dd. October 10, 2019 
 
 
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7 
ADVERSE EVENTS ........................................................................................................ 73 
7.1 
Definitions .......................................................................................................................... 73 
7.2 
Methods of adverse event detection ................................................................................... 74 
7.3 
Other significant adverse events ........................................................................................ 74 
7.3.1 
Local Reactions at the Myrcludex B Injection Site ..................................................... 74 
7.4 
Registration of adverse events ........................................................................................... 74 
7.4.1 
Evaluation of the Severity of an Adverse Event .......................................................... 75 
7.4.1.1 Evaluation of the severity of local reactions at the drug injection site ...................... 75 
7.4.1.2 Evaluation of the severity of fever .............................................................................. 75 
7.4.2 
Evaluation of the causal relationship of an adverse event with the study drug/reference 
product/Tenofovir ..................................................................................................................... 76 
7.4.3 
Evaluation of the outcome of an adverse event .......................................................... 76 
7.5 
Monitoring the dynamics of an adverse event ................................................................... 76 
7.6 
Investigator's liability to report a serious adverse event .................................................... 77 
7.7 
The sponsor's liability to provide safety information during the clinical study ................. 77 
7.8 
Pregnancy ........................................................................................................................... 77 
8 
STATISTICAL CONSIDERATIONS .............................................................................. 78 
8.1 
General Information ........................................................................................................... 78 
8.2 
Populations for the study data analysis .............................................................................. 78 
8.3 
Demographic and Baseline Characteristics........................................................................ 78 
8.4 
Prior and Concomitant Therapy ......................................................................................... 78 
8.5 
Efficacy Analysis ............................................................................................................... 78 
8.6 
Safety Analysis .................................................................................................................. 79 
8.7 
Analysis of pharmacokinetic parameters ........................................................................... 79 
8.8 
Immunogenicity analysis ................................................................................................... 80 
8.9 
Sample size justification .................................................................................................... 80 
8.10 Interim analysis .................................................................................................................. 80 
8.11 Procedures for Accounting Missing Data and Data Queries ............................................. 80 
9 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION ..................................... 81 
10 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................ 82 
10.1 Qualification of the investigator ........................................................................................ 82 
10.2 Study Monitoring ............................................................................................................... 82 


Hepatera LLC 
PROTOCOL No. MYR 203 
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10.3 Inspection and Audit .......................................................................................................... 82 
11 
ETHICS ............................................................................................................................. 83 
11.1 Declaration of Helsinki ...................................................................................................... 83 
11.2 Good Clinical Practice ....................................................................................................... 83 
11.3 Study Approval .................................................................................................................. 83 
11.4 Procedure for obtaining the written informed consent....................................................... 83 
11.5 Confidentiality ................................................................................................................... 83 
12 
DATA HANDLING AND RECORD KEEPING ............................................................. 84 
12.1 Records Retention .............................................................................................................. 84 
12.2 Data Collection .................................................................................................................. 84 
13 
SPONSORSHIP AND INSURANCE ............................................................................... 85 
13.1 Sponsorship ........................................................................................................................ 85 
13.2 Insurance ............................................................................................................................ 85 
14 
PUBLICATION OF THE CLINICAL STUDY RESULTS ............................................. 86 
15 
REFERENCE LIST........................................................................................................... 87 
 


Hepatera LLC 
PROTOCOL No. MYR 203 
Final version 7.0  
dd. September 24, 2019 
Translation into English,  
dd. October 10, 2019 
 
 
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LIST OF TABLES 
 
Table 1 - Flow Chart 
 
 
 
 
 
 
 
 
 
 
24 
Table 2 - MYR 201 substudy 
: Adverse Event Summary (Safety Set) 36 
Table 3 - Evaluation of local reactions at the drug injection site  
 
 
 
 
75 
 
 
LIST OF FIGURES 
 
Figure 1 Clinical Study results MYR201 substudy 
 
 
 
 
 
 
35 
Figure 2 - Study Scheme 
 
 
 
 
 
 
 
 
 
42 
 


Hepatera LLC 
PROTOCOL No. MYR 203 
Final version 7.0  
dd. September 24, 2019 
Translation into English,  
dd. October 10, 2019 
 
 
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SIGNATURE PAGE 1 (STUDY SPONSOR) 
 
The Clinical Study as per Protocol: A Multicenter, Open-label, Randomized, Comparative, parallel-arm 
phase II study to Assess efficacy and safety of Myrcludex B in combination  with Peginterferon alfa-2a 
versus Peginterferon alfa-2a alone in patients with chronic viral hepatitis B with delta-agent.  
The signatories of the document confirm the approval of the Protocol and guarantee that the present study 
will be conducted in accordance with all the requirements of this Protocol. 
 
Yana Anatolievna Deloveri, 
General Manager 
Hepatera LLC 
 
 
Signature _________________ 
Date: ______/______/______ 
 
Day/month/year 
 
Alexander Alexandrov, 
Medical director 
Hepatera LLC 
 
 
 
Signature _________________ 
Date: ______/______/______ 
 
Day/month/year 
 
 


Hepatera LLC 
PROTOCOL No. MYR 203 
Final version 7.0  
dd. September 24, 2019 
Translation into English,  
dd. October 10, 2019 
 
 
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Page 9 of 88 
 
 
SIGNATURE PAGE 2 (PRINCIPAL INVESTIGATOR) 
The Clinical Study as per Protocol: A Multicenter, Open-label, Randomized, Comparative, parallel-arm 
phase II study to Assess efficacy and safety of Myrcludex B in combination with Peginterferon alfa-2a 
versus Peginterferon alfa-2a alone in patients with chronic viral hepatitis B with delta-agent.  
 
I have read all the pages of this clinical study protocol, sponsored and I agree that it contains all the 
information needed to perform this study. I will conduct the study in accordance with all the requirements of 
the Protocol, including all data protection guidelines, in accordance with the ICH GCP, the ethical principles 
of the World Medical Association Declaration of Helsinki and local regulatory requirements. 
 
Clinical Center Name 
__________________________________________________ 
__________________________________________________ 
Clinical Center Address 
__________________________________________________ 
__________________________________________________ 
Principal Investigator  
(full name, title) 
__________________________________________________ 
__________________________________________________ 
 
 
Signature: _________________________________________ 
 
 
 
Date: ______/______/______ 
day/month/year 
 


Hepatera LLC 
PROTOCOL No. MYR 203 
Final version 7.0  
dd. September 24, 2019 
Translation into English,  
dd. October 10, 2019 
 
 
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GENERAL INFORMATION 
 
Study sponsor: 
 
Yana Anatolievna Deloveri, 
General Manager 
Hepatera LLC, 12/19 b.1 Verkhnyaya Radischevskaya str., 
109240 Moscow, Russia 
 
Central laboratories (Evaluation of 
pharmacokinetics, 
evaluation of immunogenicity, resistance, 
NTCP polymorphism, virology analysis, 
HBV, HDV genotyping, safety parameters 
analysis, liver biopsy study: 
pathomorphological, immunohistochemical, 
and also the examination of intrahepatic 
parameters, alfa-fetoprotein blood test, blood 
test for TSH and T4, hematology, blood 
chemistry, urinalysis): 
The information will be presented in the 
investigator's/organization's file 
 
All specialists/organizations involved in the study and not mentioned in this section will be listed in a 
separate list in accordance with the established procedure. The current version of the list will be presented in 
the main study archive, as well as in the archives of each study center. 
 


Hepatera LLC 
PROTOCOL No. MYR 203 
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Translation into English,  
dd. October 10, 2019 
 
 
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List of medical sites where the clinical study No. MYR 203 (including pharmacokinetic study) will be 
performed: 
 
Clinical Centre 1 
State-Financed Health Institution of Moscow Oblast “Moscow Regional 
Research Clinical Institute n.a. M.F. Vladimirskiy” 
129110, Moscow, 61/2 Schepkina str. 
Principal Investigator  
Pavel Olegovich Bogomolov 
Clinical Centre 2 
State-Financed Health Institution of the Stavropol Territory “Stavropol 
Regional Clinical Center of the specialized types of medical care” 
355030, Stavropol, 1 Semashko str. 
Principal Investigator  
Natalia Ioganovna Geyvandova  
Clinical Centre 9 
State-Financed Health Institution “Specialized Clinical Infectious 
Diseases Hospital” of the Ministry of Health of the Krasnodar Territory, 
350015, Krasnodar, 204 Sedina str. 
Principal Investigator  
Vladimir Nikolaevich Gorodin 
Clinical Centre 12 
Federal State-Funded Educational Institution of Higher Vocational 
Education “South Ural State Medical University” of the Ministry of 
Health of the Russian Federation 
454052, Chelyabinsk, 64 Vorovskogo 
At the premises of the Clinics of the Federal State-Funded Educational 
Institution of Higher Vocational Education “South Ural State Medical 
University” of the Ministry of Health of the Russian Federation 
454052, Chelyabinsk, 2 Cherkasskaya str. 
Principal Investigator  
Olga Igorevna Sagalova 
Clinical Centre 17 
Medical company “Hepatologist” Ltd. 
443063, Samara, 36A Serdobskaya 
Principal Investigator  
Vyacheslav Gennadievich Morozov 
Clinical Centre 18 
Federal Budget Institution of Science “Central Research Institute of 
Epidemiology” of The Federal Service on Customers' Rights Protection 
and Human Welfare 
111123, Russia, Moscow, 3a Novogireevskaya str. 
Principal Investigator  
Vladimir Petrovich Chulanov 
Clinical Centre 19 
“Clinic of Modern Medicine HD” Limited Liability Company 
121293, Moscow, 2 Victory Square, bld. 1 
Principal Investigator  
Tatiana Vladimirovna Stepanova 


Hepatera LLC 
PROTOCOL No. MYR 203 
Final version 7.0  
dd. September 24, 2019 
Translation into English,  
dd. October 10, 2019 
 
 
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LIST OF ABBREVIATIONS 
 
CTCAE 
Common Terminology Criteria for Adverse Events 
GCP 
Good Clinical Practice 
HBV 
Hepatits B virus 
HDV 
Hepatits D virus 
ICH 
The International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ITT 
Intention-to-treat 
MedDRA 
The Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NTCP 
Sodium taurocholate co-transporting polypeptide 
SUSAR 
Suspected unexpected serious adverse reaction 
ULN 
Upper limit of normal 
BMI 
Body Mass Index 
CRF 
Case report form 
NCSD 
Non-clinically significant deviations 
AR 
Adverse reaction 
AE 
Adverse event 
PCR 
Polymerase chain reaction 
SAE 
Serious adverse event 
T4 
Thyroxine 
TSH 
Thyroid-stimulating hormone 
PK 
Pharmacokinetics 
ECG 
Electrocardiogram 
 


Hepatera LLC 
PROTOCOL No. MYR 203 
Final version 7.0  
dd. September 24, 2019 
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dd. October 10, 2019 
 
 
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SYNOPSIS  
Study title 
A Multicenter, Open-label, Randomized, Comparative, parallel-arm phase 
II study to Assess efficacy and safety of Myrcludex B in combination  
with Peginterferon alfa-2a versus Peginterferon alfa-2a alone in patients 
with chronic viral hepatitis B with delta-agent. 
Study phase 
Phase II 
Protocol number 
MYR 203 
Study drug 
Myrcludex B (MXB), lyophilisate for solution for subcutaneous injection, 
2 mg/vial, 5 mg/vial. The drug is administered subcutaneously, in the 
doses of 2 mg, 5 mg or 10 mg every 24±1 hours (once a day for groups B- 
E) or every 12±1 (twice a day, group F).  
Reference Product 
Peginterferon alfa-2a (PEG-IFN alfa-2a), solution for subcutaneous 
injection, 180 mg/0.5 mL (unit-dose syringe/autoinjector) manufactured 
by F. Hoffmann-La Roche Ltd., Switzerland The drug is administered 
subcutaneously, once a week at a dose of 180 µg. 
Product in combination 
therapy for group F 
Tenofovir disoproxil fumarate (Tenofovir), film-coated tablets, 300 mg, 
manufactured by Gilead Sciences (Ireland). Should be administered orally, 
once daily, 300 mg 
Study purpose 
The purpose of this clinical study is to investigate the efficacy and safety 
of the monotherapy with Myrcludex B, the combination of Myrcludex B 
and the peginterferon alfa-2a (PEG-IFN alfa-2a) and in combination with 
Tenofovir as compared to the monotherapy with peginterferon alfa-2a in 
patients with chronic viral hepatitis B with delta-agent. 
Study Objectives 
Primary objective: 
• 
To Investigate the efficacy of Myrcludex B in monotherapy in 
combination with PEG-IFN alfa-2a and with Tenofovir as compared with 
PEG-IFN alfa-2a monotherapy, based on the achievement of undetectable 
viral load at the end of follow-up period: 6 months (24 weeks) after the 
end of treatment. 
Secondary objectives: 
• 
To investigate the efficacy of Myrcludex B in monotherapy and in 
combination with PEG-IFN alfa-2a and with Tenofovir as compared with 
monotherapy with PEG-IFN alfa-2a, based on the secondary efficacy 
endpoints. 
• 
To investigate the safety of Myrcludex B in monotherapy and in 
combination with PEG-IFN alfa-2a and in combination with Tenofovir 
compared with PEG-IFN alfa-2a monotherapy. 
• 
To investigate the pharmacokinetics of Myrcludex B in 
monotherapy and when administered in combination with PEG-IFN alfa-
2a and in combination with Tenofovir. 
• 
To investigate the immunogenicity of Myrcludex B 
Planned number of patients  
Screened: 123 patients 
Randomised: 90 patients 
Study design and 
methodology 
This study is a multicenter, open-label, randomized, comparative, 
controlled, parallel-arm phase II study. 
The study will be performed in Russia. 
The study objective is to investigate the efficacy and safety of the 
monotherapy with Myrcludex B and the combination of Myrcludex B and 
the peginterferon alfa-2a and also Myrcludex B + Tenofovir as compared 
to the monotherapy with peginterferon alfa-2a in patients with chronic 
viral hepatitis B with delta-agent. In the course of the study, it is also 
planned to investigate the immunogenicity of Myrcludex B and the 


Hepatera LLC 
PROTOCOL No. MYR 203 
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pharmacokinetics of the drug when administered alone and in combination 
with PEG-IFN alfa-2a and in combination with Tenofovir. 
It is planned that 123 patients will be screened and 90 of them will be 
randomized into 6 treatment groups in a 1:1:1:1:1:1 ratio: 
• 
Arm A (n=15): PEG-IFN alfa-2a 180 µg during 48 weeks 
• 
Arm В (n=15): Myrcludex B 2 mg + PEG-IFN alfa-2a 180 μg 
during 48 weeks 
• 
Arm С (n=15): Myrcludex B 5 mg + PEG-IFN alfa-2a 180 μg 
during 48 weeks 
• 
Arm D (n=15): Myrcludex B 2 mg during 48 weeks. 
• 
Arm E (n=15): Myrcludex B 10 mg (10 mg once a day) + PEG-IFN 
alfa-2a 180 μg during 48 weeks 
• 
Arm F (n=15): Myrcludex B 10 mg (5 mg twice a day) + Tenofovir 
during 48 weeks 
After the end of the treatment period, there will be a follow-up period of 
24 weeks. Patients from group F will continue Tenofovir treatment during 
follow-up period. 
It is planned to perform a pharmacokinetic study of Mircludex B during 
the study: 
1. Pharmacokinetic substudy (PK-substudy) 
10 patients of groups B and C (20 patients in total) are planned to be 
enrolled. Blood samples for estimation of drug concentration will be 
collected at Days 1, 2 and 14, 15 in the following timepoints: 
• 
Day 1 – before the first injection  of Myrcludex B, in 00:30, 1:00, 
1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 14:00 
(hh:min) after the drug injection. 
• 
Day 2 – in 24:00 (hh:min) after the drug injection. 
• 
Day 14 – before injection of Myrcludex B, in 00:30, 1:00, 1:30, 
2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 14:00 
(hh:min) after the drug injection. 
• 
Day 15 – in 24:00 (hh:min) after the drug injection. 
2. Pharmacokinetic main study (PK-main study). 
For a more precise investigation of the possible study drug accumulation 
in all patients of each Myrcludex B treatment arm, blood sampling points 
for the pharmacokinetic study are assigned: week 4, 8, 12, 16, 20, 24, 28, 
32, 40, 481 (in 1hour +/-15 min after the drug injection). For the patients 
not enrolled into the pharmacokinetic substudy, a sampling point at a 
randomization visit (in 1hour +/-15 min after the first drug injection) is 
introduced. 
3. Pharmacokinetic study in group F (the second part of the study) 
10 patients of group F will take part in the study. Blood samples for 
estimation of drug concentration will be collected at Days 1, 2 and 14,  15 
in the following timepoints: 
• Day 1 – before the first injection of Myrcludex B, in 00:30, 1:00, 
1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00 
(hh:min) after the drug injection. 
Blood sampling in 12 hours after the first injection should be performed 
before the second injection of MXB. 
• Day 2 – in 12:00 (hh:min)  after the second injection on Day 1 
Blood sampling should be performed before the third injection of 
Myrcludex B. 
• Day 14 - before injection of Myrcludex B, in 00:30, 1:00, 1:30, 
2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00 (hh:min) 


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after the drug injection. 
Blood sampling in 12 hours should be performed before next injection of 
MXB. 
• Day 15 - in 12:00 (hh:min) after the second injection on Day 14 
Blood sampling should be performed before next injection of Myrcludex 
B. 
The study plan includes a screening period – maximum 4 weeks, treatment 
period - 48 weeks, follow-up period - 24 weeks. 
The total number of visits is 19 (screening visit, 13 visits of the treatment 
period, 5 visits of the follow-up period). 
Patients participating in the pharmacokinetic substudy (PK-substudy and 
pharmacokinetic study in group F) will be hospitalized before the start of 
study treatment and will stay in the hospital (day-stay or 24-hour) during 
Days 1, 2, 14, 15. Other visits of pharmacokinetics (PK-main study) will 
be done outpatiently. 
Patients not participating in the pharmacokinetic substudy (PK-substudy 
and pharmacokinetic study in group F) during the whole study period will 
receive treatment and have scheduled observations outpatiently. 
The study includes 2 phases:  
I phase – patients enrollment in groups A – D (Protocol version 1.0, dd. 
16.12.2015, Protocol version 1.1, dd. 16.03.2016, Protocol version 2.0, dd. 
31.05.2016, Protocol version 3.0, dd. 23.08.2017) 
II phase - patients enrollment in groups E – F (Protocol version 4.0, dd. 
19.01.2018) 
Efficacy criteria 
Primary efficacy endpoint: 
• 
Proportion of patients with a negative PCR result of HDV RNA 
(undetectable HDV RNA level) at week 72 (end of the follow up 
period) 
Secondary efficacy endpoints: 
• 
Proportion of patients with a negative PCR result of HDV RNA 
(undetectable HDV RNA level ) at weeks 24 and 48 
• 
Proportion of patients with HDV RNA response (decrease ≥ 2 log10 
HDV RNA or an undetectable level of HDV RNA) at weeks 24, 48 
and 72 
• 
Proportion of patients with ALT normalization in weeks 24, 48 and 
72 
• 
Proportion of patients with combined treatment response (result of 
HDV RNA negativation and ALT normalization) at weeks 24, 48 
and 72 
• 
Proportion of patients with a combined response to therapy 
((decrease ≥ 2 log10 HDV RNA or an undetectable level of HDV 
RNA) and normalization of ALT) at weeks 24, 48 and 72 
• 
Proportion of patients with HBsAg response (HBsAg negativation or 
>1 log10 IU/mL decline) at weeks 24, 48 and 72 
• 
Proportion of patients with HBsAg negativation with the appearance 
of anti-HBsAg antibodies and without it at weeks 48 and 72 
• 
Proportion of patients with a negative PCR result of HBV DNA at 
weeks 24, 48 and 72 
• 
The intensity of liver fibrosis based on results of transient 
elastometry at weeks 48 and 72  
• 
Changes in the results of liver biopsy before and after the treatment 
As part of the study of efficacy, HBV, HDV genotyping, resistance assay 
and NTCP polymorphism will be performed additionally. 


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Safety criteria 
• 
Adverse events, serious adverse events 
• 
Physical examination 
• 
Ophthalmological examination 
• 
Vital signs 
• 
12-lead ECG. 
• 
Hematology 
• 
Blood chemistry 
• 
Total bile acids 
• 
Coagulogram 
• 
Urinalysis 
• 
Blood test for Blood test for TSH, T4  
Immunogenicity 
Assessment of immunogenicity will be performed in the arms of patients 
administered the study drug (Arms B - F). 
Antibodies to Myrcludex B will be assessed during the treatment period 
(drug injection pre-dose [Day 1], weeks 12, 24, 48) and during follow-up 
period (4, 12, 24 weeks after the end of treatment). 
Pharmacokinetic parameters 
The following PK parameters will be assessed using the non-
compartmental methods: 
• 
Cmax – maximum concentration 
• 
Тmax – time of maximum concentration 
• 
Kel – elimination rate constant 
• 
T1/2 – elimination half-life 
• 
CL/F – total clearance 
• 
AUC0-t – area under the curve "drug concentration-time" from time 
0 to the sampling time (t) of the last sample 
• 
AUC0-∞ – area under the curve "drug concentration-time" from time 
0 to ∞ 
Inclusion Criteria 
To be included in the study, patients must meet all of the following 
inclusion criteria: 
1. 
Signed informed consent form. 
2. 
Males and females 18 to 65 years of age (inclusively). 
3. 
Patients with chronic hepatitis B (HBeAg-positive or negative) and 
HBsAg-positive for at least 6 months prior to Screening. 
4. 
Positive for anti-HDV antibodies for at least 6 months prior to 
Screening. 
5. 
HDV RNA-positive at Screening. 
6. 
ALT more than or equal 1 x ULN and less than 10 x ULN 
7. 
The patient agrees to use adequate method of contraception during 
the study, starting from the time of Informed Consent signing and until 
completion of Follow-up Period. 
Exclusion criteria 
Patients cannot be enrolled into the study if they meet any of the following 
criteria:  
1. 
Intolerance or hypersensitivity to the active ingredient or other 
components of the study drug Myrcludex B. 
2. 
Intolerance or hypersensitivity to interferons alfa, genetically 
engineered E.coli medications, polyethylene glycol or other components 
of peginterferon alfa-2a. 
3. 
Previous treatment with Myrcludex B (patients with previous 
exposure to interferon are eligible). 
4. 
Therapy with antiviral drugs for chronic viral hepatitis B with delta-
agent over the previous 6 months. 
5. 
Therapy with anti-tumor agents (including radiotherapy) or 
immunomodulatory medications (including systemic glucocorticoids) 


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over the previous 6 months. 
6. 
The following laboratory test results at Screening: 
a) 
Hemoglobin less than 100 g/L 
b) 
Leucocytes less than 3000/µL  
c) 
Neutrophils less than 1500/µL  
d) 
Platelets less than 90000/µL 
e) 
Serum creatinine more than 1.5 x ULN. 
7. 
Total bilirubin more than 34.2 µM/L. Patients with higher total 
bilirubin may be enrolled upon consultation with the study Medical 
Monitor, if there is clear evidence that the elevated bilirubin is caused by 
Gilbert's syndrome. 
8. 
Current or previous decompensated liver disease, including 
coagulopathy, 
hyperbilirubinemia, 
hepatic 
encephalopathy, 
hypoalbuminemia, ascites, and esophageal varices hemorrhage; Child-
Pugh score of B/C or more than or equal 6 points. 
9. 
HCV or HIV coinfection (patients with anti-HCV antibodies and no 
HCV RNA at Screening are eligible). 
10. Hepatocellular carcinoma. 
11. Signs of drug- or alcohol-induced liver disease or any other medical 
conditions associated with chronic liver disease (e.g. autoimmune 
hepatitis, hemochromatosis, thalassemia, alcoholic hepatitis, toxic liver 
disease).  
12. Contraindications for liver biopsy. 
13. Concurrent 
malignancy 
(current 
diagnosed 
or 
suspected 
malignancy; risk of a previous malignancy recurrence). 
14. Severe decompensated cardiovascular diseases, including unstable 
and poorly controlled conditions, over 6 months before Screening. 
15. History of poorly controlled thyroid conditions or clinically 
significant signs of thyroid dysfunction at Screening. 
16. Previous or current severe renal failure or significant renal 
dysfunction at Screening. 
17. Previous or current chronic pulmonary disease with respiratory 
distortion at Screening. 
18. Previous or current severe retinopathy, significant ophthalmology 
disorders associated with diabetes mellitus or hypertension. 
19. Previous or current severe psychiatric disorders at Screening (e.g. 
severe depressions, suicidal attempts, severe neuroses or cognitive 
disorders). 
20. Previous 
or 
current 
endocrine 
disorders 
(hypoglycemia, 
hyperglycemia, diabetes mellitus) that are not adequately controlled at 
Screening. 
21. History of visceral organ transplantation. 
22. Signs of drug and/or alcohol dependence (80 g of alcohol/day for 
men and 40 g of alcohol/day for women) within 1 year before Screening. 
23. History of immune disorders (e.g. idiopathic thrombocytopenic 
purpura, lupus erythematosus, sclerodermia, severe psoriasis, rheumatoid 
arthritis). 
24. Need for concomitant use of glucocorticoids or myelotoxic agents. 
25. Participation in another clinical study within 30 days prior to 
enrollment into this study. 
26. Pregnant or breast-feeding females.   
27. 
Any other condition that, in the opinion of Investigator, precludes 
the patient from taking part in this study. 


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Translation into English,  
dd. October 10, 2019 
 
 
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Duration of the study for each 
patient 
The total duration of the patient's participation in the study is up to 76 
weeks: 
• 
The screening period is up to 4 weeks. 
• 
The treatment period is 48 weeks. 
• 
The follow-up period is 24 weeks. 
The total number of visits is 19 (screening visit, 13 visits of the treatment 
period, 5 visits of the follow-up period). 
Blinding procedure 
Not applicable. The study is an open-label one. 
Randomization 
Randomization will be performed in a ratio of 1:1:1:1:1:1 using the IWRS 
(Interactive Web Response System).  
Sample size justification 
This clinical study is an exploratory, controlled, parallel-arm study with a 
control arm and five test arms to demonstrate the differences in 
monotherapy with the study drug, the combination of the study drug and 
standard treatment, and combination of the study drug and Tenofovir 
versus the standard treatment. The study results will be used to select the 
optimal treatment regimen with Myrcludex B in the next phase. 
The primary endpoint (negative result of PCR on HDV RNA at week 72) 
was used to justify the minimum size of treatment arms. 
The calculation of the sample size was carried out according to the method 
described in the book by Chow Sh.-Ch., Sample Size Calculations in 
Clinical Research [Chow Sh.-Ch., Shao J., Wang H., 2008], by means of 
the Trial Size package for the R programming language. The results of the 
previous MYR 201 substudy, data at the 24 treatment week were used: in  
treatment group with study drug (peginterferon alfa-2a 180 μg for 48 
weeks), the proportion of participants with negative PCR result of HDV 
RNA was 29% (2 of 7 participants), in treatment group with combination 
therapy (Myrcludex B 2 mg + peginterferon alfa-2a 180 μg for 24 weeks, 
followed by peginterferon alfa-2a 180 μg for 24 weeks), the proportion of 
participants with a negative PCR result of HDV RNA was 71% (5 of 7 
participants). It is expected that 5 tested groups will demonstrate the 
efficacy comparable to the results of MYR201 substudy. Under such 
assumptions and a given critical value of the significance level of 0.1, the 
arm size n = 15 will make it possible to reach the power of a study at the 
level more than 60%. Considering the exploratory nature of the study, the 
calculated number of arms can be considered sufficient to obtain 
conclusions about the optimal dosing schedule to be used in clinical 
studies of the following phases. 
Interim data analysis 
The interim analysis will be performed when efficacy and safety data are 
available after the end of follow up period of participants in the first phase 
of the clinical study (Arms A-D). 
Considering the fact that the study is exploratory, there is no provision for 
adjusting the level of significance due to intermediate analysis. 
The premature termination of the study based on the results of the interim 
analysis is not planned. 
 


Hepatera LLC 
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Table 1 Flow Chart 
Procedures 
SCR 
Treatment period 
Follow-up period 
Visits 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/EO
T 
FU1 
FU2 
FU3 
FU4 
FU5/EO
F 
Week (W) 
W-4 
-1 
W
0 
W
1 
W
2 
W
4 
W
8 
W
12 
W1
6 
W2
0 
W2
4 
W2
8 
W3
2 
W4
0 
W48 
EOT+
W2 
EOT+
W4 
EOT+
W8 
EOT+
W12 
EOT+
W24 
Day  
–28 -
1 
1 
8±
2 
15
±2 
29
±2 
57
±2 
85
±2 
113
±2 
141
±2 
169
±2 
197
±2 
225
±2 
281
±2 
337+2 
351±3 
365±3 
393±3 
421±3 
505±3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography, medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Body height, weight, 
BMI1 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Urine drug screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol-breath test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alpha-fetoprotein blood 
test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood test for HIV (HIV 
antibodies)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood test for Hepatitis 
C (anti-HCV antibodies, 
HCV RNA)2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-HDV antibodies  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBeAg, anti-HBeAg 
antibodies4 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
HBsAg quantification 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Body height, weight, BMI are measured at screening; only weight is evaluated in the course of the study. 
2 Evaluation of HCV RNA is performed only if there is a positive result of anti-HCV antibodies. 
3 Randomization should be performed after confirmation of patient`s eligibility according to inclusion/exclusion criteria within Day-3 – Day -1 of the study  
4 In the course of the study, a re-evaluation of HBeAg, anti-HBeAg antibodies is performed only in patients with positive results in screening. 
5 Local laboratory, to confirm participation in the study 


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Procedures 
SCR 
Treatment period 
Follow-up period 
Visits 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/EO
T 
FU1 
FU2 
FU3 
FU4 
FU5/EO
F 
Week (W) 
W-4 
-1 
W
0 
W
1 
W
2 
W
4 
W
8 
W
12 
W1
6 
W2
0 
W2
4 
W2
8 
W3
2 
W4
0 
W48 
EOT+
W2 
EOT+
W4 
EOT+
W8 
EOT+
W12 
EOT+
W24 
Day  
–28 -
1 
1 
8±
2 
15
±2 
29
±2 
57
±2 
85
±2 
113
±2 
141
±2 
169
±2 
197
±2 
225
±2 
281
±2 
337+2 
351±3 
365±3 
393±3 
421±3 
505±3 
Anti-HBsAg antibodies 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
X7 
 
 
 
 
X8 
HDV RNA9 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV DNA 
(quantification) 
 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
HBsAg (quantification) 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
Х 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulogram 
Х 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry  
Х 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood bile acids  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood test for TSH, T4  
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Abdominal ultrasound 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Transient elastometry 
(Fibroscan) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Liver biopsy 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
Х10 
 
 
 
 
Х11 
Evaluation of 
immunogenicity 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
HBV, HDV genotyping 
 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NTCP polymorphism 
(frozen blood clot) 
 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6  Local laboratory, to confirm participation in the study 
7 At the end of the study, the determination of anti-HBsAg antibodies will be performed in a central virology laboratory using the appropriate archival samples (for the HBsAg determination) in those patients for whom a negative result 
of the HBsAg quantification was obtained at Week 48. 
8 At the end of the study, the determination of anti-HBsAg antibodies will be performed in a central virology laboratory using appropriate archival samples (for HBsAg determination) in those patients for whom a negative result of the 
HBsAg quantification was obtained at Week 72. 
9 At screening – a blood sample at room temperature, later – frozen blood samples. 
10 It shall be performed within ± 7 days from the date of the visit, only for groups D and F 
11 Should be performed only for groups A, B, C, E within ± 7 days from the date of the visit 


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Procedures 
SCR 
Treatment period 
Follow-up period 
Visits 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/EO
T 
FU1 
FU2 
FU3 
FU4 
FU5/EO
F 
Week (W) 
W-4 
-1 
W
0 
W
1 
W
2 
W
4 
W
8 
W
12 
W1
6 
W2
0 
W2
4 
W2
8 
W3
2 
W4
0 
W48 
EOT+
W2 
EOT+
W4 
EOT+
W8 
EOT+
W12 
EOT+
W24 
Day  
–28 -
1 
1 
8±
2 
15
±2 
29
±2 
57
±2 
85
±2 
113
±2 
141
±2 
169
±2 
197
±2 
225
±2 
281
±2 
337+2 
351±3 
365±3 
393±3 
421±3 
505±3 
Resistance assay (frozen 
samples) 
 
Х 
 
 
 
 
 
 
 
 
 
 
 
Х12 
 
 
 
 
 
Drug dispensing 
 
Х 
 
 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
T13 
T 
T 
T 
T 
 
Filling the patient diary 
in 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
T14 
T 
T 
T 
T 
Adverse events 
 
Х 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant treatment 
X 
Х 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic main 
study (PK-main study, 
for patients in arms B -
F) 
 
Х 
 
 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
X15 
 
 
 
 
 
Pharmacokinetic 
substudy (PK-substudy), 
for 10 patients from 
group B and 10 patients 
from group  C 
 
Days 1, 2, 14, 15 (hospitalization to the study center)16 
Pharmacokinetic study 
for group F 
 
Days 1, 2, 14, 15 (hospitalization to the study center)16 
Ophthalmological 
examination17 
X 
If there are any indications for the examination 
 
12 In case of a patient's drop out of the study before the end of the treatment period, a resistance analysis is performed during the Premature Dropout Visit. 
13 “T” means Tenofovir dispensing during follow-up period 
14 “T” means filling the data into Patient’s diary regarding Tenofovir in the follow-up period 
15 Only for patients from groups E - F 
16 Patients from groups B, C and F participated in the PK sub-study are not allowed to deviate in the schedule of visits in Day 1 and 2. Sample collection for PK analysis should be performed before and after the first injection of 
Myrcludex B. The second part of PK sub-study could be performed within +1 day (Days 15 – 16) 
17 Ophthalmological examination during screening is performed for patients with mild and moderate retinopathy in history to evaluate baseline ocular changes. 


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Procedures 
SCR 
Treatment period 
Follow-up period 
Visits 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/EO
T 
FU1 
FU2 
FU3 
FU4 
FU5/EO
F 
Week (W) 
W-4 
-1 
W
0 
W
1 
W
2 
W
4 
W
8 
W
12 
W1
6 
W2
0 
W2
4 
W2
8 
W3
2 
W4
0 
W48 
EOT+
W2 
EOT+
W4 
EOT+
W8 
EOT+
W12 
EOT+
W24 
Day  
–28 -
1 
1 
8±
2 
15
±2 
29
±2 
57
±2 
85
±2 
113
±2 
141
±2 
169
±2 
197
±2 
225
±2 
281
±2 
337+2 
351±3 
365±3 
393±3 
421±3 
505±3 
SCR: screening; W: week; FU: follow up; EOT: End of treatment; EOF: End of follow up, BMI: body mass index, EKG: electrocardiography, TSH: thyroid-stimulating 
hormone, T4: thyroxine 
 
 


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1 
INTRODUCTION 
1.1 
Chronic viral hepatitis B with delta agent 
Chronic viral hepatitis B with Delta Agent (ICD-10: B 18.0) is an inflammatory liver disease induced by 
hepatitis D virus that requires HBsAg replication. Hepatitis D virus (HDV) is a hepatotropic virus with a 
small RNA genome, which also contains HDV antigen. HDV is necessarily associated with infection with 
the hepatitis B virus (HBV), since HDV ribonucleoprotein is packaged in HBsAg. The HDV genome is a 
single-stranded RNA with 1680 bases that is historically homogeneous with viroids or with RNA satellite 
viruses affecting plants [20]. HDag (hepatitis delta virus antigen) consists of 2 isoforms - a small 24 kD 
protein required for replication, and a larger 27 kD protein needed to form a virion [23]. There are eight 
genotypes of HDV, where genotype-1 is the most widespread in the world and in Europe [18]. 
Hepatitis D virus is a highly pathogenic virus inducing acute and chronic hepatic injury. Although cases of 
the benign disease have been described [19], a progressive hepatic disorder leading to compensated or 
decompensated cirrhosis usually develops in patients with chronic viral hepatitis B with delta-agent. There is 
evidence in the literature that unlike HBV, HDV can lead to direct cytotoxicity, which can lead to an 
acceleration of the fibrosis process [3, 14]. Although the immune system plays an important role in the 
eradication of infected hepatocytes; the level of HDV viremia has no direct relationship with histological 
changes [29]. There are no histological signs that make it possible to distinguish chronic viral hepatitis B 
with delta agent from other forms of viral hepatitis. The biopsy materials taken from patients with chronic 
viral hepatitis B with delta-agent have no signs of portal and periportal inflammation, fragmentary necrosis, 
often accompanied by fibrosis and cirrhosis. There are pronounced intralobular mononuclear cell infiltration 
and degenerative changes of hepatocytes [23]. The clinical events of chronic viral hepatitis B with delta-
agent can be acute or fulminant, a chronic infection can lead to asymptomatic carriage and progress to 
chronic liver disease rapidly. 
Chronic viral hepatitis B with delta-agent develops in 70-90% of patients with viral hepatitis B with HDV 
superinfection. The hepatic injury associated with HDV has a more progressive course, compared to chronic 
hepatitis B, and can lead to cirrhosis in 10-15% of patients in a period of 2 years [28]. Chronic viral hepatitis 
B with delta-agent is the most severe form of viral hepatitis in humans [25], accompanied by progression of 
hepatic injury, development of cirrhosis and decompensation [21, 25]. 
In a study performed with a cohort of patients who had been observed for a long time in a specialized center, 
it was shown a clear trend to decrease survival in HBeAg-negative patients with HDV compared to patients 
with HBV-monoinfection [16]. In HDV endemic regions, liver disease is a serious medical problem. A 
study, performed in Italy in 1987, found the presence of anti-HDV antibodies in 40% of patients with 
cirrhosis. Despite the fact that in 2000 their portion has reduced to 11% [6], HDV infection still represents a 
significant public health problem. In a long-term study, it was shown that 20% of patients with chronic viral 
hepatitis B with delta-agent develop an adverse event associated with liver injury within on an average of 4 
years. During the same period, only 8.5% of patients with HBV monoinfection develop such events [17]. 
Initially, cirrhosis was diagnosed in 19.8% of patients from this cohort versus 7.3% of patients with chronic 
hepatitis B. HDV caused the death of 60% of patients participated in the 28-year study performed in Italy 
[22]. Co-infection with HDV is associated with a faster progression to fibrosis and cirrhosis, an earlier onset 
of hepatic complications and an increased probability of liver transplantation [2, 11]. Liver cirrhosis and 
cancer develop 10-15 years earlier in patients with co-infections with HBV/HDV, and a 5-year mortality of 
patients with co-infection is twice as high as that of patients with monoinfection with HBV [4]. Chronic 
HDV infection causes cirrhosis and hepatocellular carcinoma with an average annual rate of 4% and 2.8%, 
respectively [22]. 
On average, 5-10% of HBsAg-positive patients undergoing screening in specialized centers in Europe have a 
positive HDV test result. The number of patients with chronic viral hepatitis B with delta-agent in the EU is 
estimated to be 145,000 people. Given the total population of the EU is 505,665,700 people (2013), the 
estimated prevalence rate of HDV among residents of the EU countries, under the given assumptions (95% 
confidence interval), is 1.6 and 4.7 per 10,000 people, respectively. The prevalence of the disease is below 
the threshold for assigning the drug the orphan product designation, which is 5 cases per 10,000 people. 
Data on the prevalence of HDV in the United States are very limited. In a recent study that evaluated the 
highly specific center’s database, the prevalence rate of HDV among HBsAg carriers was fixed at 8% [8]. 
11% of injecting drug partners in Baltimore had a positive HDV test result; 50% of drug users with chronic 
HBV infection had a positive HDV test result [13]. On average, 5-10% of HBsAg-positive patients followed 


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up in specialized centers have a positive HDV test result. The total number of patients with chronic viral 
hepatitis B with delta-agent in the US is 63,800 people (worst-case scenario). It is below the threshold for 
assigning the drug an orphan product designation that equals to 200 thousand patients. 
Therapeutic options for patients with HDV co-infection are extremely limited. Only interferons feature a 
certain efficacy in a small percentage of patients [1, 15]. Antiviral drugs that are effective in the treatment of 
HBV are ineffective in the treatment of HDV [11]. 
 
Efficacy and safety of peginterferon alfa-2a in patients with chronic viral hepatitis B with delta-agent 
The role of pegylated interferon alfa-2a in the treatment of chronic viral hepatitis B with delta-agent was 
studied in two recently performed studies HIDIT-1 and HIDIT-2. 
Study HIDIT-1 [27] 
This was a randomized, controlled study on the efficacy and safety of a 48-week treatment with 
peginterferon alfa-2a 180 μg weekly + adefovir 10 mg daily (PA) versus monotherapy with peginterferon 
alfa-2a + placebo (P) and adefovir + placebo (A). A total of 90 patients (n=31 [pa], n=29 [P], n=30 [A]) 
participated in the study. Upon the end of treatment, a follow-up period of 24 weeks followed. The efficacy 
evaluation criteria included clearance of HDV RNA, ALT normalization, decline in HBsAg level. 
Based on the results of the study, the primary endpoint –ALT normalization and negative PCR result of 
HDV RNA at week 48 – was achieved in 2 (7%, ITT) patients receiving peginterferon alfa-2a + adefovir, 
and 2 (7%, ITT) patients receiving monotherapy with peginterferon alfa-2a; the primary endpoint was not 
achieved in the patient arm receiving monotherapy with adefovir. At week 48, a negative PCR result of HDV 
RNA was observed in 7 (7/31, 23%) patients of the first arm (PA), 7 (7/29, 24%) patients of the second arm 
(P) and in none patient of the third arm (A) (p = 0.006 for the comparison of PA and A groups, p = 0.004 for 
the comparison of P and A arms). 
The efficacy of treatment with peginterferon alfa-2a persisted for a 24-week follow-up period: at week 72, a 
negative PCR result of HDV RNA was observed in 8 (26%) patients of the peginterferon alfa-2a + adefovir 
(PA) arm, 9 (31%) patients in the peginterferon alfa-2a (P) arm and none of the adefovir arm (A). 
When evaluating the peginterferon alfa-2a (with and without adefovir) in the combined arm, the proportion 
of patients with a negative PCR result of HDV RNA was 23% (14/60) at the end of treatment (week 48), 
28% (17/60) at the end of the follow-up period (week 72). 
A HBsAg decline by more than 1 log10 IU/mL at week 48 compared to baseline was observed in 10 patients 
of the peginterferon alfa-2a + adefovir (PA) arm, 2 patients in the peginterferon alfa-2a (P) arm, and none 
patient of the adefovir arm (A) (p <0.001 for the comparison of PA and A groups, p = 0.01 for the 
comparison of PA and P arms). 
The ALT normalization at week 48 was achieved in the following treatment arms: in 10 (10/31, 32%) 
patients of the peginterferon alfa-2a + adefovir (PA) group, 8 (8/29, 28%) patients of the peginterferon alfa-
2a (P) arm and 2 (2/30, 7%) patients of the adefovir arm (A). At week 72, the ALT normalization was 
observed in 11 (35%) patients of the first arm (PA), 13 (45%) patients of the second arm (P) and 3 (10%) 
patients of the third arm (A). 
Based on the results of the treatment safety evaluation, 318 adverse events were registered in 66 (73%) 
patients. The most common adverse events were recorded in the peginterferon alfa-2a treatment arms. All 
registered adverse events corresponded with the safety profile of peginterferon alfa-2a and adefovir. 
Study HIDIT-1, follow-up period [12] 
A retrospective-prospective study was performed to collect further data on the treatment efficacy in patients 
participating in the HIDIT-1 study. Data were available for 58 (58/77, 75%) patients, the median of the 
follow-up period was 4.5 years (0.5-5.5), the median number of visits was 3 visits per patient. 
Patients who received monotherapy with adefovir have more often received further treatment with 
peginterferon alfa-2a (48% vs. 19%, p=0.02). HBsAg negativation before the end of the prolonged follow-up 
period was observed in 6 patients who received peginterferon alfa-2a. 
Among patients who received peginterferon alfa-2a during the HIDIT-1 study and had a negative PCR result 
of HDV RNA at study week 72, 16 patients were enrolled into the follow-up period. Of these, 9 patients 
showed a positive PCR result of HDV RNA at least once, 7 patients showed a positive result at their last 
visit. Clinical endpoints (fatal outcome due to liver disease, liver transplantation, liver decompensation, 
hepatocellular carcinoma) were observed in 3 (8%) patients who received peginterferon alfa-2a, and in 3 
(14%) patients who received adefovir; the average annual level was 2.5% (4.9% in patients with cirrhosis). 


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In these patients, a strain of the virus detected before treatment was confirmed by the sequencing method. 
HIDIT-2 study [26] 
This study was a randomized, controlled study a study on the efficacy and safety of a 96-week treatment with 
peginterferon alfa-2a 180 μg weekly + placebo (P) versus treatment with peginterferon alfa-2a 180 μg. A 
total of 120 patients were enrolled into the study. Upon the end of treatment, a follow-up period of 5 years 
was designated. To date, the interim results of this study are available after the first 24 weeks of follow-up. 
Based on the results of the study, the primary endpoint –negative PCR result of HDV RNA at week 96 – was 
achieved in 47% of patients in the peginterferon alfa-2a + Tenofovir (PT) arm and in 33% in the 
peginterferon alfa-2a (P) arm, p=0.10 (ITT analysis). The results of the per protocol analysis (n=99) were as 
follows: 54% of responders on HDV RNA in the first arm (PT) and 41% of respondents in the second arm 
(P), p=0.19. 
After completion of the first 24 weeks of follow-up (study week 120), the proportion of patients with 
negative PCR result of HDV RNA decreased, and was 30% in the peginterferon alfa-2a + Tenofovir arm, 
23% in the peginterferon alfa-2a arm (ITT, p=0.34). 
Twenty (20) patients did not complete a minimum of 80 treatment weeks, 9 patients in the peginterferon alfa-
2a arm, and 9 patients in the peginterferon alfa-2a + Tenofovir arm. 976 adverse events (AEs) were 
registered during the analyzed period, 515 – in the peginterferon alfa-2a arm, 461 – in the peginterferon alfa-
2a + Tenofovir arm. Of these, 65 AEs met the criteria of a serious AE: 30 SAEs in the peginterferon alfa-2a 
arm (31% of patients), 22 of which were regarded as unrelated to the study treatment; 35 patients – in the 
peginterferon alfa-2a + Tenofovir arm (34% of patients), of these, 24 – unrelated to the study treatment. Two 
fatal outcomes were recorded in the study, 1 per each treatment arm, both of which were probably associated 
with the injection of peginterferon alfa-2a. The cause of death included the mitral valve rupture, pneumonia 
and sepsis developed in another patient 6 months after the end of treatment. 
Based on the results of the interim analysis of the HIDIT-2 study, the following preliminary conclusions 
were made: 
• 
96-week treatment with peginterferon alfa-2a + Tenofovir may be performed, but this modality is 
associated with a high incidence of SAE development. 
• 
Compared to the monotherapy with peginterferon alfa-2a, combined treatment showed higher values 
of the response of PCR on HDV RNA during treatment, but a comparable effect to reduce HBsAg levels. 
• 
More than one-third of patients experienced recurrence of HDV RNA, despite a long-lasting treatment. 
• 
A 96-week treatment with peginterferon alfa-2a did not result in an increase in the proportion of 
patients with a negative PCR result of HDV RNA after the end of treatment (compared to the 48-week 
treatment in the HIDIT-1 study). 
• 
For HDV-infected patients, the development of alternative treatment approaches is required at the 
earliest. 
Thus, by now, there is no therapy with proven efficacy and favorable safety profile for patients with chronic 
viral hepatitis B with delta-agent, which makes it extremely important to develop new drugs aimed at 
treating this pathological condition. 
 
1.2 
Study drug Myrcludex B 
1.2.1 General Information 
Myrcludex B (MXB) is a polypeptide chain consisting of 47 amino acids. The N-terminus of this polypeptide 
chain is represented by the fatty acid (myristoyl residue) and the C-terminus – by the amide arm. All the 
amino acids that make up the above mentioned polypeptide chain are represented by the L-configuration.  
Molecular formula: 
C248H355N65O72 (net) 
Molecular weight:  
5398.9 g/mol (average weight, net) 
Salt form, in which the active substance is 
presented in the drug composition: 
Salt of acetic acid (acetate) 
Physical form: 
White or off-white powder  
Appearance of the prepared solution: 
Transparent and clear 
Myrcludex B prevents the penetration of Hepatitis B virus (HBV) into hepatocytes by binding and 
inactivating the recently described NTCP receptor (Na+-taurocholate cotransporting polypeptide), which 
participates in the mechanism of HBV penetration into the cell. This receptor is represented mainly in the 
liver, the function of the molecule is to transport bile acids (salts) from blood to hepatocytes. Myrcludex B 


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presumably produces an effect at the stage after the interaction of the virus with the cellular receptor and 
prevents the fusion of the virus and cell membranes, thus preventing the penetration of the genetic material 
of the virus into the hepatocyte. 
To date, a wide program of preclinical studies of the drug and phases I and II clinical studies have been 
performed demonstrating the favorable safety profile of Myrcludex B and the potential efficacy of the drug 
in the treatment of chronic viral hepatitis B and chronic viral hepatitis B with delta-agent. 
 
1.2.2 Preclinical Study Results 
Preclinical Pharmacology 
Antiviral activity of the drug was evaluated in experimental studies using cell cultures susceptible to 
infection with hepatitis B virus (in the culture of HepaRG cells; liver cell culture of Tupaia belangeri tree 
shrews, and also in human liver cells culture), the virus replication was inhibited by various agents. HBeAg 
and HBsAg were determined as markers of infection in cell culture supernatants using the ELISA (enzyme 
immunoassay) method. The number of infected cells was determined by the HBcAg-specific 
immunofluorescence. At the same time, the value of the IC50 index ranged from 14.5 pM to 9.5 nM, 
depending on the virus titer, as well as on the conditions in which the cell culture was incubated. In vitro, the 
use of Myrcludex B in a wide dosage range (up to 50 μM) was not accompanied by toxic effects, which were 
evaluated by the intensity of LDH release by the destroyed hepatic cells. 
In vivo, the antiviral activity of acylated peptides derived from hepatitis B virus, close in their structure to 
Myrcludex B, was studied in uPA/RAG-2 mice with immunodeficiency, which hepatocyte cell cultures of 
Tupaia belangeri tree shrews and human, sensitive to hepatitis B virus, were transplanted. The laboratory 
mice were infected with the hepatitis B virus, then they were given active peptide (in different 
concentrations) or a control peptide that did not have any pharmacological activity. In this experimental 
model, the systemic injection of the active peptide at the lowest concentration of all studied in this study (200 
μg/kg) completely prevented the development of hepatitis B in experimental animals. 
The properties of Myrcludex B were studied in a population of experimental uPA/SCID mice previously 
infected with the hepatitis B virus, which further, human hepatocytes were transplanted. In this case, a much 
less pronounced prevalence of hepatitis B viruses in liver tissue was found (compared to the experimental 
animals in the control group that received placebo), which was confirmed by laboratory methods for 
determining the concentration of HBV DNA and HBsAg antigen in the blood serum, as well as the results of 
immunohistological study. 
The presence of additional pharmacological effects of the drug was studied in a study with chimpanzees 
under single-dosing conditions. Chimpanzees are a suitable biological model, since specific receptors to the 
hepatitis B virus are expressed in their bodies only, and it is also possible to model acute or chronic viral 
hepatitis B. The intravenous injection of Myrcludex B at a dose of 300 μg/kg was not accompanied by any 
clinically significant effects or changes in laboratory parameters that could be attributed solely to the 
injection of the study drug. 
 
Preclinical pharmacokinetics 
The HPLC-MS/MS method was developed and validated to analyze the drug content in plasma samples of 
dogs and humans. The method was applied in accordance with the GLP recommendations for the assessment 
of toxicokinetic properties of this drug. The evaluation of the pharmacokinetic properties of the drug was 
performed in the following studies: investigation of the pharmacokinetic parameters of the drug after a single 
injection to rats; investigation of the toxic properties of the drug in 4- and 26-week-old rats; in a 12-week 
study in dogs; additional studies in mice, rats, dogs and long-tailed macaques, with the injection of the 
isotopically labeled drug. 
The drug concentration in the liver tissue was further determined by the HPLC-MS/MS method during the 
following studies: investigation of the pharmacokinetic parameters of the drug after a single administration to 
rats; a 26-week study in rats and a 12-week study in dogs. 
Furthermore, the isotopically labeled Myrcludex B was indicated to the experimental animals, and after the 
injection its concentration in samples of various biological fluids and tissues was recorded by determining 
the content of radioactive components in the organs of experimental animals subjected to autopsy or by 
scintigraphic imaging methods. It is most critical, that pharmacokinetic parameters of the drug were analyzed 
in serum samples and samples of the hepatic tissue of chimpanzees, which the drug was administered 


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intravenously. 
In a 26-week study in rats that received the drug subcutaneously, plasma samples were collected on the Day 
1, 85, 177 and 183 of the study. The systemic exposure to the study drug when administered in three 
different doses was dose-dependent, which was confirmed by an almost proportional increase in the values of 
the area under the curve (AUC). When the drug was administered to males at a dose of 2.5 mg/kg/day, the 
Cmax values in 2 or 4 hours were 768.68 ng/mL, 3686.20 ng/mL and 3972.13 ng/mL at Day 1, 85, 177 of the 
study, respectively. After dosing, the drug concentration in the plasma gradually decreased; while the value 
of the drug half-life indicator ranged within the following limits: on the follow-up day 1 - from 1.08 to 2.04 
h; on the follow-up day 85 - from 1.33 to 7.05 h; on the follow-up day 177 - from 1.31 to 6.90 h. 
A 12-week study on dogs analyzed blood samples collected on the follow-up day 1 and 91. The results of the 
investigation of drug concentrations, as well as the values of the area under the curve (AUC), showed a dose-
dependent nature of the systemic exposure to the drug. This was confirmed by the nearly proportional 
increase in the values of the area under the curve (AUC). When the drug was administered to males at a dose 
of 2.5 mg/kg/day, the Cmax values in 2-3 hours were 2544 ng/mL and 5234 ng/mL at Day 1 and 91 of the 
study, respectively. In females, the Cmax values were 2095 ng/mL and 3198 ng/mL on the study day 1 and 91, 
respectively. The half-life values ranged within the following limits: on the follow-up day 1 - from 2.2 to 2.8 
h; on the follow-up day 91 - from 2.7 to 5.4 h. An increase in the values of the above indicators, which 
characterize the level of the systemic exposure to the drug, may indicate the ability of the latter to 
accumulate in the body. 
In studies in mice, rats, and dogs, which the isotopically labeled Myrcludex B was indicated, this drug was 
found to be distributed into the liver tissue relatively quickly and almost uniformly. In this case, the values of 
such indicators as the maximum drug concentration in the liver tissue, as well as the drug half-life from liver 
the tissue, were significantly higher than the values of the same indicators calculated for blood plasma. 
In the experimental chimpanzees, it was possible to perform a detailed analysis of the pharmacokinetic 
parameters of the drug with the subsequent prediction of their values in the human body. Apparent volume of 
distribution of the drug (VD), consists of components unabsorbed (3.18 L/70 kg) and absorbed (10.0 L/70 
kg) by peripheral tissues. It is estimated that the plasma clearance of the drug shall be 2.2 L/h/70 kg. It is 
assumed that the drug half-life from blood plasma depends on the degree of saturation of the peripheral 
tissues with the drug (on the volume of distribution of the component absorbed by the peripheral tissues), 
and decreases with an increase in its dosage intended for single use (the value of this index varies within 
4.31-1.19 h). The maximum hepatic binding ability to the study drug (Bmax) is 2551 ng/g of liver tissue. The 
process of the drug binding to the hepatic tissue was characterized by the following value of the equilibrium 
dissociation constant - 0.85 ng/mL (plasma). However, the half-life value for the "hepatic tissue-drug" 
complex is 12.5 hours. 
 
Preclinical Toxicology 
The acute toxicity study assessed the drug toxicity when the drug was used once in the experimental CD® 
rats. Therewith, some parameters characterizing the drug safety were evaluated in this study (including the 
Irwin test for assessing neuro-psychic reactions in rodents). In the experimental rats, the intravenous 
injection of Myrcludex B at a dose of 12.5 mg/kg was not accompanied by any toxic reaction. No fatal 
outcomes were also recorded among the experimental animals. 
An investigation of some toxicological parameters (clinical symptoms, hematology and biochemistry) was 
performed during the study of pharmacological and pharmacokinetic properties of the drug administered to 
chimpanzee in a single dose. 
In the study of chronic toxicity, the drug was administered to rats (for 7 days, 4 weeks or 6 months) and dogs 
(for 3 months) on a daily basis as a subcutaneous injection. A 4-week study in rats and a 3-month study in 
dogs included the assessment of blood cytokine levels. 
No deaths, cases of local or system drug intolerance, changes in the body weight of the experimental animals 
and in the rates of its gain, in the amounts of food and liquid consumed by the experimental animals, in the 
values of hematological and biochemical indices were recorded in all the above mentioned studies. A macro 
or microscopic examination detected no pathological changes that could be related to the study drug. 
 
1.2.3 Clinical Study Results 
Four clinical studies of Myrcludex B have been completed to date: 


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• 
MYR 101: phase I study with healthy volunteers (performed in Germany); 
• 
MYR 102: phase I study (drug interaction) with healthy volunteers (performed in Germany); 
• 
MYR 201: phase Ib/IIa study, the drug injection to patients with chronic hepatitis B (performed in 
Russia); 
• 
MYR 201 substudy (supportive study): Pilot, phase Ib/IIa study, injection of Myrcludex B and 
peginterferon alfa-2a in patients with chronic viral hepatitis B with delta agent (performed in Russia), 
The following clinical study is ongoing: 
• 
MYR 202: phase II/III study with Myrcludex B and Tenofovir in patients with chronic viral hepatitis 
B with delta-agent (ongoing in Russia and Germany). 
 
Phase I clinical study (MYR 101) was performed with the participation of 36 healthy male volunteers. 
Volunteers received the study drug in the following doses: 0.3 μg, 3 μg, 10 μg, 100 μg, 800 μg, 3 mg, 5 mg, 
10 mg and 20 mg with intravenous injection, and 800 μg, 5 mg and 10 mg with subcutaneous injection. The 
study evaluated the pharmacokinetics, safety, and tolerability of Myrcludex B. In general, 85 adverse events 
(AEs) were registered in 29 study subjects, none of the AEs met the criteria for serious AE. Based on the 
results of severity assessment, 74 AEs were assigned to mild AEs, 9 AEs were moderate, 2 AEs were severe 
(increased lipase, increased amylase) according to the CTCAE 4.0 criteria. Antibodies to the study drug were 
evaluated before the expiration of 6 months after the drug exposure, the test results were negative in all study 
subjects. 
A good tolerability of the drug was noted when it was used in healthy volunteers, there were no serious 
adverse events or dose-limiting toxicity. The adverse events were mostly mild, they resolved independently. 
The incidence and severity of adverse events were not dose-dependent. 
The following AEs were regarded as possibly related to the drug: excessive sweating (in one volunteer in a 
cohort that received 3 μg i.v.), headache (in one volunteer from each cohort that received 10 μg and 5 mg 
that AEs resolved without consequences within 24 hours). 
The following changes in laboratory parameters were regarded as AEs, possibly related to the drug: reduced 
hemoglobin, reduced hematocrit (in one volunteer in a cohort that received 3 μg, mild, resolved without 
consequences within 24 hours); increased bilirubin (in one volunteer in a cohort that received 3 μg, mild, 
returned to normal within 7 days); transient increase in lipase level (one volunteer in each of the cohorts that 
received 3 μg, 0.8 mg subcutaneously and in two of the cohort that received 5 mg, from mild to severe, 
returned to normal within ≤ 3 days). 
The pharmacokinetics of Myrcludex B was dose-dependent, the area under the curve (AUC) concentration-
time increased disproportionately, while clearance and volume of distribution decreased when the dose 
increased. The drug bioavailability after subcutaneous injection was assessed to be 88%. 
 
Phase I clinical study (MYR 102) was performed with participation of healthy volunteers. The study 
objective was to assess potential drug interaction between Myrcludex B and Tenofovir. 
12 healthy volunteers were administered monotherapy of Tenofovir 245 mg during 5 days, followed up 
combination with Myrcludex 10 mg during 6 days. 
Concentration of Tenofovir, Myrcludex B and bile acids were measured in plasma samples. Also participants 
were administered midazolam 30 µg for assessment of influence anti-viral drugs for activity of CYP3A. 
Co-administration of Tenofovir with Myrcludex B was well tolerated and revealed no clinically relevant 
change in Tenofovir pharmacokinetics and activity of CYP3A. 
 
Phase Ib/IIa clinical study (MYR 201) was performed in 48 patients with HBeAg-negative chronic viral 
hepatitis B of mild to moderate activity (HBV DNA ≥ 10,000 copies/mL, and ALT ≥ 1.5 ULN and ≤ 6 
ULN). Patients were randomized to 6 treatment arms. 
Arm A (n=8): Myrcludex B 0.5 mg/day/s/c/12 weeks + 12 weeks of follow-up 
Arm B (n = 8): Myrcludex B 1 mg/day/s/c/12 weeks + 12 weeks of follow-up 
Arm C (n = 8): Myrcludex B 2 mg/day/s/c/12 weeks + 12 weeks of follow-up 
Arm D (n=8): Entecavir 0.5 mg/day/orally/24 weeks 
Arm E (n=8): Myrcludex B 5 mg/day/s/c/12 weeks + 12 weeks of follow-up 
Arm F (n=8): Myrcludex B 10 mg/day/s/c/24 weeks + 12 weeks of follow-up 
The efficacy, safety, pharmacokinetics and immunogenicity of the drug Myrcludex B were investigated in 


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the study. The efficacy criteria included the evaluation of HBsAg, HBV DNA and ALT levels before, during 
treatment and during the follow-up period. 
When evaluating the HBV DNA response, defined as a > 1 log IU/mL decline in HBV DNA by or its 
negativation, among the Myrcludex B treatment arms at week 12, the largest proportion of responders was 
observed in the patient arm receiving the drug at a dose of 10 mg (6/8, 75% of patients). In the remaining 
study drug arms, the proportion of responders was: 2/8 (25%) patients in the Myrcludex B 0.5 mg and 2 mg 
arms, 1/8 (12.5%) patient in the Myrcludex B 5 mg arm. In the Myrcludex B 1 mg arm, none of the patients 
reached the HBV DNA level corresponding to the response criteria. In the joint Myrcludex B arm, the 
proportion of responders was 11/40 (27.5%). Patients receiving the drug at a dose of 10 mg continued the 
treatment to 24 weeks, the proportion of responders at the end of treatment remained the same (6/8, 75%). 
Based on the study findings, no significant effect of Myrcludex B on the dynamics of HBsAg level was 
found. At week 12, the change in the level of HBsAg compared to the baseline was: 0.10 log IU/mL in the 
0.5 mg dose arm; 0.16 log IU/mL in the 1 mg arm; 0.04 log IU/mL in the 2 mg arm; -0.01 log IU/mL - in the 
5 mg arm; 0.13 log IU/mL - in the 10 mg arm. At week 24, the change in the HBsAg level was 0.10 log 
IU/mL in the Myrcludex B 10 mg arm. However, a small number of patients in each treatment arm should be 
noted, since the study was a pilot and an exploratory one. 
When assessing the biochemical response, defined as the normalization of ALT levels, among the Myrcludex 
B treatment arm, the proportion of responders at week 12 was: 3/7 (42.9%) patients in the 0.5 mg dose arm, 
4/7 (57.1%) - in the 1 mg arm, 4/8 (50%) - in the 2 mg arm, 2/4 50%) - in the 5 mg arm, 4/6 (66.7%) - in the 
10 mg arm. At week 24, the proportion of responders was 3/6 (50%) in the Myrcludex B 10 mg treatment 
arm. The biochemical response was assessed only in patients with abnormal baseline ALT levels. 
A total of 69 AEs were registered during the study, of which 45 AEs were associated with the study drug 
Myrcludex B: 
• 
Myrcludex B 0.5 mg arm: 14 AEs were registered in 4 (4/8, 50%) patients - increased blood amylase 
(1 AE), increased body temperature (1 AE), increased lipase (1 AE), weight gain (1 AE), eosinophilia (2 
AEs), erythema (2 AEs), hyperhidrosis (1 AE), psoriasis (1 AE), xeroderma (1 AE), drowsiness (1 AE), 
respiratory infection (1 AE), hematuria (1 AE). 
• 
Myrcludex B 1 mg arm: 4 AEs were registered in 4 (4/8, 50%) patients - drug withdrawal syndrome (1 
AE), injection site reaction (1 AE), increased blood bilirubin (1 AE), ventricular ectopic beats (1 AE). 
• 
Myrcludex B 2 mg arm: 4 AEs were registered in 3 (3/8, 37.5%) patients - increased blood creatinine 
(1 AE), a furuncle (1 AE), drowsiness (1 AE), drug withdrawal syndrome (1 AE). 
• 
Myrcludex B 5 mg arm: 10 AEs were registered in 4 (4/8, 50%) patients - injection site reaction (4 
AEs), increased GGT (1 AE), increased reticulocytes (1 AE), leukopenia (1 AE), right bundle branch block 
(1 AE), ventricular arrhythmia (1 AE), hypersensitivity (1 AE). 
• 
Myrcludex B 10 mg arm: 13 AEs were registered in 5 (5/8, 62.5%) patients- dermatitis at the injection 
site (5 AEs), injection site reaction (1 AE), increased blood creatinine (1 AE), eosinophilia (2 AEs), rash (1 
AE), respiratory infection (1 AE), diarrhea (1 AE), nasopharyngitis (1 AE). 
Most AEs (41 AEs) were mild. Moderate AEs included: erythema, increased GGT, reticulocyte, dermatitis at 
the injection site (a total of 4 AEs). No severe AEs were recorded. 
Two AEs were considered as serious AEs: the drug withdrawal syndrome in one patient from the Myrcludex 
1 mg arm, and in one patient from the Myrcludex 2 mg arm. Both cases of serious AEs were recorded at a 
follow-up visit after the end of treatment, and were considered as mild ones directly associated with the study 
drug. One of these cases was regarded as a suspected unexpected serious adverse drug reaction, information 
about which was sent to the regulatory authorities as part of expedited reporting. There were no prematurely 
withdrawn patients due to the development of AEs/SAEs during this study. No fatal outcomes were also 
registered. 
The data for the immunogenicity assessment were available in the Myrcludex B 0.5 mg, Myrcludex B 5 mg 
and Myrcludex B 10 mg treatment arm. The result was evaluated as positive when the antibody titer 
increased twice at treatment weeks 1, 4 or 12. Based on the assessment results, 14/24 (58.3%) patients had a 
positive result: 4/8 (50%) in the Myrcludex 0.5 mg B arm and 5/8 (62.5%) in each of the Myrcludex B 5 mg 
and 10 mg arms. There were no differences in the level of virologic and biochemical response, 
pharmacodynamic parameters of the drug in patients with positive and negative immunogenicity evaluation 
results. 
In general, the MYR 201 study demonstrated potential antiviral activity and a favorable safety profile of the 


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drug Myrcludex B in the studied range of doses. 
 
Phase Ib/IIa clinical study MYR 201(supportive study). 
This study is a randomized, open-label study on the efficacy, safety, tolerability, pharmacokinetics, 
pharmacodynamics, immunogenicity of the drug Myrcludex B when administered to patients with chronic 
viral hepatitis B with delta-agent. 48 patients were randomized into the study with HBeAg-negative chronic 
viral hepatitis B and HDV coinfection of mild to moderate activity (HBV DNA ≥ 10,000 copies/mL, and 
ALT ≥ 1.5 ULN and ≤ 6 ULN). Treatment arms included: 
Arm A (n=8): Myrcludex B 2 mg during 24 weeks, followed by peginterferon alfa-2a 180 μg during 48 
weeks 
Arm В (n=8): Myrcludex B 2 mg + peginterferon alfa-2a 180 μg during 24 weeks, followed by peginterferon 
alfa-2a 180 μg during 24 weeks 
Arm С (n=8): peginterferon alfa-2a 180 µg during 48 weeks 
Interim results of MYR201 study (brief description below) formed the basis of MYR203 clinical study. 
Interim efficacy results, 24 treatment weeks 
Based on the evaluation of the HDV RNA response, defined as a > 1 log 10 decline in HDV RNA by or its 
negativation, the number of responders after 24 treatment weeks was 6 patients in arm A (6/7), 7 patients in 
arm B (7/7), 7 patients in arm C (7/7). 
A negative PCR result of HDV RNA was observed in 2 patients of arm A (2/7), 5 patients of arm B (5/7) and 
2 patients of arm C (2/7). 
A decrease in ALT level was observed in 6 patients of arm A (6/7), 4 patients of arm B (4/7), and 3 patients 
of arm C, week 12 (3/7). A tendency to decrease in the median ALT in the Myrcludex B monotherapy arm 
from 66 U/L to 40 U/L (p = 0.06) was noted. Such tendency was not noted in the treatment arms B and C. 
One patient - from arm A -had both a negative PCR result of HDV RNA and ALT normalization at treatment 
week 24. 
The obtained results suggest a significant potential efficacy of Myrcludex B in the treatment of chronic viral 
hepatitis B with delta-agent that was used as the basis for the development and planning of the MYR 203 
clinical study specified in this protocol. 
 
Interim safety results, 24 treatment weeks 
No serious adverse events were recorded during the study. One patient, according to the decision of the 
physician investigator, discontinued the treatment prematurely due to the development of an AE - a patient of 
arm B, who had eczema, according to the investigator's assessment, associated with the use of peginterferon 
alfa-2a. 
The Myrcludex-related AEs included single cases of hematological disorders (leucopenia, neutropenia, 
thrombocytopenia and eosinophilia). Related to PEG IFN-alpha 2a were leucopenia, neutropenia, 
thrombocytopenia, anemia, ALT, AST, GGT, bilirubin increased, APTT prolonged, influenza-like illness, 
fatigue, pyrexia, dizziness, irritability and rash. 
 
Summary results of MYR201 sub study 
The main efficacy results (absolute number of responders for each of investigated parameters) are shown on 
Figure 1. There were the following responders criteria in the Study protocol: HbsAg response - HBsAg 
decline of at least 0.5 log IU/mL or HBsAg negativation; HBV DNA response - reduction of HBV DNA by 
>1 log IU/mL or negativation; HDV RNA response - reduction of HDV RNA by >1 log IU/mL or 
negativation; ALT response – ALT normalization. 
There were not a lot of HbsAg responders during 24 weeks of treatment with Myrcludex B in groups A and 
B compared with group C, however there were substantial proportion of HBV DNA responders. Herewith 
the majority of HBV DNA responders (week 12) were shown in the group of combination of Myrcludex B 
and PEG IFN-alpha 2a.   
The combination treatment of Myrcludex B plus PEG IFN alfa-2a during 24 weeks demonstrated the highest 
HDV RNA responder’s rate. HDV RNA became negative in 5 of 8 patients while only 2 of 7 patients treated 
with Myrcludex B (Arm A) and PEG IFN alfa-2a (Arm C). After the treatment of Myrcludex B there was an 
obvious decrease in the number of HDV RNA responders in Arm A and Arm B. 


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24-week monotherapy with Myrcludex B (Arm A) showed the highest rate of ALT responders, however 
further switching to PEG IFN alfa-2a led to the decrease of ALT response. No considerable difference was 
observed between Arm B and Arm C  
Study results suggest that Myrcludex B in combination and in monotherapy regimen is very perspective for 
the treatment of hepatitis B with delta agent. 
For more detailed information about the study drug Myrcludex B, the results of preclinical and clinical 
studies refer to the Investigator's Brochure. 


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Figure 1. Results of MYR 201 substudy 
 
 
 
 
MXB: Myrcludex B, IFN: Peginterferon alfa-2a, EOT: End of treatment, EOF: End of follow up 
Note: For HBsAg, HBV DNA, ALT, the absolute number of responders in presented for FAS population, for 
HDV RNA data – among the patients with measurable HDV RNA at baseline. 


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The main results of the safety assessment are shown in Table 2. In general, Myrcludex B demonstrated a 
favorable safety profile both when prescribed in monotherapy and as part of combination therapy with 
Peginterferon alfa-2a. 
Table 2. MYR 201 substudy: Brief Summary of Adverse Events (Safety Set) 
SOC, PT 
(MedDRA 18.1) 
Arm A 
MXB 24w, 
IFN 48 w 
(N=8) 
Arm B 
MXB+IFN 24w, 
IFN 24w (N=8) 
Arm C 
IFN 48w 
(N=8) 
 
Number of reported AEs  
85 
59 
82 
Number of patients reporting at least one AE, 
n (%) 
8 (100.0) 
8 (100.0) 
8 (100.0) 
AEs by SOC, n (%)/c 
 
 
 
Blood and lymphatic system disorders 
8 (100.0)/57 
8 (100.0)/40 
7 (87.5)/58 
Investigations 
7 (87.5)/19 
4 (50.0)/14 
3 (37.5)/15 
General disorders and administration site 
conditions 
5 (62.5)/8 
4 (50.0)/4 
4 (50.0)/8 
Nervous system disorders 
1 (12.5)/1 
0 (0.0)/0 
1 (12.5)/1 
Skin and subcutaneous tissue disorders 
0 (0.0)/0 
1 (12.5)/1 
0 (0.0)/0 
AEs by severity, n (%)/c 
 
 
 
Mild 
Moderate 
Severe 
8 (100.0)/55 
8 (100.0)/25 
2 (25.0)/5 
7 (87.5)/33 
7 (87.5)/24 
1 (12.5)/2 
8 (100.0)/49 
6 (75.0)/28 
2 (25.0)/5 
AEs by relatedness to study medication, n(%)/c 
 
 
 
AEs judged to be related to Myrcludex B 
3 (37.5)/4 
1 (12.5)/1 
N/A 
AEs judged to be related to PEG IFN alfa-2a 
8 (100.0)/76 
8 (100.0)/56 
8 (100.0)/82 
Number of patients who died or experienced SAE, 
n (%) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Number of patients who withdrew from the study 
due to AE, n (%) 
0 (0.0) 
1 (12.5) 
0 (0.0) 
n: number of patients, c: number of events 
AE: adverse event; PT: preferred term; SOC: system organ class; IFN: Peginterferon alfa-2a; MXB: 
Myrcludex B 
 
1.3 
Study Justification 
1.3.1 Overall Study Design and Plan 
This study is a multicenter, open-label, randomized, comparative, parallel-arm phase II study. 
The study objective is to investigate the efficacy and safety of the monotherapy with Myrcludex B and the 
combination of Myrcludex B and the peginterferon alfa-2a and Tenofovir as compared to the monotherapy 
with peginterferon alfa-2a in patients with chronic viral hepatitis B with delta-agent. 
Previously performed preclinical studies of Myrcludex B make it possible to consider Myrcludex B as a 
promising drug for treatment of chronic viral hepatitis B with delta-agent. In addition, the results of the MYR 
201 substudy (refer to Section 1.2.3) suggest that both monotherapy with Myrcludex B and combination 
treatment with Myrcludex B in combination with peginterferon alfa-2a make it possible to achieve a better 
response than monotherapy with interferon.  
In the second phase of this study, it is also planned to investigate the efficacy and safety of the combination 
therapy of Mircludex B with Tenofovir from the nucleoside / nucleotide analog group. Tenofovir disoproxil 


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fumarate (Tenofovir) is a highly effective inhibitor of HBV polymerase, approved for the treatment of 
chronic hepatitis B. Nucleoside / nucleotide analogues can be used in clinical practice for the treatment of 
patients with chronic hepatitis B with delta agent. The possibility of their use in this category of patients is 
regulated by the Guidelines for Diagnosis and Treatment of Adult Hepatitis B Patients (Ministry of Health of 
the Russian Federation, 2014), EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus 
infection (European Association for the Study of Liver Disease, 2017). The use of these drugs is aimed at 
suppressing the replication of the hepatitis B virus, which plays an important role in the progressive lesion of 
the liver in the presence of a delta agent. 
This study MYR 203 is an exploratory one, and is aimed at determination of efficacy and safety parameters 
of Myrcludex B used in monotherapy, for the selection of the optimal dose of parameters B as part of a 
combination treatment with a peginterferon alfa-2a and Tenofovir for the treatment of chronic viral hepatitis 
B with delta-agent. Patients will be randomly assigned to one of six treatment arm: 
• 
Arm A (n=15) - monotherapy with peginterferon alfa-2a 180 μg during 48 weeks, 
• 
Arm B (n = 15) - combination treatment with Myrcludex B 2 mg and peginterferon alfa-2a 180 μg 
during 48 weeks, 
• 
Arm C (n = 15) - combination treatment with Myrcludex B 5 mg and peginterferon alfa-2a 180 μg 
during 48 weeks, 
• 
Arm D (n = 15) - monotherapy with Myrcludex B 2 mg during 48 weeks. 
• 
Arm E (n=15) – combination treatment with Myrcludex B 10 mg (10 mg once a day) and 
peginterferon alfa-2a 180 μg during 48 weeks. 
• 
Arm F (n=15) - combination treatment with Myrcludex B 10 mg (5 mg twice a day) and Tenofovir 
during 48 weeks. 
After the end of the treatment period, a 24-week follow-up period will follow to assess the stability of the 
viral response. Patients from group F will continue Tenofovir treatment during follow-up period. In other 
treatment arms there will no treatment. 
Peginterferon alfa-2a has been chosen as a reference product, since it is currently a type of drug treatment of 
chronic viral hepatitis B with delta agent, that shows the most efficient and acceptable safety profile. The 
efficacy and safety of the peginterferon alfa-2a in the treatment of chronic viral hepatitis B with delta-agent 
has been demonstrated in recent studies with a long period of treatment and follow-up (HIDIT-1, HIDIT-2, 
refer to Section 1.1). 
The main efficacy criterion in this study (primary endpoint) is the proportion of patients with negative PCR 
result of HDV RNA (undetectable level of HDV RNA) at week 72 (end of follow-up period). The evaluation 
of the proportion of patients with a stable virologic response after a long (6 months) period without treatment 
is considered one of the most reliable criteria for evaluating the effectiveness of treatment of chronic viral 
hepatitis B with delta-agent and is widely used in similar clinical studies and routine clinical practice. 
Additional efficacy criteria include evaluation of the dynamics of ALT, HBsAg, HBV DNA, the severity of 
fibrosis in the liver tissue, both after the end of treatment, and after the end of the 6-month follow-up period. 
Before and after the treatment all patients should be performed liver biopsy for histological and virological 
tests. HBV, HDV genotyping, resistance and polymorphisms NTCP is also planned as a part of the 
examination of efficacy. The listed criteria for assessing the treatment efficacy meet the requirements of 
guidelines for the study of drugs for the treatment of chronic viral hepatitis [5]. 
Criteria for the safety evaluation of the treatment being studied include the collection of data on adverse 
events, physical examination, ophthalmological examination, evaluation of vital signs, electrocardiography, 
standard laboratory tests (hematology, coagulogram, biochemistry, urinalysis), determination of common 
bile acids, as well as the estimation of TSH and T4 levels. This list of parameters appears to be complete for 
the evaluation of the safety profile of the treatment as a part of the study, and takes into account the safety 
data of Myrcludex B and peginterferon alfa-2a and Tenofovir obtained so far. 
The study also plans to study the immunogenicity of the drug Myrcludex B (arms B - F,) and the 
pharmacokinetics of the drug in the monotherapy and in the combined therapy with Myrcludex B + 
peginterferon alfa-2a and Myrcludex B + Tenofovir. The level of antibodies to the study drug Myrcludex B 
will be determined before, during, and after the end of treatment. The pharmacokinetic substudy will enroll 
20 patients (10 patients from arms B and C), in pharmacokinetic of second phase – 10 patients from arm F 
who, during the study, will be hospitalized (day-stay or 24-hour hospital) for blood sampling for the 
investigation of the pharmacokinetic parameters of the study drug after single and multiple dosing as part of 


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a combination therapy. The selection of time points for the pharmacokinetic evaluation is based on the 
accumulated data of preclinical and clinical studies of the pharmacokinetics of Myrcludex B. In addition, for 
a more exact investigation of the possible cumulation of the study drug, blood sampling is planned for all 
patients receiving Myrcludex B (the main study, PK main study). 
 
1.3.2 Study population 
The study plans to randomize 90 male and female patients aged 18 through 65 years of age with chronic viral 
hepatitis B with delta-agent. Taking into account the possible drop-out during the randomization period, 123 
patients are planned to be screened for the study. 
The study selection criteria suggest the enrollment of patients with a positive result of HDV RNA, anti-HDV 
antibodies, HBeAg-positive or negative chronic hepatitis B, ALT level ≥ 1 ULN and <10 ULN, and with no 
co-infection with the hepatitis C virus or HIV. Antiretroviral therapy must be completed at least in six 
months before screening, and the prior interferon therapy is allowed (interferon therapy must be completed at 
least in 6 months before screening). 
The study population is of representative nature, maximally close to clinical practice in the studied 
therapeutic area. 
 
1.3.3 Justification of the administration route, dose, dosage regimen and treatment duration 
The test drug Myrcludex B will be administered in doses of 2 mg, 5 mg or 10 mg in the form of 
subcutaneous injections, which should be performed daily, every 24±1 hours (once a day for groups B – E) 
or 12+1 hours (twice a day, group F). The administration route, the dosage regimen, the study dose selection 
are based on the results of previously performed studies of Myrcludex B, which demonstrated a favorable 
efficacy and safety profile of the drug use (refer to Section 1.2.3). 
The peginterferon alfa-2a will be administered at a dose of 180 μg in the form of subcutaneous injections, 
which should be administered subcutaneously, once a week. The administration route and the dosage 
regimen comply with the Instruction for medical use. 
Tenofovir will be taken internally, 300 mg (1 tablet), once a day, daily. Dosage regimen corresponds to the 
instruction for medical use. 
The main treatment duration in all study arms will be 48 weeks, which corresponds to the recommendations 
for the investigation of drugs for the treatment of chronic viral hepatitis and the standards of routine clinical 
practice. Patients in group F will follow Tenofovir treatment during follow-up phase. 
 
1.3.4 Brief description of known and potential risks and benefits for study subjects 
According to previous studies and considering that chronic viral hepatitis B with delta-agent is difficult to 
treat with modern available drugs of different pharmacological groups, it is quickly reactivated and can lead 
to severe liver injury, but also, therapy being investigated may be useful for the patient. With that, patients 
will be under close medical control for a long time and will undergo examinations, including laboratory and 
instrumental procedures, which will enable them to obtain complete information about their health status 
during the entire period of participation in this clinical study. 
In the course of the study, side effects that are characteristic of Myrcludex B, Tenofovir and peginterferon 
alfa-2a may be registered, as well as side effects not identified earlier may be identified. 
The procedures and examinations performed as a part of this protocol are routine in clinical practice. 
However, during the collection of blood samples from patients and performing biopsy procedure, discomfort 
or painful sensations, which resolve rapidly, may appear. In rare cases, biopsy procedure could be 
accompanied with such adverse events: accidental puncture of another organ (bowel, lung, gallbladder, 
kidneys), contamination of abdomen, bleeding. 
If patients develop adverse events, appropriate corrective therapy will be prescribed. If there is any health 
damage caused by the clinical study, the patient will be provided with the necessary medical care and 
compensated for the expenses in accordance with the insurance procedure. 
 
1.4 
Regulatory documents 
This study will be performed in accordance with the protocol, ICH GCP requirements, the provisions of the 
World Medical Association Declaration of Helsinki, and the relevant regulatory requirements of the Russian 
Federation listed below. 


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1. 
Federal Law N 61-FZ dd. April 12, 2010 “On Medicine Circulation”. 
2. 
Federal Law No. 323-FZ dd. November 21, 2011 "On the fundamentals of protection of the public 
health in the Russian Federation". 
3. 
Order of the Ministry of Health of the Russian Federation No. 200n dd. 01.04.2016 "On Approval of 
Rules of Good Clinical Practice" 
4. 
National Standard of the Russian Federation GOST R 52379-2005 “Good Clinical Practice” 
5. 
Guidelines for the drug expertise (FSBI "Scientific Center for Expertise of Means of Medical 
Application", 2013). 
6. 
Guidelines for clinical studies of drugs (FSBI "Scientific Center for Expertise of Means of Medical 
Application", 2012). 


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2 
OBJECTIVES AND ENDPOINTS OF THE STUDY 
2.1 
Study objective 
The objective of this clinical study is to investigate the efficacy and safety of Myrcludex B used in 
monotherapy and the combination of Myrcludex B with peginterferon alfa-2a (PEG-IFN alfa-2a) and with 
Tenofovir as compared to the monotherapy with peginterferon alfa-2a in patients with chronic viral hepatitis 
B with delta-agent. 
 
2.2 
Study objectives 
Primary objectives: 
To investigate the efficacy of Myrcludex B in monotherapy and in combination with PEG-IFN alfa-2a and 
with Tenofovir compared to monotherapy with PEG-IFN alfa-2a, based on the achievement of undetectable 
viral load at the end of the follow-up period (6 months after the end of treatment). 
Secondary objectives: 
• 
To investigate the efficacy of Myrcludex B in monotherapy and in combination with PEG-IFN alfa-2a 
and with Tenofovir as compared with monotherapy with PEG-IFN alfa-2a, based on the secondary efficacy 
endpoints. 
• 
To investigate the safety of Myrcludex B in monotherapy and in combination with PEG-IFN alfa-2a 
and with Tenofovir compared with PEG-IFN alfa-2a monotherapy. 
• 
To investigate the pharmacokinetics of Myrcludex B when administered in combination with PEG-
IFN alfa-2a and with Tenofovir. 
• 
To investigate the immunogenicity of Myrcludex B 
 
2.3 
Study Endpoints 
Primary efficacy endpoint: 
• 
Proportion of patients with a negative PCR result of HDV RNA (undetectable level of HDV RNA ) at 
week 72 (end of the follow up period) 
Secondary efficacy endpoints: 
• 
Proportion of patients with a negative PCR result of HDV RNA (undetectable level of HDV RNA ) at 
weeks 24 and 48. 
• 
Proportion of patients with HDV RNA response (decrease ≥ 2 log10 HDV RNA or an undetectable 
level of HDV RNA) at weeks 24, 48 and 72 
• 
Proportion of patients with ALT normalization at weeks 24, 48 and 72. 
• 
Proportion of patients with combined treatment response (negative PCR result of HDV RNA and ALT 
normalization) at weeks 24, 48 and 72. 
• 
Proportion of patients with a combined response to therapy ((decrease ≥ 2 log10 HDV RNA or an 
undetectable level of HDV RNA) and normalization of ALT) at weeks 24, 48 and 72 
• 
Proportion of patients with HBsAg response HBsAg negativation or >1 log10 IU/mL decline) at 
weeks 24, 48 and 72. 
• 
Proportion of patients with the HBsAg negativation with the appearance of anti-HBsAg antibodies and 
without it at weeks 48 and 72. 
• 
Proportion of patients with a negative PCR result of HBV DNA at weeks 24, 48 and 72. 
• 
The intensity of liver fibrosis  based on results of transient elastometry of liver at weeks 48 and 72 
• 
Changes in the results of liver biopsy before and after the treatment  
As part of the study of efficacy, HBV, HDV genotyping, resistance assay and study of NTCP polymorphism 
will be performed additionally. 
Safety criteria: 
• 
Adverse events, serious adverse events 
• 
Physical examination 
• 
Ophthalmological examination 
• 
Vital signs 
• 
12-lead ECG 
• 
Hematology 


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• 
Blood chemistry 
• 
Total bile acids 
• 
Coagulogram 
• 
Urinalysis 
• 
Blood test for TSH, T4  
Evaluation of immunogenicity: 
• 
The level of antibodies to Myrcludex B (arms B - F) 
2.4 
Investigated pharmacokinetic parameters 
The following pharmacokinetic parameters will be evaluated using non-compartmental analysis: 
• 
Cmax – maximum concentration 
• 
Тmax – time of maximum concentration  
• 
Kel – elimination rate constant 
• 
T1/2 – elimination half-life 
• 
CL/F – total clearance 
• 
AUC0-t – area under the curve "drug concentration-time" from time 0 to the sampling time (t) of the 
last sample 
• 
AUC0-∞ 
– 
area 
under 
the 
curve 
"drug 
concentration-time" 
from 
time 
0 
to 
∞


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3 
STUDY DESIGN AND PLAN 
3.1 
Study design and plan 
This study is a multicenter, open-label, randomized, comparative, parallel-arm phase II study 
The study will be performed in the Russian Federation. 
The study objective is to investigate the efficacy and safety of the monotherapy with Myrcludex B and the 
combination of Myrcludex B with peginterferon alfa-2a and with Tenofovir as compared to the monotherapy 
with peginterferon alfa-2a in patients with chronic viral hepatitis B with delta-agent. In the course of the 
study, it is also planned to investigate the immunogenicity of Myrcludex B and the pharmacokinetics of the 
drug when administered in monotherapy and in combination with PEG-IFN alfa-2a and with Tenofovir. 
It is planned that 123 patients will be screened and 90 of them will be randomized into 6 treatment arms in a 
1:1:1:1:1:1 ratio: 
• 
Arm A (n=15): PEG-IFN alfa-2a 180 µg during 48 weeks 
• 
Arm В (n=15): Myrcludex B 2 mg + PEG-IFN alfa-2a 180 μg during 48 weeks 
• 
Arm С (n=15): Myrcludex B 5 mg + PEG-IFN alfa-2a 180 μg during 48 weeks 
• 
Arm D (n=15): Myrcludex B 2 mg during 48 weeks 
• 
Arm E (n=15): Myrcludex B 10 mg (10 mg once a day) + PEG-IFN alfa-2a 180 μg during 48 weeks 
• 
Arm F (n=15): Myrcludex B 10 mg (5 mg twice a day) + Tenofovir during 48 weeks 
 
After the end of treatment period, there will be a follow-up period of 24 weeks. Patients from group F will 
continue Tenofovir treatment during follow-up period. 
The study includes 2 phases:  
I phase – patients enrollment in groups A – D (Protocol version 1.0, dd. 16.12.2015, Protocol version 1.1, dd. 
16.03.2016, Protocol version 2.0, dd. 31.05.2016, Protocol version 3.0, dd. 23.08.2017) 
II phase - patients enrollment in groups E – F (Protocol version 4.0, dd. 19.01.2018) 
An additional pharmacokinetic study (PK substudy) is planned to be performed as a part of the I phase of the 
study, in which 10 patients randomized to each of treatment arms B and C (20 patients in total) will be 
enrolled. During II phase of the study patients from group F (the first 10 randomized patients) will take part 
in the pharmacokinetic study. Blood samples for the assessment of the drug concentration will be collected at 
the following time points: Days 1, 2, 14, 15. 
For a more precise investigation of the possible study drug accumulation in all patients of each Myrcludex B 
treatment arm (PK main study), blood sampling points for the pharmacokinetic study are assigned: week 4, 
8, 12, 16, 20, 24, 28, 32, 40, 48 (in 1hour +/-15 min after the drug administration) (week 48 only for patients 
from groups E – F). For the patients not participating in the pharmacokinetic substudy, a blood sampling 
point at a randomization visit (in 1hour +/-15 min after the drug injection) is assigned. 
The study plan includes a screening period – up to 4 weeks, treatment period - 48 weeks, follow-up period - 
24 weeks. Study scheme is presented on Figure 2. The flow chart is presented in Table 1. 
The total duration of the patient's participation in the study is up to 76 weeks. 
The total number of visits is 19 (screening visit, 13 visits of the treatment period, and 5 visits of the follow-
up period). 
Patients enrolled into the pharmacokinetic substudy (PK substudy) and pharmacokinetic study for group F 
will be taken to hospital (day-stay of 24-hour) on the day before the start of treatment and will stay in the 
hospital during the blood sampling period to assess the pharmacokinetics (Days 1, 2, 14, 15). 
Throughout the entire study, patients not enrolled into these pharmacokinetic substudies will undergo 
treatment and planned examinations on an outpatient basis. 
 


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Figure 2 Study scheme 
 
3.2 
Randomization 
Randomization will be performed in a ratio of 1:1:1:1:1:1 using the IWRS (Interactive Web Response 
System). The separate randomization list will be created for both phases of the study. 
Randomization must be implement only after approval study Sponsor based of signed by Investigator “Form 
for assessing inclusion/non-inclusion criteria” and scans of listed in the form documents, confirming patient's 
compliance with the eligibility criteria (in blind form). No later than 3 days before scheduled randomizing 
date, this form must be shipped to monitor of the center and study sponsor to receive signed randomization 
approval. 
3.3 
Blinding procedure 
Not applicable. The study is an open-label one. 
 
3.4 
Schedule of study procedures and stages 
3.4.1 Informed consent 
All procedures provided for in this clinical study protocol will be performed only after the patient has signed 
a written form of informed consent to participate in the study. 
Each participant in the study will be provided with appropriate and reliable information on the study 
objectives and methods, risks and difficulties associated with the participation in the study, and other aspects 
of this study. If a patient agrees to participate in the study, he/she signs and dates a written informed consent 
form in 2 copies. The investigator also signs and dates the informed consent form, certifying that the consent 
was received and that the patient had the opportunity to ask questions of interest and received full answers to 
them. The patient will be given one original informed consent form, and the other original will be deposited 
at the study center along with other study documentation. 
 
3.4.2 Screening period (Day-28 – Day-1) 
The screening procedures will be carried out during the Days-28 – 1. Screening period may be less than 28 
days (not less than 3 days) subject to receipt all required for randomization results of procedures/analyzes 
during the screening period. A detailed description of the procedures and a list of data recorded in the patient 
CRFs are provided in Section 6. 
• 
Collection of demographics and medical history data 
• 
Collection of data on previous and concomitant treatment 
• 
Physical examination 
• 
Ophthalmological examination (for patients with a history of mild and moderate retinopathy to 


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evaluate baseline ocular changes) 
• 
Measurement of body height, weight, calculation of BMI 
• 
Evaluation of vital signs 
• 
Urine pregnancy test (for women with reproductive potential) 
• 
Urine drug screening 
• 
Alcohol-breath test 
• 
Anti-HDV antibodies (local laboratory) 
• 
Alpha-fetoprotein test (central laboratory) 
• 
Blood test for HIV (HIV antibodies) (local laboratory) 
• 
Blood test for Hepatitis C (anti-HCV antibodies, HCV RNA (if the test is positive for anti-HCV 
antibody) (local laboratory) 
• 
Blood test for TSH, T4 (central laboratory) 
• 
HDV RNA tests (room temperature samples, central laboratory) (qualitative and quantitative) 
• 
HBeAg, anti-HBeAg antibody tests (local laboratory) 
• 
HВsAg, anti-HВsAg antibody tests (local laboratory) 
• 
Urinalysis (сentral laboratory) 
• 
12-lead ECG 
• 
Abdominal ultrasound 
• 
Fibroscan (transient elastometry of liver) 
• 
Liver biopsy 
• 
Hematology(central laboratory) 
• 
Biochemistry (central laboratory) 
• 
Coagulogram (central laboratory). 
Once the screening criteria are confirmed, patients will be randomized in one of the treatment arms. 
Randomization should be performed on Day -3 – Day-1 of the study. 
Patients from groups B, C, F participating in the pharmacokinetic study will be hospitalized to the clinical 
center for sample collection on Days 1-2 of the study. 
The patients not enrolled into the pharmacokinetic substudy start treatment and planned examinations and 
procedures on an outpatient basis. 
 
3.4.3 Treatment period (Week 1 – Week 48) 
The treatment period is 48 weeks. 13 visits to the study center are planned during this period. A detailed 
description of the procedures and a list of data recorded in the patient CRFs are provided in Section 6. 
 
Visit 1/Week 0/Day 1 
Randomization must be implemented after the approval of patient’s conformity to selection criteria for the 
study in interval from Day 3-Day 1 of the investigation. The following procedures are performed during the 
visit. All blood samples will be analyzed in the central laboratory. The results of laboratory studies on Visit 
1/Day 1 will be used as baseline data for the efficacy and safety evaluation. 
The sequence of the procedures should be in accordance with the list below. 
• 
Urinalysis (central laboratory) 
• 
Evaluation of vital signs 
• 
HDV RNA blood test 
• 
HBV DNA, HBsAg tests (quantification)  
• 
Hematology 
• 
Coagulogram 
• 
Blood chemistry 
• 
Blood bile acids 
• 
Blood sampling to estimate immunogenicity 
• 
Blood sampling for HBV, HDV genotyping 
• 
Resistance assay 
• 
Examination of NTCP polymorphism 


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• 
Issuance of patient diaries, instructions on how to fill it 
• 
Dispensing the study drug/ PEG-IFN alfa-2a/Tenofovir and accompanying materials over, instruction 
on how to conduct the self-injection 
• 
Injection of the first dose of the Myrcludex B (groups B- F)/ PEG-IFN alfa-2a (group A –
 C, E)/Tenofovir (group F) 
• 
Blood sampling for the pharmacokinetic main study in 1 hour ±15 min after the first injection of 
Myrcludex B (groups B – F) 
• 
Filling the patient diary in 
• 
Collection of data on adverse events 
• 
Collection of data on concomitant treatment 
 
Procedures for patients participating in the PK-substudy (10 patients from groups B, C, F) 
The following procedures will be performed under the conditions of the inpatient hospitalization (all blood 
samples will be analyzed in the central laboratory): 
 
Day 1 
• Urinalysis (central laboratory) 
• Evaluation of vital signs 
• HDV RNA blood test 
• HBV DNA, HBsAg tests (quantification)  
• Hematology 
• Coagulogram 
• Blood chemistry 
• Blood bile acids 
• Blood sampling to estimate immunogenicity 
• Blood sampling for HBV, HDV genotyping 
• Resistance 
• NTCP polymorphisms 
• Issuance of patient diaries, instructions on how to fill it 
• Instructions on the self-injection of the drug  
• Blood sampling before the start of the treatment 
• Injection of the first dose of the Myrcludex B (groups B, C, F)/ PEG-IFN alfa-2a (groups B, C)/Tenofovir 
(group F) 
• Blood sampling for PK study  
Groups B and C: Blood sampling after the injection of the first dose of Myrcludex B: in 00:30, 1:00, 1:30, 
2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 14:00 (hh:min) after the drug injection. 
Group F: Blood sampling after the injection of the first dose of Myrcludex B: in 00:30, 1:00, 1:30, 2:00, 
2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00 (hh:min) after the drug injection 
Blood sampling in 12 hours after the first dose should be performed before the second injection of МХВ. 
• Injection of the second dose of the Study drug (for group F only) 
• Filling the patient diary in 
• Collection of data on adverse events, Evaluation of the Myrcludex B injection site 
• Collection of data on concomitant treatment 
 
Day 2 
The following procedures will be performed in hospital (day-stay or 24-hour): 
• 
Blood sampling for PK study 
Groups B and C: Blood sampling 24 hours after the injection of Myrcludex B (before injection of the second 
dose in Day 2) 
Group F: Blood sampling in 12 hours after the second injection of Myrcludex B in Day 1 (before injection of 
third dose on Day 2) 
• 
Injection of the second (groups B and C)/third (group F) dose of Myrcludex B 
• 
Tenofovir intake (group F) 


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• Filling the patient diary in 
• Handing the study drug/reference product/Tenofovir and accompanying materials over for the self-
injection of drugs by the patients at home 
• Collection of data on adverse events, evaluation of the Myrcludex B injection site 
• Collection of data on concomitant treatment 
Further procedures are performed on an outpatient basis until the next hospitalization as per the study 
protocol. 
 
Visit 2/Week 1/Day 8 ± 2 
The following procedures are performed during the visit. All blood samples will be analyzed in the central 
laboratory. 
• Evaluation of vital signs 
• Hematology 
• Coagulogram 
• Blood chemistry 
• Blood bile acids 
• Return of used packages of the study drug/reference product 
• Evaluation of the patient diary, registration of data in the patient CRFs 
• Collection of data on adverse events, evaluation of the Myrcludex B injection site 
• Collection of data on concomitant treatment 
 
Visit 3/Week 2/Day 15 + 2 
The following procedures are performed during the visit. All blood samples will be analyzed in the central 
laboratory. 
• Evaluation of vital signs 
• HDV RNA blood test 
• HBV DNA, HBsAg tests (quantification) (central laboratory) 
• Hematology 
• Coagulogram 
• Blood chemistry 
• Blood bile acids 
• Return of used packages of the study drug/reference product 
• Evaluation of the patient diary, registration of data in the patient CRFs 
• Collection of data on adverse events, evaluation of the Myrcludex B injection site 
• Collection of data on concomitant treatment 
 
Procedures for patients participating in the PK-substudy (10 patients from group B, C and F) 
The following procedures will be performed under the conditions of the inpatient hospitalization (all blood 
samples will be analyzed in the central laboratory): 
 
Day 14 
• Evaluation of vital signs 
• HDV RNA blood test 
• HBV DNA, HBsAg tests (quantification) (central laboratory) 
• Hematology 
• Coagulogram 
• Blood chemistry 
• Blood bile acids 
• Return of used packages of the study drug/reference product 
• Evaluation of the patient diary, registration of data in the patient CRFs 
• Blood sampling before the injection of Myrcludex BInjection of Myrcludex B (groups B, C and F)/ PEG-
IFN alfa-2a (groups B, C)/Tenofovir (group F) according to treatment scheme 
• Blood sampling for PK study  
Groups B and C: Blood sampling after the injection of Myrcludex B: in 00:30, 1:00, 1:30, 2:00, 2:30, 3:00, 


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4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 14:00 (hh:min) after the drug injection. 
• Group F: Blood sampling after injection of Myrcludex B in 00:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 
6:00, 8:00, 10:00, 12:00 (hh:min) after the drug injection 
Blood sampling in 12 hours after injection should be performed before the second injection of MXB on Day 
14. 
• Second injection of study drug on Day 14 (only for group F) 
• Collection of data on adverse events, evaluation of the Myrcludex B injection site 
• Collection of data on concomitant treatment 
 
Day 15 
The following procedures will be performed in hospital (day-stay or 24-hour): 
• 
Blood sampling for PK study 
Groups B and C: Blood sampling 24 hours after the injection of Myrcludex B (before injection on Day 15) 
Group F: Blood sampling in 12 hours after the second injection of Myrcludex B in Day 14 (before the first 
injection on Day 2) 
• 
Injection of Myrcludex B (groups B, C, F) 
• 
Tenofovir intake (group F) in the investigational site or at home according to treatment scheme 
• 
Filling the patient diary in 
• 
Collection of data on adverse events, evaluation of the Myrcludex B injection site 
• 
Collection of data on concomitant treatment 
Further visits and procedures are performed on an outpatient basis. 
 
Visit 4/Week 4/Day 29±2 
The following procedures are performed during the visit. All blood samples will be analyzed in the central 
laboratory. 
• Urinalysis (central laboratory) 
• Evaluation of vital signs 
• HDV RNA blood test 
• HBV DNA, HBsAg tests (quantification)  
• Hematology 
• Coagulogram 
• Blood chemistry 
• Blood bile acids 
• Blood sampling for the pharmacokinetic substudy (in 1h±15min after the injection of Myrcludex B 
(groups B – F; injection in the investigational site) 
• Return of used and unused packages of the study drug/reference product/Tenofovir 
• Evaluation of the patient diary, registration of data in the patient CRFs 
• Dispensing the study drug/reference product/Tenofovir and study materials 
• Collection of data on adverse events, evaluation of the Myrcludex B injection site 
• Collection of data on concomitant treatment 
 
Visit 5/Week 8/Day 57±2 
The following procedures are performed during the visit. All blood samples will be analyzed in the central 
laboratory. 
• Urinalysis (central laboratory) 
• Evaluation of vital signs 
• HDV RNA blood test 
• HBsAg test (quantification) 
• Hematology 
• Coagulogram 
• Blood chemistry 
• Blood bile acids 
• Blood sampling for the pharmacokinetic substudy (in 1h±15min after the injection of Myrcludex B 
(groups B – F, injection at the investigational site) 


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• Return of used and unused packages of the study drug/reference product/Tenofovir 
• Evaluation of the patient diary, registration of data in the patient CRFs 
• Dispensing the study drug/reference product and accompanying materials 
• Collection of data on adverse events, evaluation of the Myrcludex B injection site 
• Collection of data on concomitant treatment 
 
Visit 6/Week 12/Day 85±2 
The following procedures are performed during the visit. All blood samples will be analyzed in the central 
laboratory. 
• Urinalysis (central laboratory) 
• Physical examination 
• Measurement of the body weight 
• Evaluation of vital signs 
• HDV RNA blood test 
• HBV DNA, HBsAg tests (quantification)  
• Hematology 
• Coagulogram 
• Blood chemistry 
• Blood bile acids 
• Blood sampling for the pharmacokinetic substudy (in 1h±15min after the injection of Myrcludex B 
(groups B – F, injection at the investigational site) 
• Blood test for TSH, T4  
• Blood sampling to estimate immunogenicity 
• Electrocardiography 
• Return of used and unused packages of the study drug/reference product/Tenofovir 
• Evaluation of the patient diary, registration of data in the patient CRFs 
• Dispensing the study drug/reference product/Tenofovir and accompanying materials 
• Collection of data on adverse events, evaluation of the Myrcludex B injection site 
• Collection of data on concomitant treatment 
 
Visit 7/Week 16/Day 113±2 
The following procedures are performed during the visit. All blood samples will be analyzed in the central 
laboratory. 
• Urinalysis (central laboratory) 
• Evaluation of vital signs 
• HDV RNA blood test 
• HBsAg test (quantification) 
• Hematology 
• Coagulogram 
• Blood chemistry 
• Blood bile acids 
• Blood sampling for the pharmacokinetic substudy (in 1h±15min after the injection of Myrcludex B 
(groups B – F, injection at the investigational site) 
• Return of used and unused packages of the study drug/reference product/Tenofovir 
• Evaluation of the patient diary, registration of data in the patient CRFs 
• Dispensing the study drug/reference product/Tenofovir and accompanying materials 
• Collection of data on adverse events, evaluation of the Myrcludex B injection site 
• Collection of data on concomitant treatment 
 
Visit 8/Week 20/Day 141±2 
The following procedures are performed during the visit. All blood samples will be analyzed in the central 
laboratory. 
• Urinalysis (central laboratory) 
• Evaluation of vital signs 


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• HDV RNA blood test 
• HBsAg test (quantification) 
• Hematology 
• Coagulogram 
• Blood chemistry 
• Blood bile acids 
• Blood sampling for the pharmacokinetic substudy (in 1h±15min after the injection of Myrcludex B 
(groups B – F, injection at the investigational site) 
• Return of used and unused packages of the study drug/reference product/Tenofovir 
• Evaluation of the patient diary, registration of data in the patient CRFs 
• Dispensing the study drug/reference/Tenofovir product and accompanying materials 
• Collection of data on adverse events, evaluation of the Myrcludex B injection site 
• Collection of data on concomitant treatment 
 
 
Visit 9/Week 24/Day 169±2 
The following procedures are performed during the visit. All blood samples will be analyzed in the central 
laboratory. 
• Urinalysis (central laboratory) 
• Urine pregnancy test (for women with reproductive potential) 
• Physical examination 
• Measurement of the body weight 
• Evaluation of vital signs 
• HDV RNA blood test 
• HBV DNA, HBsAg tests (quantification)  
• HBeAg, anti-HBeAg antibody tests (only in patients with positive results at screening) 
• Hematology 
• Coagulogram 
• Blood chemistry 
• Blood bile acids 
• Blood sampling for the pharmacokinetic substudy (in 1h±15min after the injection of Myrcludex 
B (groups B – F, injection at the investigational site) 
• Blood test for TSH, T4  
• Blood sampling to estimate immunogenicity 
• Electrocardiography 
• Return of used and unused packages of the study drug/reference product/Tenofovir 
• Evaluation of the patient diary, registration of data in the patient CRFs 
• Dispensing the study drug/reference product/Tenofovir and accompanying materials 
• Collection of data on adverse events, evaluation of the Myrcludex B injection site 
• Collection of data on concomitant treatment 
 
Visit 10/Week 28/Day 197±2 
The following procedures are performed during the visit. All blood samples will be analyzed in the central 
laboratory. 
• Urinalysis (central laboratory) 
• Evaluation of vital signs 
• HDV RNA blood test 
• HBsAg test (quantification) 
• Hematology 
• Coagulogram 
• Blood chemistry 
• Blood bile acids 
• Blood sampling for the pharmacokinetic substudy (in 1h±15min after the injection of Myrcludex B 
(groups B – F, injection at the investigational site) 


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• Return of used and unused packages of the study drug/reference product/Tenofovir 
• Evaluation of the patient diary, registration of data in the patient CRFs 
• Dispensing the study drug/reference/Tenofovir product and accompanying materials 
• Collection of data on adverse events, evaluation of the Myrcludex B injection site 
• Collection of data on concomitant treatment 
 
Visit 11/Week 32/Day 225±2 
The following procedures are performed during the visit. All blood samples will be analyzed in the central 
laboratory. 
• Urinalysis (central laboratory) 
• Evaluation of vital signs 
• HDV RNA blood test 
• HBV DNA, HBsAg tests (quantification)  
• Hematology 
• Coagulogram 
• Blood chemistry 
• Blood bile acids 
• Blood sampling for the pharmacokinetic substudy in 1h±15min after the injection of Myrcludex B 
(groups B – F, injection at the investigational site) 
• Return of used and unused packages of the study drug/reference product/Tenofovir 
• Evaluation of the patient diary, registration of data in the patient CRFs 
• Dispensing the study drug/reference/Tenofovir product and accompanying materials 
• Collection of data on adverse events, evaluation of the Myrcludex B injection site 
• Collection of data on concomitant treatment 
 
Visit 12/Week 40/Day 281±2 
The following procedures are performed during the visit. All blood samples will be analyzed in the central 
laboratory. 
• Urinalysis (central laboratory) 
• Evaluation of vital signs 
• HDV RNA blood test 
• HBsAg test (quantification) 
• Hematology 
• Coagulogram 
• Blood chemistry 
• Blood bile acids 
• Blood sampling for the pharmacokinetic substudy in 1h±15min after the injection of Myrcludex B 
(groups B – F, injection at the investigational site) 
• Return of used packages of the study drug/reference product/Tenofovir 
• Evaluation of the patient diary, registration of data in the patient CRFs 
• Dispensing the study drug/reference product/Tenofovir and accompanying materials 
• Collection of data on adverse events, evaluation of the Myrcludex B injection site 
• Collection of data on concomitant treatment 
 
Visit 13 (End of treatment visit, EOT visit)/Week 48/Day 337+2 
The following procedures are performed during the visit. All blood samples will be analyzed in the central 
laboratory. 
• Urinalysis (central laboratory) 
• Urine pregnancy test (for women with reproductive potential) 
• Physical examination 
• Measurement of the body weight 
• Evaluation of vital signs 
• HDV RNA blood test 
• HBV DNA, HBsAg tests (quantification)  


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• HBeAg, anti-HBeAg antibody tests (only in patients with positive results at screening) 
• Hematology 
• Coagulogram 
• Blood chemistry 
• Blood bile acids 
• Resistance assay 
• Blood test for TSH, T4  
• Blood sampling to estimate immunogenicity 
• Groups E and F: blood sampling for PK main study in 1 hour + 15 min after Myrcludex injection (injection 
at the investigational site) 
• Electrocardiography 
• Abdominal ultrasound 
• Fibroscan (transient elastometry of liver) 
• Liver biopsy for patients from groups D and F (allowable time for liver biopsy: ± 7 days from the date of 
the end of treatment visit) 
• Return of used and unused packages of the study drug/reference product/Tenofovir 
• Tenofovir dispensing for follow-up period (group F) 
• Evaluation of the patient diary, registration of data in the patient CRFs 
• Collection of data on adverse events, evaluation of the Myrcludex B injection site 
• Collection of data on concomitant treatment 
 
3.4.4 Follow-up period (Week 49 –Week 72) 
The duration of the follow-up period is 24 weeks. 5 visits to the study center are planned during this period. 
1) Follow-up visit 1/Week 50(EOT+2 weeks)/Day 351±3 
2) Follow-up visit 2/Week 52(EOT+4 weeks)/Day 365±3 
3) Follow-up visit 3/Week 56(EOT+8 weeks)/Day 393±3 
4) Follow-up visit 4/Week 60(EOT+12 weeks)/Day 421±3 
5) Follow-up visit 5 (End of treatment visit)/Week 72 / 
(EOT+24 weeks)/Day 505±3 
Procedures during the Follow-up visits 1-4 (all blood samples will be analyzed in the central laboratory): 
• Evaluation of vital signs 
• HDV RNA blood test 
• HBsAg test (quantification) 
• Hematology 
• Coagulogram 
• Blood chemistry 
• Blood bile acids 
• Collection of data on adverse events 
• Collection of data on concomitant treatment 
• Return of used and unused packages of Tenofovir (Week 52, 56, 60) 
• Evaluation of the patient diary, registration of data in the patient CRFs 
• Dispensing of Tenofovir for FUP period (Week52, 56, 60) 
In addition, blood sampling to assess immunogenicity will be performed at Follow-up visits 2 (Week 52) 
and 4 (Week 60). The HBV DNA test will be performed at Follow-up Visit 4 (Week 60). 
Procedures during the Follow-up visit 5/End of treatment (all blood samples will be analyzed in the central 
laboratory): 
• Urinalysis (central laboratory) 
• Physical examination 
• Measurement of the body weight 
• Evaluation of vital signs 
• HDV RNA blood test 
• HBV DNA, HBsAg tests (quantification) (central laboratory) 
• HBeAg, anti-HBeAg antibody tests (only in patients with positive results at screening) 


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• Hematology 
• Coagulogram 
• Blood chemistry 
• Blood bile acids 
• Blood sampling to estimate immunogenicity 
• Electrocardiography 
• Abdominal ultrasound 
• Fibroscan (transient elastometry of liver) 
• Liver biopsy for patients from groups A - C and E (allowable time for liver biopsy: ± 7 days from the date 
of the end of treatment visit) 
• Collection of data on adverse events 
• Collection of data on concomitant treatment 
• Return of used and unused packages of Tenofovir 
Evaluation of the patient diary, registration of data in the patient CRFs 
 
3.5 Acceptable window periods for planned visits and procedures 
Acceptable days for window periods for visits are presented in Table 1. During the treatment period, window 
of ± 2 days are allowed for visits 2-12, +2-day window is allowed for the end of treatment visit, a ±3-day 
window is allowed for all visits during the follow-up period. 
For patients in Arms B, C and F participating in the pharmacokinetic substudy, there is no time window for 
Day 1 and 2, blood sampling for assessment of pharmacokinetics of Myrcludex B should be performed 
before and after the first dose of Myrcludex B. The second part of the PK study may be performed within 
time window + 1 Day (Day 15 – 16 of the study). Directly during the visits the following window periods for 
blood sampling to evaluate pharmacokinetics are allowed: 
• 
in 00:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00 (hh:min) after the injection of Myrcludex B – a 
window of ±5 minutes, 
• 
in 6:00, 8:00, 10:00, 12:00, 14:00, 24:00 (hh:min) after the injection of Myrcludex B – a window of 
±10 minutes. 
Blood sampling for PK main study for all patients from Myrcludex B groups on weeks, 4, 8, 12, 16, 20, 24, 
28, 32, 40, 48 should be performed in accordance with time window indicated in Table 1. Blood sampling 
during the visit should be performed in 1 hour after injection of Murcludex B, allowed deviation is ± 15 min. 
 
3.6 
Limitations of the study 
Limitations on concomitant treatment 
For information on the limitations of concomitant treatment, refer to Section 5.4. 
During the clinical study, the patient consumption of alcohol should not exceed 20 g/day. 
 
Method of birth control during the study 
All women of childbearing potential and men who have a partner of childbearing potential must, upon 
signing informed consent, agree to the adhere to the adequate contraceptive methods during the study from 
the date of signing the informed consent and to the end of the follow-up period. 
Requirements for registration and reporting of cases of pregnancy are presented in Section 7.8. 
Women of no childbearing potential meet one of the following criteria: 
• 
women in the postmenopausal period, which is defined as the absence of menstruation for 24 
consecutive months, for no alternative medical reason, 
• 
women who have been sterilized (for example, a bilateral tube ligation for more than one menstrual 
cycle before the enrollment; hysterectomy or bilateral oophorectomy). 
The following are considered to be appropriate methods of birth control: 
1. 
Complete sexual abstinence [periodic sexual abstinence (e.g., calendar, symptomatic methods) is not an 
adequate method of contraception]. 
2. 
Male sterilization (with documented confirmation of the absence of spermatozoa in the ejaculate after a 
performed vasectomy). 


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3. 
Intrauterine device or intrauterine system. 
4. 
Hormonal birth control method: oral, injectable hormonal contraceptives or implants. Women using 
hormonal birth control methods should apply a certain method for at least 4 weeks/1 menstrual cycle before 
initiating the treatment, and should continue using the same birth control method throughout the study and 
until the end of the follow-up period. 
5. 
Condom plus spermicide (foam/gel/film/cream/suppository). 
6. 
Occlusal cap (diaphragm, cervical or vaulted caps) plus spermicide (foam/gel/film/cream/suppository). 
7. 
Double barrier method: condom and occlusive cap (diaphragm, cervical or vaulted caps) plus 
spermicide (foam/gel/film/cream/suppository). 
 


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4 
PATIENT SELECTION AND DROP-OUT 
4.1 
Patient selection 
The study plans to randomize 90 male and female patients aged 18 through 65 years with chronic viral 
hepatitis B with delta-agent (ICD-10: B 18.0). Taking into account the possible drop-out during the 
randomization period, 123 patients are planned to be screened for the study. 
According to inclusion criteria only patents with positive results of HDV RNA (qualitative and quantitative), 
presence of HDV antibodies, with chronic hepatitis B (HBeAg positive or negative), ALT ≥ 1 ULN but < 10 
ULN and absence of co-infection of HCV and HIV should be included in the study. Antiviral therapy should 
be stopped at least in 6 months before the screening. Interferon therapy is allowed (should be stopped at least 
6 months before screening). 
 
4.2 
Inclusion Criteria 
To be included in the study, patients must meet all of the following inclusion criteria: 
1. 
Signed informed consent form. 
2. 
Male and female patients aged from 18 through 65 years. 
3. 
Patients with chronic hepatitis B (HBeAg positive or negative) and presence of HBsAg for at least 6 
months prior to screening. 
4. 
Positive results on anti-HDV antibodies for at least 6 months prior to screening. 
5. 
Positive result of HDV RNA during screening. 
6. 
ALT ≥ 1 ULN but < 10 ULN. 
7. 
Patient agrees to use adequate methods of contraception during the study from the time of signing the 
informed consent and until the follow-up period is completed. 
 
4.3 
Exclusion criteria 
Patients cannot be enrolled into the study if they meet any of the following criteria: 
1. 
Intolerance, hypersensitivity to the active ingredient and other components of Myrcludex B. 
2. 
Intolerance, hypersensitivity to alpha interferons, genetically engineered drugs obtained with  E.coli, 
to polyethylene glycol or other components of peginterferon alfa-2a 
3. 
A history of therapy with Myrcludex B. (Patients who were treated with interferon drugs are allowed 
to be included in the study 
4. 
Antiviral therapy to treat chronic viral hepatitis B with delta-agent during the previous 6 months. 
5. 
Anticancer therapy (including radiation therapy) or immunomodulatory therapy (including systemic 
glucocorticoids) during the previous 6 months. 
6. 
Results of laboratory tests performed at screening: 
a. Hemoglobin < 100 g/L 
b. Leucocytes <3000/μL 
c. Neutrophils <1500/μL 
d. Platelets <90 000/μL 
e. Serum creatinine >1.5 ULN 
7. 
Total bilirubin >34.2 μmol/L. Patients with a higher level of total bilirubin may be enrolled into the 
study after consultation with the Medical Monitor of the study, if it has been clearly established that such an 
increase is a manifestation of Gilbert's syndrome. 
8. 
Decompensated liver disease in the current or past medical history, including blood-clotting disorder, 
hyperbilirubinemia, hepatic encephalopathy, hypoalbuminemia, ascites and bleeding esophageal varices; В/С 
class or Child-Pugh-Score ≥6 
9. 
Co-infection with the hepatitis C or HIV. (Patients with presence of anti-HCV antibodies at screening 
but absence of HCV RNA are allowed to participate in the study) 
10. 
Hepatocellular carcinoma 
11. 
Signs of medication or alcohol-induced liver impairment or other medical conditions associated with 
chronic liver disease (for example, autoimmune hepatitis, hemochromatosis, thalassemia, alcoholic hepatitis, 
toxic hepatitis). 
12. 
Contraindications to liver biopsy. 
13. 
Concomitant oncological diseases (active or suspected cancer; risk of recurring oncological disease, 


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observed in the past medical history). 
14. 
Decompensated severe cardiovascular disorders, including those unstable and poorly controlled during 
the previous 6 months prior to screening. 
15. 
History of poorly controlled thyroid disease or clinically significant manifestations of thyroid 
dysfunction at screening. 
16. 
History or evidence at the screening of severe renal insufficiency or significant renal function 
disorders. 
17. 
History or evidence at screening of chronic pulmonary diseases with functional limitation. 
18. 
History or evidence at screening of severe retinopathy, severe ophthalmological disorders due to 
diabetes mellitus or idiopathic hypertension. 
19. 
History or evidence at screening of significant psychiatric disorders (e.g., severe depression, suicidal 
attempts, severe neurosis or cognitive disorders. 
20. 
Endocrine disorders (hypoglycemia, hyperglycemia, diabetes mellitus), which cannot be adequately 
corrected, in the past medical history or at screening. 
21. 
History of organ transplantation. 
22. 
Evidence of drug and/or alcohol abuse (80 g of alcohol/day for men and 40 g of alcohol/day for 
women) within 1 year prior to screening. 
23. 
History of immunologically mediated diseases (e.g., idiopathic thrombocytopenic purpura, lupus 
erythematosus, scleroderma, severe psoriasis, rheumatoid arthritis). 
24. 
The need for concomitant treatment with glucocorticoids, drugs with myelotoxic effect. 
25. 
Participation in another clinical study within 30 days before enrollment into this study. 
26. 
Pregnancy and lactation. 
27. 
Any other condition that, in the opinion of the investigator, makes the patient unsuitable for this study. 
 
4.4 
Enrollment of patients who are unable to give informed consent to participate in the study 
This study does not intend to enroll patients who are unable to give informed consent for their participation. 
 
4.5 
Exclusion criteria 
In accordance with the principles of the World Medical Association Declaration of Helsinki and other 
relevant regulations, a patient is entitled to withdraw from the study at any time and for any reason that 
should not in any way affect the quality of medical care provided to him in the future. 
In addition, patients may be withdrawn from the study/study treatment for the following reasons: 
• 
Development of intolerable adverse events 
• 
Changes in the patient’s health that, in the opinion of the investigator or sponsor, prevent the patient to 
continue his participation in the study or to continue the treatment under the study 
• 
Violation of the study protocol requirements 
• 
Inability to contact the patient 
• 
Pregnancy of the female patient participating in the study 
If a patient prematurely discontinues the treatment as per the clinical study protocol, and there is no reason 
preventing further monitoring of the patient's health, the investigator must notify the sponsoring company 
thereof as soon as possible. Upon the decision of the sponsoring company, the patient may be invited to visit 
the study center for scheduled visits, even if the treatment was discontinued prematurely, and provided that 
the patient has not withdrawn his/her consent to participate in the clinical study. 
If a patient discontinues the participation in the study prematurely, the investigator should notify the 
sponsoring company thereof within a short time. The date of the patient's discontinuation of the participation 
in the study and the reason for the patient's drop-out must be recorded in the patient's CRF, as well as in the 
patient's medical history. 
Patients prematurely withdrawn during the treatment period should complete procedures of Visit 13/Week 
48. 
Patients prematurely withdrawn during the follow-up period should complete the Follow-up visit 
procedure/week 72. 
The need to perform transient elastometry of liver (Fibroscan) and liver biopsy at the prematurely withdrawal 
visit should be discussed with the sponsoring company. 
There is no substitution for the patients withdrawn from the study. This is with the exception of patients who 


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underwent screening procedures and who meet the inclusion criteria, but who for some reason dropped out of 
the study before randomization and start of the study treatment. 
 
4.6 
Premature Termination of the Study 
The sponsoring company reserves the right to terminate the study at any time for medical and/or 
administrative reasons. The operating revision of new medical data and information on the treatment safety, 
performed together with the investigator is a standard practice. As a result of this revision, it may be decided 
to discontinue the study before all patients complete their participation. 
In case of premature termination of the study, regardless of the reason for this decision, the investigator 
should immediately notify all patients and provide them with appropriate follow-up and further treatment. 
The sponsoring company will notify the investigator, regulatory authorities and the Institutional Review 
Board/Independent Ethics Committee in writing of the termination of the study, specifying the reasons for 
the decision. 
In case of the premature termination of the study, the investigator should, if possible, conduct the procedures 
and examinations described in Section 4.5 to all the patients who have not completed their participation in 
the study by that time. 


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5 
TREATMENTS 
5.1 
General Information 
5.1.1 Drug Myrcludex B 
The study drug Myrcludex B is manufactured as sterile vials with lyophilized powder. The content of the vial 
is to be reconstituted in 1 mL water for injections 
Name: 
Myrcludex B (MXB) 
Chemical name: 
Myristoyl-Gly-Thr-Asn-Leu-Ser-Val-Pro-Asn-Pro-Leu-Gly-Phe-Phe-Pro-Asp-
His-Gln-Leu-Asp-Pro-Ala-Phe-Gly-Ala-Asn-Ser-Asn-Asn-Pro-Asp-Trp-Asp-
Phe-Asn-Pro-Asn-Lys-Asp-His-Trp-Pro-Glu-Ala-Asn-Lys-Val-Gly-NH2, 
salt 
of acetic acid (acetate) 
Dosage form: 
Lyophilized powder for solution for subcutaneous injection 
Formula: 
Active pharmaceutical ingredient: Myrcludex-B acetate, 
2.0 mg/vial, 5.0 mg/vial. 
Excipients: sodium carbonate, sodium hydrogen carbonate, mannitol, 
hydrochloric acid and sodium hydroxide are used as excipients for dissolution 
and lyophilization of the drug 
Description: 
White to off-white powder 
Appearance of the 
prepared solution: 
Transparent and clear 
Administration route: 
Subcutaneous 
Originator: 
Hepatera LLC, Russia 
Manufacturers: 
Baccinex SA, Rue de la Source 3, 2822 Kuru, Switzerland 
LYOcontract GmbH, Pulverwiese 1, 38871 Ilsenburg, Germany (5.0 mg/vial) 
 
5.1.2 Peginterferon alfa-2a (PEG-IFN alfa-2a) 
Brand name: 
Pegasys® 
Dosage form: 
Solution for subcutaneous injection 
Formula: 
Active pharmaceutical ingredient: peginterferon alfa-2a (40 kDa)-180 μg/0.5 
mL. 
Excipients: sodium chloride, benzyl alcohol, sodium acetate trihydrate, ice 
acetic acid, polysorbate 80, 10% sodium acetate, 10% acetic acid, water for 
injection. 
Description: 
Transparent clear to light yellow solution 
Administration route: 
Subcutaneous 
Marketing 
authorization 
holder: 
F. Hoffmann-La Roche Ltd., Switzerland 
5.1.3 Tenofovir  
Trademark: 
VIREAD® 
Pharmaceutical form: 
Film-coated tablets 
Ingredients: 
Active ingredient: Tenofovir disoproxil, 245 mg that is equivalent to 300 
mg of Tenofovir disoproxil fumarate. 
Excipients: 
Tablet core: pregelatinized starch, croscarmellose sodium, lactose 
monohydrate, microcrystalline cellulose, magnesium stearate; 
Coat: glycerol triacetate, indigo carmine aluminum lake, hypromellose, 
lactose monohydrate, titanium dioxide. 
 
Description: 
 
Almond shaped tablets coated with a light blue film coat, 16.8 mm*10.3 
mm, engraved with “GILEAD” and “4331” on one side, and “300” on the 
other side 


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Administration route: 
Per os 
Marketing authorization 
holder: 
Gilead Sciences International, Ireland 
 
5.2 
Packaging, labeling, storage conditions and drug accountability 
 
Packaging 
Drug Myrcludex B 
2R vials for injection, colorless glass, European Pharmacopoeia, hydrolytic class I, capped with rubber 
stopper, European Pharmacopoeia, type I (diameter 13 mm), and aluminum lid, diameter 13 mm, with a 
plastic disc. 
The vial is for single use. 
 
Peginterferon alfa-2a 
Presentation and packaging comply with the Instructions for medical use of the registered medicinal product 
Pegasys®. 
 
Tenofovir 
Presentation and packaging comply with the Instructions for medical use of the registered medicinal product 
Viread®. 
 
Labeling 
The drug labeling is performed in accordance with local regulatory requirements for the clinical studies of 
drugs. The label states "For clinical studies." 
 
Storage conditions 
The authorized employee or pharmacy technician of the study center should monitor the temperature regime 
of drug storage, and record the temperature in a special log. If any deviation from the prescribed temperature 
regime is detected, an authorized employee or pharmacy technician of the study center should immediately 
notify the clinical study monitor thereof. 
 
Drug Myrcludex B 
In the study center, the vials with the drug Myrcludex B should be stored in a dark place at minus 20 ± 
5°C. 
At the patient's home, the vials with the drug should be stored in the refrigerator, at 2-8°C. 
The authorized employee or pharmacy technician of the study center should instruct the patient in detail 
about the Myrcludex B transportation and storage conditions. The patient should immediately notify the site 
staff of any deviations in the drug storage conditions. 
Temporary storage of the drug at room temperature up to 25°C for not more than three days is allowed. 
The prepared drug solution remains stable for 2 hours at room temperature. 
 
Peginterferon alfa-2a 
The storage conditions must comply with the Instruction for medical use of the registered medicinal product. 
The authorized employee or pharmacist of the investigational site should instruct the patient in detail about 
the peginterferon alfa-2a transportation and storage conditions at home. The patient should immediately 
notify the site staff of any deviations in the drug storage conditions. 
Tenofovir 
The storage condition must comply with the Instruction for medicinal use of the registered medicinal 
product. 
The authorized employee or pharmacist of the Investigational site should instruct the patient in detail about 
the Tenofovir transportation and storage conditions at home. The patient should immediately notify the site 
staff of any deviations in the drug storage conditions. 


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Drug Accountability 
For the drug accountability, special forms for entering relevant information will be sent to the study center. 
After the completion of the study, the authorized employee of the study center must provide originals of 
completed forms for recording the receipt and return of the study drug/reference product/Tenofovir together 
with unused and used drug packages. 
The investigator is responsible for the drugs to be used for patients in this clinical study only; to be stored in 
a safe place, access to which is provided for the authorized site staff only; drug accountability is documented 
according to the established procedure. 
Requirements for self-injections performed by patients at home are described in Section 5.3.56, Tenofovir 
use in Section 5.3.7. 
 
5.3 
Administration route, dose, dosage regimen 
5.3.1 Myrcludex B 
The study drug Myrcludex B should be injected subcutaneously daily, once a day, every 24±1 hour (once 
daily for groups B- E) and 12±1 hour (twice a day for group F). Application rules: 
1. Patient should establish the consent time for daily injection of study drug in the first days of treatment 
and then should follow the estimated schedule of injection during all period of the study.  
2. For patients from group F: First injection should be performed from 6:00 a.m. till 11:59 a.m. (hh:min), 
the second injection – from 18:00 p.m. to 23:59 p.m. (hh:min). 
3. The interval between injections should be 24±1 hours for groups В-Е and 12±1 hours for group F. The 
exact time for the next injection should be calculated from the previous injection with possible deviation 
±1 hour. 
Actions in case of deviations from schedule of injection are described in Section 5.3.1.2. 
The duration of therapy is 48 weeks. Totally patient should receive 337-339 injections of Myrcludex B 
(groups В-Е) or 674-678 injections (group F) of Myrcludex B during the study, the last injection should be 
performed at the Investigation site on Visit 13 (End of treatment, EOT) / week 48 / Day 337+2). 


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Depending on the dose of the study drug, injections of Myrcludex B should be performed as 
follows: 
Myrcludex B dose 
Drug form,  
Necessary quantity of vials  
Volume of solution of study drug 
necessary for injection  
2 mg/per day 
2,0 mg/vial 
1 vial 
1 ml 
 
5 mg/per day 
5,0 mg/vial 
1 vial 
1 ml 
 
10 mg/per day 
(10 mg once daily) 
5,0 mg/vial 
2 vials 
2 ml 
Should be injected by two separate 
injection for 1 ml  
10 mg/per day 
(5 mg twice daily) 
Each injection: 
5,0 mg/vial 
1 vial 
Each injection: 
1 ml 
 
 
The contents of the vial (2.0 mg/vial, 5.0 mg/vial) should be dissolved in 1 mL of water for injection. The 
prepared drug solution remains stable for 2 hours at room temperature. 
Injection sites: outer surface of the shoulder, anterolateral surface of the thigh, anterolateral surface of the 
abdominal wall with well-developed subcutaneous fat. During the treatment period, the injection sites may 
be changed. 
Patients will make self-injections of Myrcludex B, except for the visits on the days of blood sampling for 
pharmacokinetic evaluation of Myrcludex B. The rules for preparing and performing self-injections are 
described below in Section 5.3.6. 
 
5.3.1.1 Doses, dosage regimen 
Patients randomized to arms B-F, will be treated with the study drug Myrcludex B at doses of 2 mg/day, 5 
mg/day or 10 mg/day: 
• 
Arm В (n=15): Myrcludex B 2 mg + PEG-IFN alfa-2a 180 μg during 48 weeks 
• 
Arm С (n=15): Myrcludex B 5 mg + PEG-IFN alfa-2a 180 μg during 48 weeks 
• 
Arm D (n=15): monotherapy with Myrcludex B 2 mg during 48 weeks 
• 
Arm E (n=15): Myrcludex B 10 mg (once a day) + PEG IFN alfa-2a 180 μg during 48 weeks 
• 
Arm F (n=15): Myrcludex B 10 mg (5 mg twice a day) and Tenofovir 300 mg during 48 weeks 
 
Sequence and localization of the subcutaneous injection sites on the days of co-prescribing of drugs 
Myrcludex B and peginterferon alfa-2a: injection(s) of Myrcludex B should be done at first and after that 
peginterferon alfa-2a. Subcutaneous injections of Myrcludex B and peginterferon alfa-2a should be 
performed in different anatomical regions. 
 
5.3.1.2 Measures to be taken when the dose of the study drug Myrcludex B is missed 
If the  injection is not performed at the scheduled time (i.e. after 25 hours [24+1] hours from the previous 
injection in Arms B-E  and 13 hours [12+1] hours from previous injection in arm F), but can be performed 
within 4 hours after the scheduled injection (i.e. not more than 28 hours [24+4] in Arms B-E and 16 hours 
[12+4] hours in Arm F), it is necessary to perform the injection and specify the exact time of drug injection 
in the appropriate section of the Patient Diary. Further treatment is not carried out from the time of this 
dosing with a deviation, but according to the previously planned administration schedule, i.e., relative to a 
previous time set up by the schedule. 
If the injection cannot be performed within 4 hours after the planned injection, the drug is not injected, the 
dose is missed. Further treatment is provided according to the previously planned and administration 
schedule, i.e., relative to previous time on schedule. No injection of the missed and planned dose is allowed! 
If injection was done incorrectly with interval more than 4 hours from previous one (i.e. the interval between 
the two injections was more than 28 hours in arms B-E and 16 hours in arm F), than further treatment should 
also be carried out according to previously planned administration schedule, i.e. relative to previous time set 


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up by the schedule. 
All cases of deviation from the schedule of injection should be reported in the Patient Diary and the patient's 
case report form. The patient should be instructed on measures in case of the missing the dose.  
 
5.3.1.3 Adjustment of the dose of Myrcludex B 
Dose adjustment can be performed only in arms C, E, F, which receive treatment with Myrcludex B at a dose 
of 5 mg or 10 mg. The dose correction in arms B and D receiving the drug at a dose of 2 mg is not 
performed. 
If a patient receiving Myrcludex B at a dose of 5 mg or 10 mg develops the study drug related adverse event, 
which is not resolved or stabilized during the subsequent follow-up to a state that, in the opinion of the 
investigator, is acceptable, then can be made a decision to reduce the dose of Myrcludex B up to one level 
(from 5 mg to 2 mg or from 10 mg to 5 mg) in accordance with the following provisions: 
1. 
The dose reduction of Myrcludex B is performed after receiving a written confirmation by the 
sponsoring company. 
2. 
 The treatment duration, the schedule of planned visits and the list of necessary examinations is not 
changed after the reducing of the dose and is performed in accordance with the flow chart presented in 
Table 1. 
3. 
If during the subsequent treatment period, the patient develops intolerable adverse events/toxic 
reactions, or the patient's health, in the opinion of the investigator or the sponsoring company, does not allow 
continuing the treatment with the study drug, the treatment should be discontinued. 
 
Grade 3 and 4 toxic reactions 
• 
If a clinically significant laboratory abnormality or a Grade 3 clinical event under CTCAE develops 
(refer to Section 7.4.1), the treatment with the study drug can be continued if this event was found not to be 
related to the study drug. 
• 
If a Grade 3 adverse event (clinical event or a clinically significant laboratory abnormality), considered 
to be related to the study drug, develops, the treatment should be discontinued until the toxic reaction is 
reduced to Grade 2 and below. 
• 
If, after the renewal of the treatment with the study drug, toxicity returns to Grade 3 and above and its 
aggravation is found to be associated with the study drug, the treatment with the study drug should be 
completely discontinued. Recurrence of adverse events considered not to be related to the study drug does 
not require the discontinuation of the treatment. 
• 
If a clinically significant laboratory abnormality or a Grade 4 clinical event under CTCAE, considered to 
be related to the study drug, develops, the treatment with the study drug should be completely discontinued. 
A Grade 4 clinically significant laboratory abnormality, not confirmed by repeated analyzes, should be 
adjusted in accordance with the algorithm for a new toxicity grade. 
• 
If a Grade 4 clinically insignificant laboratory abnormality is found (for example, increased triglyceride 
level when blood is sampled not under fasting condition or subject to medical correction) or Grade 4 clinical 
events, which are evaluated as not related to the study drug, treatment can be continued without interruption. 
 
5.3.2 Peginterferon alfa-2a (PEG-IFN alfa-2a) 
Peginterferon alfa-2a should be injected subcutaneously, in the area of the anterior abdominal wall or in the 
thigh area, once a week. The drug must be injected in different sites every time. The treatment lasts 48 
weeks. Totally, Patients should receive 48 injections of drug during the treatment (arms A-C, E). 
Preparation and performance of injections must comply with the requirements of the Instruction for medical 
use of the registered drug Pegasys®. 
Patients will make self-injections of peginterferon alfa-2a, except for the visits on the days of 
pharmacokinetic evaluation of Myrcludex B for patients in arms B and C (10 patients in each arm). Patients 
of arms B and C enrolled into the additional pharmacokinetic substudy should receive injections of 
peginterferon alfa-2a at the study center on Days 1 and 14. However, injections PEG-IFN alfa- 2a for other 
treatment arms may be performed in investigational site, if it is necessary.  
The rules for preparing and performing self-injections are described below in Section 5.3.6. 
 
 


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5.3.2.1 Doses and dosage regimen 
The drug peginterferon alfa-2a will be injected at a dose of 180 μg: 
• 
Arm A (n=15): PEG-IFN alfa-2a 180 µg during 48 weeks 
• 
Arm В (n=15): Myrcludex B 2 mg + PEG-IFN alfa-2a 180 μg during 48 weeks 
• 
Arm С (n=15): Myrcludex B 5 mg + PEG-IFN alfa-2a 180 μg during 48 weeks 
• 
Arm E(n=15): Myrcludex B 10 mg (once a day) + PEG-IFN alfa-2a 180 μg during 48 weeks 
 
Sequence and localization of the subcutaneous injection sites on the days of co-prescribing of drugs 
Myrcludex B and PEG-IFN alfa 2a: injection(s) of Myrcludex B should be done at first and after that 
peginterferon alfa-2a. Subcutaneous injections of Myrcludex B and peginterferon alfa-2a should be 
performed in different anatomical regions. 
 
5.3.2.2 Adjustment of the dose of peginterferon alfa-2a 
Dose adjustment instructions are provided according to the Instruction for medical use. 
 
General disorders 
If dose adjustment is required due to moderate and severe clinical or laboratory reactions, it is usually 
sufficient to reduce the dose of the drug to 135 μg. However, in some cases, it is necessary to reduce the dose 
to 90 μg or 45 μg. When adverse reactions are resolved, it may be possible to consider increasing the drug 
dose up to the initial dose (additional information is provided in the sections "Special instructions" and "Side 
effect" in the Instruction for medical use). 
 
Hematologic disorders 
Dose reduction is recommended when the neutrophil count decreases less than 750 cells/μL. Treatment of 
patients with an absolute neutrophil count of less than 500 cells/μL, should be discontinued until this value 
exceeds 1,000 cells/μL. The drug injection should be reinitiated at a dose of 90 μg under periodic control of 
the neutrophil count (the control period is determined by the doctor in each case individually). 
The dose reduction to 90 μg is recommended when the platelet count decreases less than 50,000 cells/μL. 
The drug should be discontinued in patients with a platelet count of less than 25,000 cells/μL. 
 
Neuropsychiatric disorders 
In accordance with the Instruction for medical use of Pegasys®, severe adverse reactions of the central 
nervous system (CNS) were observed in some patients, both during the drug treatment and within 6 months 
after the discontinuation of treatment. In particular: depression, suicidal trials, and attempted suicides. In the 
treatment with alpha interferons, there were other CNS side effects, including aggressive behavior, 
sometimes against other people (e.g., homicidal ideation), confused mental state, mental disorders. Patients 
should be closely monitored to identify signs and symptoms of mental disorders. If such symptoms develop, 
the patient should be carefully monitored, and a psychiatrist should be appointed if necessary. If symptoms 
of mental disorders persist or worsen, or if suicidal trials are identified, treatment with Pegasus® should be 
discontinued. 
 
Endocrine system disorders 
When alpha interferons, including Pegasys® were used, thyroid dysfunction or worsening of previous thyroid 
diseases were observed. If there are clinical symptoms of possible thyroid dysfunction and/or clinically 
significant abnormalities based on the results of the TSH and T4 tests performed during the study, a decision 
to adjust the dose and/or the duration of the drug treatment may be made. 
As with other interferon therapy, hypoglycemia, hyperglycemia, and diabetes mellitus were observed with 
the injection of Pegasys®. In the case of the development of such conditions, which cannot be adequately 
corrected, the drug treatment should be discontinued. 
 
Cardiovascular system 
If cardiovascular status worsens during the study, the drug treatment should be suspended or discontinued. 
 
Autoimmune diseases 


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Autoantibodies and autoimmune diseases are described to develop during treatment with alpha interferons. If 
necessary, treatment of patients with signs or symptoms similar to those of autoimmune diseases should be 
discontinued. 
There are reports of cases of Vogt-Koyanagi-Harada syndrome in patients with chronic hepatitis C treated 
with interferons. If the Vogt-Koyanagi-Harada syndrome is suspected, the drug treatment should be 
discontinued. 
Fever and infections 
Although fever may be associated with the flu-like syndrome often related to interferon therapy, other causes 
of persistent fever (severe bacterial, viral and fungal infections, in particular) should be excluded, especially 
in patients with neutropenia. When interferon alfa, including Pegasys®, were used, severe infections 
(bacterial, viral, fungal) were reported. When these conditions develop, the drug treatment should be 
discontinued. 
 
Ophthalmic changes 
As with other interferon treatment, when treated with Pegasys®, retinopathy was rarely noted, including 
retinal hemorrhage, cotton wool spots, swelling of the optic nerve, optic neuritis and thrombosis of retinal 
arteries and veins. If there are any complaints of the worsening of visual acuity or narrowing of the visual 
fields, an ophthalmological examination should be performed immediately. If an ophthalmic disease occurs 
or deteriorates, the treatment should be discontinued. 
 
Changes in the respiratory system 
As with other interferon treatment, when treated with Pegasys®, respiratory adverse reactions were observed, 
including shortness of breath, pulmonary infiltrates, pneumonia and pneumonitis. If there are persistent 
(persistent) infiltrates or infiltrates of unknown origin or if there is a respiratory failure, the treatment should 
be discontinued. 
 
Skin disorders 
The use of alpha interferons was associated with aggravation or induction of psoriasis and sarcoidosis. In 
case of the disease development or aggravation, the drug withdrawal should be considered. 
 
5.3.2.3 Rules for dose adjustment, delayed injection and dose delay 
If the acceptable safety profile of the treatment is preserved, no missed drug dose or delayed injection is 
allowed. These recommendations are stipulated by the risk of re-activation of resistant strains of the virus in 
presence of a decrease in the blood drug concentration, which may prevent the development of a stable 
treatment response. 
If, in the opinion of the physician investigator, the patient is required to skip the dose or delay the injection 
of the drug, these cases should be discussed with the study's sponsoring company. First of all, it is 
recommended to consider the possibility of dose adjustment (temporarily or permanently), and only then a 
dose will be skipped or delayed. 
The dose adjustment of peginterferon alfa-2a must be performed in accordance with the following rules: 
Initial dose 
180 µg 
1st level of dose reduction (75%) 
135 μg 
2nd level of dose reduction (50%) 
90 µg 
3rd level of dose reduction (25%) 
45 µg 
After the reduction, the dose may be adjusted upward to an acceptable level, subject to the following 
conditions: 
• 
The medical event that led to the dose correction has resolved or improved. 
• 
If the patient received 4 or more consecutive reduced drug doses or a total of 6 reduced doses, no 
upward adjustment should be made. 
If the delay of the planned dose is necessary, further treatment should be performed in accordance with the 
following recommendations: 
Dose delayed 1-2 days: 
 
The following doses are assigned according to the originally planned schedule of 
injection (e.g., if the drug is injected every Monday, due to the need for delayed 
injection, the next injection is performed on Wednesday, the next injection 


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should be performed on Monday, according to the schedule) 
Dose delayed 3-5 days: 
The following doses are assigned every 5 or 6 days before the renew of the initial 
schedule (e.g., if the drug is administered every Monday, the delayed injection is 
performed on Saturday, the following injections must be performed on Thursday, 
then on Tuesday, then on Monday [until the original schedule is renewed]) 
Dose delayed 6 days: 
The weekly dose is missed, the following doses are assigned according to the 
originally planned schedule of injection (e.g., if the drug is administered every 
Monday, the delayed injection is performed on Sunday, the nearest planned 
injection is missed [Monday], the next injection is performed next Monday) 
Dose delayed ≥7 days: 
The treatment is reinitiated at the required time, if necessary, injections can be 
performed at intervals of every 5 or 6 days, until the original schedule is 
renewed. 
If the patient has not received 4 or more sequential drug doses (for medical or any other reasons), further 
treatment with the peginterferon alfa-2a drug should be discussed with the study's sponsoring company. 
 
5.3.3 Tenofovir 
Tenofovir should be administered orally, once daily, 300 mg. Duration of the treatment is 72 weeks. 
Patients will take the drug on their own at home. Mode of application, rules of dosing regimen must comply 
with Instructions for medical use of the registered medicinal product Viread®. 
  
5.3.4 Dose adjustment of Myrcludex B and peginterferon alfa-2a with increased ALT and AST activity 
With a progressive or clinically significant increase in ALT activity, the dose of peginterferon alfa-2a should 
be reduced. The dose adjustment of Myrcludex B should be discussed with the sponsoring company. The 
patient's condition should be followed under careful medical supervision; additional examinations and visits 
to the study center may be prescribed, if necessary. 
If, despite the treatment correction, the ALT activity continues to increase or, if this increase is accompanied 
by an increase in the direct bilirubin concentration, the drug treatment should be discontinued. 
 
5.3.5 Missing one or more drug doses in connection with the development of adverse events 
If, in the opinion of the investigator, the patient needs to miss one or more doses of Myrcludex B and/or 
peginterferon alfa-2a and/or Tenofovir due to the development of adverse events, these cases should be 
discussed with the study's sponsoring company in an expedited fashion. 
If a patient randomized to a combination treatment arm requires the suspension/discontinuation of treatment 
with one of the drugs, these cases should be discussed with the study's sponsoring company in an expedited 
fashion. If the patient's health state allows to continue his/her participation in this clinical study, treatment 
will be continued as a monotherapy in accordance with the planned dosage regimen. 
 
5.3.6 Rules for preparation and performance of self-injections Myrcludex B + Peginterferon alfa 2a 
For the patient's self-injections at home, Myrcludex B and/or peginterferon alfa-2a will be handed over in an 
amount sufficient for the 28(+2)-day treatment, at visits 11 and 12 (weeks 32 and 40) in an amount sufficient 
for the 56(+2)-day treatment. Together with the package of the drug, the patient is provided with the required 
amount of sterile injection water, injection syringes and other related materials for the subcutaneous 
injections. 
Before the beginning of treatment, patients will receive a Patient Diary with Instructions on preparing and 
performing injections of Myrcludex B and/or peginterferon alfa-2a. Patients should personally record the 
injection of the drug on a daily basis, the date of receipt of drugs for continuing therapy and the number of 
packs received, complaints and any health status deviations during the study treatment period. Data on the 
treatment with Myrcludex B and/or peginterferon alfa-2a should be transferred from the Patient Diary to the 
appropriate form of the CRF. 
During each visit to the study center, the patient should demonstrate the filled Patient Diary, and return used 
and unused vials/packages of the drug (except for visits days 8 and 15, vials/packages these days are not 
returned). The physician investigator must record the following information in the Patient Diary: date of the 
diary review, name and the signature of the physician investigator, the number of vials/packs of the drug 
returned by the patient. Copies of the filled pages of the Patient Diary will be archived in the study center. 


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In advance, the investigator should train the patient how to perform self-injections at home, and document in 
the source documentation that following information has been provided to the patient: 
• 
the drug(s) storage conditions at the patient's home; 
• 
rules for the preparing and performing the drug(s) injections; 
• 
the patient's actions in the event of deviations from the treatment regimen; 
• 
rules for filling the Patient Diary in; 
• 
rules for storage and return of used and unused vials/packs of the drug(s) to the study center. 
If necessary, the patient can visit the study center for additional training and performing self-injections under 
the supervision of medical personnel at the beginning of treatment 


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5.3.7  Rules of Tenofovir self-taking  
For the patient’s self-taking of Tenofovir at home the drug will be issued in a quantity sufficient for 
treatment during 28(+2) days, on visits of weeks 32 and 40 - in a quantity sufficient to treatment during 
56(+2) days, on visit of the week 48 – in a quantity sufficient to treatment during 14(+2) days, on visit of the 
week 50 – in a quantity sufficient to treatment during 14(+3) days, on visits of the weeks 52 and 56 – in a 
quantity sufficient to treatment during 28(+3) days, on visit of the week 60 – 84(+3) days. On visit of the 
week 48 drug dispensing is permitted in a quantity sufficient to treatment during 28(+3) days, In that case 
there will be no drug dispensing on the week 50.  
Before the beginning of treatment, patients will receive a Patient Diary with Instructions of drug use. Patients 
should personally record the information about drug use on a daily basis, the date of receipt of the drug to 
continue treatment and the number of received packs, complaints and any health status deviations during the 
study treatment period. Data on the treatment with Tenofovir should be transferred from the patient diary to 
the appropriate form of the CRF. 
During each visit to the study center the patient should demonstrate the filled Patient Diary and return used 
vials/packages of the drug (except for visits days 8 and 15 on the week 50, vials/packages these days are not 
returned). The physician investigator should record the following information in the Patient Diary: date of 
the diary review, name and the signature of the physician investigator, the number of vials/packs of the drug 
returned by the patient. Copies of the filled pages of the Patient Diary will be archived in the study center. 
 
5.4 
Concomitant treatment 
Authorized concomitant treatment 
During the study period, the concomitant treatment is allowed to correct the patient condition due to the 
effect of Myrcludex B and/or peginterferon alfa-2a and/or Tenofovir. 
Prohibited concomitant treatment 
• 
Other study drugs 
• 
Other antiretroviral therapy (drugs intended for treatment of common cold are allowed) 
• 
Antineoplastic drugs 
• 
Myelotoxic drugs 
• 
Systemic glucocorticoids (except for substitution therapy), radiation therapy, other immunomodulatory 
treatment (drugs intended for treatment of common cold are allowed and Haematopoiesis -stimulating agents 
are allowed during interferon therapy only). 
In case of concomitant treatment with paracetamol, the daily dose should not exceed 4 g. 
During the clinical study, the patient consumption of alcohol should not exceed 20 g/day. 
For patients participating in the pharmacokinetic study (patients of arms B, C, F), the use of concomitant 
treatment during Days 1-15 is allowed only upon the decision of the investigator, provided there are no signs 
of the drug effect on the pharmacokinetics of the drug Myrcludex B. 


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6 
STUDY PROCEDURES 
6.1 
Collection of data on demographic and other baseline characteristics 
6.1.1 Demographic data 
The following demographic data will be recorded during the screening period: 
• 
Date of birth 
• 
Gender 
• 
Race 
• 
Data on bad health habits: smoking, drinking and drug use, drug abuse 
 
6.1.2 Medical history 
Detailed medical history data will be collected, including information on all present illnesses and all 
significant (in the opinion of the investigator) past diseases during the screening. 
Information on all the past and present pathologies at the time of the screening visit or those developed 
between the signing of the informed consent form and the start of treatment are recorded in the case report 
form in the section "Medical history". At least the following data must be registered in the CRFs: 
diagnosis/symptom, degree of severity of the disease according to CTCAE, start date, end date, information 
if the disease is resolved. If the patient has past or concomitant ophthalmic diseases, an ophthalmological 
examination may be required, as described in Section 6.3.2. 
The aggravation of the present illness or any untoward change in the patient's health after the administration 
of the first dose of the study drug/reference product considered by the investigator as clinically significant 
should be recorded as an adverse event. 
 
6.1.3 Collection of data on previous and concomitant treatment 
Information on the treatment of the underlying disease and other comorbidities, including drug and non-
medicinal methods of treatment (for previous 6 months), should be recorded in the case report form. Data on 
any concomitant treatment performed after the patient has been included in the study are also recorded in 
CRFs. 
Information on prohibited and permitted concomitant treatment is provided in Section 5.4. 
 
6.1.4 Measurement of the body height, weight 
During the screening period, the patient's body height (cm), weight (kg) and body mass index (BMI) will be 
measured. Repeated measurements of body weight will be performed during the study in accordance with the 
flow chart presented in Table 1. 
 
6.1.5 Urine pregnancy test 
The urine pregnancy test will be performed for women of childbearing potential during the screening and 
during the treatment period (Table 1). The analysis will be performed at the study center using test strips. 
 
6.1.6 Urine drug screening 
Urine drug screening will be performed during the screening period using test strips to analyze the urinary 
methadone, 
benzodiazepines, 
cocaine, 
amphetamines, marijuana, 
opiates, 
barbiturates, 
tricyclic 
antidepressants. 
 
6.1.7 Alcohol-breath test 
The alcohol-breath test will be performed during the screening period using an electronic device. 
 
6.1.8 Alpha-fetoprotein blood test 
To exclude hepatocellular carcinoma all patients will be tested for serum alpha-fetoprotein during the 
screening period. 
 
6.1.9 Serologic assay 
• 
Anti-HIV antibodies; 
• 
Anti-HCV antibodies; 


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• 
Anti-HDV antibodies; 
• 
Non-quantitative HBsAg analysis to assess the acceptability of the patient to participate in the study; 
• 
Non-quantitative HBeAg analysis; 
• 
Anti-HBsAG antibodies, 
• 
Anti-HBeAG antibodies. 
The above tests should be performed at the local laboratory of the study center, unless otherwise indicated. If 
any anti-HCV antibodies are found, an analysis on RNA HCV should be performed. If the results of HCV 
RNA analysis are negative, the patient can be enrolled into the study. 
 
6.2 
Efficacy evaluation 
The study will evaluate the virology parameters: HDV RNA, HBsAg and HBV DNA. Venous blood samples 
will be collected at specified time points. 
The following parameters will be evaluated: 
● 
HDV RNA by a quantitative PCR method; 
● 
HBsAg level by a quantitative EIA method 
● 
HBV DNA by a quantitative PCR method; 
● 
At the end-of-treatment and follow-up visits: anti-HBsAg antibodies, only in patients with 
undetectable quantitative HBsAg 
No separate sample will be collected for this analysis. At the end of the study, the determination of anti-
HBsAg antibodies will be performed at a central virology laboratory using appropriate archival samples (for 
HBsAg determination) in those patients for whom a negative result of the HBsAg quantification was 
obtained at Visits 48 and 72. 
The blood samples will be collected in sterile, hermetically sealed disposable plastic K2-EDTA Vacutainer® 
tubes. All collected samples of plasma are stored at -20°C before being sent to a central laboratory in a 
validated thermal container at a temperature -20° C ± 5°С. 
Both qualitative and quantitative HDV RNA blood test may be performed at screening. Plasma samples for 
HDV RNA analysis at the screening stage are stored until shipping at -20°C, then sent to the central 
laboratory at room temperature (transport at +2+8°C is also allowed). When samples are transported to the 
central laboratory on the day of blood sampling, the samples are not frozen. 
 
6.2.1 Fibroscan 
To assess fibrosis, transient elastometry of the liver (Fibroscan) will be performed during the screening 
period, at the end of treatment period (Week 48, End of treatment) and at the end of follow-up period (Week 
72, End of follow up). All study patients undergo the transient elastometry. Liver biopsy is not exclusive of 
transient elastometry. 
The procedure of the transient elastometry of liver can be performed directly at the study center, or, if it is 
impossible, in authorized medical institution, which have a proper equipment and qualification staff. 
 
6.2.2 Liver biopsy 
Liver biopsy will be performed during screening period, then for arms D and F – at the end of treatment 
(week 48, End of treatment), for all other arms – at the end of follow up period (week 72, End of follow up). 
The second biopsy can be performed within ±7 days after the end-of-treatment visit /follow up period. 
Repeated liver biopsy is necessary to determine the effect of treatment on the degree of fibrosis and 
necroinflammation, as well as the correlation of the possible negativation or decline of HDV RNA and 
cccDNA with viral load and HBsAg dynamics. Loss of cccDNA is the most important endpoint of 
HBV/HBV infection treatment.  
Liver tissue samples should be divided into 3 parts, one part is fixed in the Allprotect Tissue Reagent reagent 
(Qiagen) and frozen at -20°C, the second part is fixed to get paraffin sections, and the third is fixed in 
formalin solution for the production of histological slides. 
Detailed information on the liver biopsy procedure will be described in the laboratory manual. 
The biopsy procedure can be performed directly at the study center as part of the study, or, if it is impossible, 
in authorized medical institution, which have a proper equipment and qualification staff. 
 
6.2.3 Abdominal ultrasound 


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Abdominal ultrasound will be performed during the screening period, at the end of treatment period (Week 
48, End of treatment) and at the end of follow-up period (Week 72, End of follow up). The procedure will be 
performed locally, the evaluations should be performed by the same employee of the study center. 


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6.2.4 HBV and HDV genotyping, resistance assay and analysis of NTCP polymorphism 
HBV and HDV genotyping 
Blood sample will be taken to perform genotyping of hepatitis B viruses (HBV) and D (HDV) at a 
randomization visit on Day 1. Blood samples will be frozen and sent to the central laboratory. Detailed 
instructions for the collection, preparation and sending of blood samples will be provided in the Laboratory 
manual. 
 
Resistance assay 
One blood sample will be taken for a resistance assay at a randomization visit on Day 1, and another one will 
be taken at visit 13 (end of treatment visit) on Week 48 /  Day 337+2. Blood samples will be frozen and sent 
to the central laboratory. Detailed instructions for the collection, preparation and sending of blood samples 
will be provided in the Laboratory manual. Resistance assay on the Week 48 (or visit of premature drop-out) 
will be performed only in those patients who have a viral load following the result of virological study. 
 
NTCP polymorphism 
NTCP polymorphism will be evaluated once during the study (initially) in the central laboratory, using the 
sequencing method. Blood sample received by resistance assay on visit 1 in a Day 1 will be used for 
investigation. 
 
6.3 
Safety Evaluation 
The safety parameters under the evaluation include: 
• 
Adverse events, serious adverse events (for the detailed description refer to Section 7) 
• 
Physical examination 
• 
Ophthalmological examination 
• 
Vital signs 
• 
12-lead ECG. 
• 
Hematology 
• 
Blood chemistry 
• 
Coagulogram 
• 
Urinalysis 
• 
Total bile acids 
• 
Blood test for TSH, T4  
To identify the adverse events in this study, an evaluation of the patient health abnormalities will be made 
(based on physical examination findings, results of laboratory and instrumental study methods) from the data 
obtained during the Screening, from other Visits of the planned study and accepted reference values. 
After receiving the necessary information, the investigator will classify the patient's condition as "norm", 
"clinically insignificant deviations" or "clinically significant deviations". If the observed deviations were not 
previously recorded and, according to the investigator's assessment, are clinically significant, or the patient's 
condition will worsen compared to the data obtained during the Screening, the observed deviations will be 
classified as adverse events (AEs) and identified under the severity as per CTCAE. 
 
6.3.1 Physical examination 
A general physical examination will be performed during the screening, treatment and follow-up period 
according to the flow chart presented in Table 1. 
The following patient's organ systems will be evaluated during the physical examination: 
• 
General condition 
• 
Skin, hair and nails 
• 
Ears, nose and throat 
• 
Endocrine system 
• 
Cardiovascular system 
• 
Respiratory system 
• 
Gastrointestinal tract 
• 
Kidneys and urinary system 


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• 
Reproductive system 
• 
Musculoskeletal system 
• 
Nervous system 
• 
Visual system 
• 
Lymphatic system 
All new clinically significant abnormalities or results obtained at the screening, including clinically 
significant cases of deterioration in the physical examination findings, should be recorded as adverse events 
and monitored in a proper way. 
 
6.3.2 Ophthalmological examination 
In case of interferon treatment retinopathy was rarely noted, including retinal hemorrhage, cotton wool spots, 
swelling of the optic nerve, optic neuritis and thrombosis of retinal arteries and veins. In view of possible 
development of these adverse events, an ophthalmological examination of patients with mild and moderately 
retinopathy will be performed during the screening period in order to assess the baseline ocular changes. If 
necessary, an ophthalmological examination can be performed in patients with other concomitant visual 
organ disorders. During the study, an ophthalmological examination should be performed in patients with 
complaints of impaired visual acuity, narrowing of the visual fields or worsening of the symptoms of the 
concomitant ocular disease observed at the screening. 
 
6.3.3 Evaluation of vital signs 
A vital signs examination will be performed during the screening, treatment and follow-up period according 
to the flow chart presented in Table 1. 
The following vital signs will be measured in the sitting position after the patient is at rest for 5 minutes: 
• 
Systolic arterial pressure (in mm Hg) 
• 
Diastolic arterial pressure (in mm Hg) 
• 
Heart rate (in beats per minute) 
• 
Body temperature (in C) 
During the study, blood pressure measurement of each patient should be performed using the same 
measuring instrument, on the same arm. The heart rate is determined at the radial artery for 30 seconds, then 
the calculation of the number of beats per minute is performed. The body temperature is measured in the 
axillary (retromuscular) region. 
All new clinically significant abnormalities or results obtained at the screening should be recorded as adverse 
events and monitored in a proper way. 
 
6.3.4 Electrocardiography 
A standard 12-lead electrocardiographic study will be performed during the screening, treatment and follow-
up period according to the flow chart presented in Table 1. 
The tracking of the rhythm in corresponding leads should contain estimable data of at least three cardiac 
cycles. 
 
6.3.5 Hematology 
Hematology will be performed during the screening, treatment and follow-up period according to the flow 
chart presented in Table 1. 
Hematology will be performed in the central laboratory. 
Investigators must perform the evaluation of the clinical significance of all laboratory abnormalities. 
Clinically significant hematology abnormalities, found after the first injection of the study drug/reference 
product, should be recorded as adverse events. 
The following indicators will be evaluated: 
• 
Hematocrit 
• 
Hemoglobin 
• 
Red blood cells 
• 
Reticulocytes 
• 
Platelets 


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• 
Leucocytes 
• 
WBC differential (neutrophils, eosinophils, monocytes, basophils, lymphocytes) 
• 
Erythrocyte sedimentation rate (ESR) 
 
6.3.6 Blood chemistry 
Blood chemistry will be performed during the screening, treatment and follow-up period according to the 
flow chart presented in Table 1. 
During the screening, the blood chemistry will be performed in the central laboratory. 
Investigators must perform the evaluation of the clinical significance of all laboratory abnormalities. 
Clinically significant blood chemistry abnormalities, found after the first injection of the study 
drug/reference product, should be recorded as adverse events. 
The following indicators will be evaluated: 
• 
Total protein 
• 
Albumins 
• 
ALT 
• 
AST 
• 
GGT 
• 
LDH 
• 
p-amylase 
• 
Alkaline phosphatase 
• 
Lipase 
• 
Triglycerides 
• 
Total bilirubin 
• 
Direct bilirubin 
• 
Total cholesterol 
• 
Creatinine 
• 
Urea 
• 
Glucose 
• 
Potassium 
• 
Sodium 
• 
Calcium 
• 
Chlorides 
• 
Phosphates 
• 
C-reactive protein 
 
6.3.7 Coagulogram 
Coagulogram will be evaluated during the screening, treatment and follow-up period according to the flow 
chart presented in Table 1. 
During the screening, the coagulogram will be performed in the central laboratory. 
The following indicators will be evaluated: 
• 
Activated partial thromboplastin time [aPTT]: 
• 
Prothrombin time 
Investigators must perform the evaluation of the clinical significance of all laboratory abnormalities. 
Clinically significant abnormalities, found after the first injection of the study drug/reference product, should 
be recorded as adverse events. 
 
6.3.8 Urinalysis 
Urinalysis will be performed in the central laboratory. Sampling will be performed during the screening, 
treatment and follow-up period according to the flow chart presented in Table 1. 
Investigators must perform the evaluation of the clinical significance of all laboratory abnormalities. 
Clinically significant abnormalities, found after the first injection of the study drug/reference product, should 
be recorded as adverse events. 
The following indicators will be evaluated: 


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• 
рН 
• 
Specific gravity 
• 
Protein 
• 
Glucose 
• 
Bilirubin 
• 
Urobilinogen 
• 
Ketones 
• 
Red blood cells 
• 
White blood cells 
• 
Nitrites 
If any infection is suspected, the urine culture will be performed. If more than trace amounts of blood or 
protein are detected in the sample, a microscopic urine analysis for blood or protein will be performed. Urine 
culture and microscopy will be performed in the local laboratory of the study center using standard methods. 
 
6.3.9 Total bile acids 
A total bile acids test will be performed during the screening, treatment and follow-up period according to 
the flow chart presented in Table 1. Blood samples will be frozen and sent to the central laboratory for an 
analysis. Detailed instructions for the collection, preparation and sending of blood samples will be provided 
in the Laboratory manual. 
 
6.3.10  Blood test for TSH, T4  
When alpha interferons were used, thyroid dysfunction or worsening of previous thyroid diseases were 
observed. In view of possible development of these adverse events, this study will assess TSH and T4 levels 
at the screening and during the treatment according to the flow chart presented in Table 1. Blood samples 
will be sent to the central laboratory for analysis. Detailed instructions for the collection, preparation and 
sending of blood samples will be provided in the Laboratory manual. 
 
6.4 
Pharmacokinetics Evaluation 
6.4.1. Pharmacokinetic substudy (PK-substudy) 
An additional pharmacokinetic study (PK substudy) is planned to be performed as a part of the study, in 
which 20 patients randomized to each of treatment groups B and C (a total of 20 patients) will be enrolled. 
Blood samples for the assessment of the drug concentration will be collected at the following time points: 
Days 1-2, 14-15: 
• 
Day 1 – before the first injection  of Myrcludex B, in 00:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 
6:00, 8:00, 10:00, 12:00, 14:00 (hh:min) after the drug injection. 
• 
Day 2 – in 24:00 (hh:min) after the drug injection. 
• 
Day 14 – before injection  of Myrcludex B, in 00:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 
8:00, 10:00, 12:00, 14:00 (hh:min) after the drug injection. 
• 
Day 15 – in 24:00 (hh:min) after the drug injection. 
For patients in arms B and C participating in the pharmacokinetic study, there are no window periods for 
visits on Days 1 and 2, blood sampling for evaluation the pharmacokinetics of Myrcludex B must be 
performed before and after the first dose. Directly during the visits the following window periods for blood 
sampling to evaluate pharmacokinetics are allowed: 
• 
in 00:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00 (hh:min) after the injection of Myrcludex B – a 
window of ±5 minutes, 
• 
in 6:00, 8:00, 10:00, 12:00, 14:00, 24:00 (hh:min) after the injection of Myrcludex B – a window of 
±10 minutes. 
Patients participating into the pharmacokinetic substudy (PK-substudy) will be hospitalized (in day-stay or 
24-hour hospital) before the start of study treatment and will stay in the hospital during Days 1, 2, 14, 15. 
Other visits of pharmacokinetics (PK-main study) will be done outpatiently. 
Blood samples will be frozen and sent to the central laboratory for analysis by the means of the validated 
analytical method. Detailed instructions for the collection, preparation and sending of blood samples will be 
provided in the Laboratory manual. 


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6.4.2. Pharmacokinetic main study (PK-main study). 
For a more precise investigation of the possible study drug accumulation in all patients of each Myrcludex B 
treatment arm, blood sampling points for the pharmacokinetic study are assigned: week 4, 8, 12, 16, 20, 24, 
28, 32, 40, 48 (Week 48 only in arms E-F)  in 1hour ±15 min after the drug administration. For the patients 
not participating in the additional pharmacokinetic studies, a blood sampling point at a randomization visit 
on a Day 1 (in 1 hour ±15 min after the first drug injection) is assigned. 
6.4.3. Pharmacokinetic study in Arm F (the second part of the study). The first 10 patients randomized in 
Arm F will participate in the study. Blood samples for assessment of drug concentration will be collected on 
days 1, 2 and 14, 15 at the following time points: 
• 
Day 1 – before the first injection of Myrcludex B, in 00:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 
6:00, 8:00, 10:00, 12:00 (hh:min) after the drug injection. 
Blood sampling in 12 hours after the first injection must be performed before the second drug injection 
MXB. 
• 
Day 2 – in 12:00 (hh:min) after the second drug injection on Day 1. 
Blood sampling must be performed before the third drug injection MXB. 
• 
Day 14 – before injection of Myrcludex B, in 00:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 
8:00, 10:00, 12:00, (hh:min) after the drug injection. 
Blood sampling in 12 hours after the first injection must be performed before the next drug injection MXB 
on Day 14. 
• 
Day 15 – in 12:00 (hh:min) after the second drug injection on Day 14. 
Blood sampling must be performed before the first drug injection MXB on Day 15. 
For patients in Arm F participating in the pharmacokinetic study, there are no window periods for visits in 
days 1 and 2, blood sampling for evaluation the pharmacokinetics must be performed before and after the 
first dose of Myrcludex B. The second part of pharmacokinetic study may be performed with deviation +1 
day (i.e. Days 15-16 of the study). Directly during the visits the following window periods for blood 
sampling to evaluate pharmacokinetics are allowed: 
• 
in 00:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00 (hh:min) after the injection of Myrcludex B – a 
window of ±5 minutes, 
• 
in 6:00, 8:00, 10:00, 12:00, 14:00, 24:00 (hh:min) after the injection of Myrcludex B – a window of 
±10 minutes. 
Patients participating into the pharmacokinetic substudy (PK-substudy) will be hospitalized before the start 
of study treatment and will stay in the hospital during Days 1, 2, 14, 15. Other visits of pharmacokinetics 
(PK-main study) will be done outpatiently. 
Blood samples will be frozen and sent to the central laboratory for analysis by the means of the validated 
analytical method. Detailed instructions for the collection, preparation and sending of blood samples will be 
provided in the Laboratory manual. 
 
6.5 
Immunogenicity 
Assessment of immunogenicity will be performed in the groups of therapy with the studied drug Myrcludex 
B. Blood sampling for the detection of the antibodies to Myrcludex B will be determined during the 
treatment period (before the drug injection [Day 1], at 12, 24, 48 treatment weeks) and during the follow-up 
period (at 4, 12, 24 weeks after the end of treatment). 
Blood samples will be frozen and sent to the central laboratory. The evaluation will be performed by the 
method of radioimmunoassay. Detailed instructions for the collection, preparation and sending of blood 
samples will be provided in the Laboratory manual. 
 
6.6 
Patient Diary 
Before the treatment is started, the Patient Diary will be issued to all patients to collect the information about 
investigational drugs intake with Instructions on the preparation and administration of the study drug 
injections Myrcludex B and peginterferon alfa-2a.and Instructions about Tenofovir intake. A detailed 
description of the collection of therapeutic data is presented in Section 5.3.6, 5.3.7. 
 
6.7 
Justification of the selected study parameters 


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All selected parameters of the efficacy, safety, pharmacokinetics, immunogenicity, and genetic evaluation 
are standard, reliable, significant and generally accepted in clinical studies of drugs for the treatment of 
chronic viral hepatitis. 
The above studies are planned to determine the compliance of patients with the criteria for participating in 
the study and to assess the treatment safety, efficacy, and to obtain new data on the study drug Myrcludex B. 
Each of these analyzes will require 2 to 9 mL of blood. On average, approximately 720 mL of blood will be 
collected for an entire 19-month (1.5-year) study for such analyzes in patients of the peginterferon alfa-2a 
(Arm A) group, approximately 790 mL of blood - in patients with the Myrcludex B monotherapy and 
combination therapy, approximately 915 mL of blood - in patients in Arms B, C, F additionally participating 
in the pharmacokinetic substudy. 
In case of clinically significant laboratory abnormalities of grade 3 and 4 in accordance with the Common 
Terminology Criteria for Adverse Events of the National Cancer Institute, version 4.0, or in case of inability 
to analyze the sample collected (e.g., in case of hemolysis, damage during transportation, etc.), the additional 
blood volume will be required for repeated analyzes. 
If repeated blood tests or the treatment safety monitoring are necessary, additional visits can be performed. 
After an unscheduled visit, the next visit is performed according to the previously approved schedule as per 
protocol. 


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7 
ADVERSE EVENTS 
7.1 
Definitions 
Adverse event; AE: any untoward change in the patient's health status whom the drug was prescribed to, 
regardless of the causal relationship with its use. 
An adverse event can be any unfavorable and unintended change (including a laboratory abnormality), a 
symptom or a disease whose time of occurrence does not exclude a causal relationship with the use of the 
drug, regardless of the presence or absence of the relationship with the use of the drug. 
Adverse events, for example, can include: 
• 
New symptom/disease, 
• 
New diagnosis, 
• 
Clinically significant changed laboratory parameters, 
• 
Concomitant diseases and accidents, 
• 
Deterioration of medical conditions/diseases that existed before the beginning of the clinical study, 
• 
Recurrence of the disease, 
• 
Increased rate of occurrence and intensity of episodic worsening disease. 
The disease or symptom already existing in the patient will be considered as an AE only if their intensity, 
rate of occurrence or features have changed during the study. The principle investigator will register such 
changes as AEs. 
Surgical procedures as such are not considered as AEs; they are measures taken to treat diseases requiring an 
operative treatment. An AE can become such a condition, stipulating the necessity of an operative treatment. 
Planned hospitalization, surgery, or conditions that have led to the need for these measures are not AEs, if 
the condition that has led to the need for hospitalization/surgery has existed before the subject’s enrollment 
into the study. 
The planned/recommended surgical treatment and condition(s) that determine the use of operative measures 
are not considered as AEs if the cause of the operative treatment was identified prior to the enrollment into 
the study. 
All adverse events should be registered in the patient's case report form. 
Adverse drug action; ADR: any noxious and unintended responses to a medicinal product related to its use 
in any dose. The phrase "drug reaction" means that the causal relationship with the drug is evaluated as at 
least possible, i.e. the relationship is not ruled out. 
Unexpected adverse drug reaction: an adverse reaction, which nature, severity or outcome do not 
correspond to information in the current Instruction for medical use or in the Investigator Brochure for an 
unauthorized drug. 
Serious adverse event; SAE or serious adverse reaction; serious ADR: any untoward medical event that, 
regardless of the drug dose: 
• 
results in death, 
• 
is life-threatening, 
Note: the term "life-threatening" in the definition of "seriousness" means an immediate danger to the 
patient's life at the time the medical event develops. This category does not include adverse events that could 
hypothetically lead to the patient's death if their intensity was higher. 
• 
requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
results in persistent or significant disability/incapacity, 
• 
results in a congenital anomaly/birth defect in children whose parents received the drug. 
Hospitalization in the absence of a precipitating AE developed during treatment (i.e. not associated with the 
development of a new AE or the deterioration of a previous disease) may meet the criteria of "seriousness", 
but may not be an adverse event and, therefore, avoids the need to be immediately reported to the sponsor. 
Hospitalization for routine or elective treatment/operative treatment should not be registered as a SAE, 
provided that there are no complications or consequences that meet the above mentioned seriousness criteria. 
In addition, serious adverse events/reactions may include important medical events if, based on his/her 
medical experience, the investigator believes that without medical intervention, this event can lead to one of 
the outcomes described above. Examples of such medical events include intensive treatment of allergic 
bronchospasm in the intensive care unit or at home; pathological changes in the blood system, or convulsions 
that do not require hospitalization; development of drug dependence or abuse. 


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The terms "serious" and "severe" adverse events are not synonymous. The term "severe" is used to describe 
the intensity/severity of an adverse event (mild, moderate, severe), and the event may have a relatively minor 
medical significance (e.g., severe headache). This term is different from the evaluation of "seriousness", 
which is based on the outcome of an event or measures taken in connection with the development of events 
that are life-threatening or pose the risk of disability of the patient. The evaluation of seriousness (not 
severity) is the basis for determination of the need to be reported to the regulatory authorities. 
Suspected unexpected serious adverse reaction, SUSAR: unexpected serious adverse reaction, which 
relation to the drug is regarded as at least possible. 
Information on the development of SUSAR is subject to expedited reporting and should be sent to the 
Institutional Review Board/Independent Ethics Committee and the appropriate regulatory authority within 
the time limits established by local regulatory requirements. 
 
7.2 
Methods of adverse event detection 
Adverse events can be detected by a physician investigator (e.g., as based on the examination findings or 
laboratory test results), self-reported by the patient, or information thereon can be obtained during visits 
specified in the study protocol, during which the investigator will ask the patient "Have you ever had any 
health problems since your previous visit?"  
In addition, a field for the patient to enter information about any complaints and/or health abnormalities 
during the treatment period will be assigned in the Patient diary in the registration form for the performed 
planned injections and taking Tenofovir. 
 
7.3 
Other significant adverse events 
7.3.1 Local Reactions at the Myrcludex B Injection Site 
Local reactions at the Myrcludex B injection site belong to adverse event of special interest that will be 
actively monitored during the study. 
At each visit as per this study protocol, the doctor will evaluate the Myrcludex B injection site, all observed 
changes should be recorded in the CRF, and if the condition is regarded by the investigator as a clinically 
significant event, then it should be recorded as an adverse event. 
When registering data on AEs, the recommendations in Section 7.4.1 should be followed. 
 
7.4 
Registration of adverse events 
Adverse events are recorded in the original medical records and the relevant sections of the patient's case 
report form. 
During this study, adverse events will be recorded after the first dose of the study drug/reference product and 
until the end of the patient's participation in the study. Adverse or unexpected symptoms or illnesses 
identified between the signing of the informed consent and the administration of the first study drug dose 
should be recorded as a medical history. 
To identify the adverse events in this study, an evaluation of the patient health abnormalities will be made 
(based on physical examination findings, results of laboratory and instrumental study methods) from the data 
obtained during the Screening, at other Visits of the planned study and accepted reference values. Moreover, 
at the moment of inclusion into the study Investigator will ask the patient about complaints and symptoms. 
Then will ask about appearance of new complaints and symptoms during the study. Also information 
registered in Patient’s diary and spontaneous patient’s reports about appearance of new complaints and 
symptoms will be used. 
After receiving the necessary information, the physician investigator will classify the patient's condition as 
"norm", "clinically insignificant deviations" or "clinically significant deviations". If the observed deviations 
were not previously recorded and, according to the investigator's assessment, are clinically significant, or the 
patient's condition will worsen compared to the data obtained during the Screening, the observed deviations 
will be classified as adverse events (AEs) and identified under the severity as per CTCAE 
The following information should be specified during the registration of adverse events: 
• 
The nature of adverse event (it is preferably to indicate the diagnosis, not the list of symptoms); 
• 
Date of development and resolution of the manifestation (and time, if applicable); 
• 
Severity of the adverse event; 
• 
The relationship with the study drug/reference product/Tenofovir (in the opinion of the investigator); 


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• 
Measures taken in connection with the adverse event (not applied, the indication of concomitant 
treatment, etc.); 
• 
Measures taken with regard to ongoing treatment (permanent drug withdrawal, temporary drug 
withdrawal, dose reduction, etc.); 
• 
Correspondence of the adverse event to the criteria of a serious adverse event; 
• 
Outcome of the adverse event; 
• 
Additional information about the adverse event (if applicable). 
Information about drugs and other types of treatment, which is indicated in connection with the development 
of an adverse event, must be recorded in the original medical records and the relevant sections of the patient's 
case report form. 
 
7.4.1 Evaluation of the Severity of an Adverse Event 
The severity of AEs is evaluated in accordance with National Cancer Institute Common Terminology 
Criteria for Adverse Events, NCI CTCAE, version 4.0. 
Description of the severity of adverse events under CTCAE is listed on the official website of the National 
Cancer Institute: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
If the CTCAE does not provide a detailed description of the observed adverse event, its severity must be 
evaluated and recorded according to the description in the subsection "Other, specify". 
If the severity of the AE changes during its development, a maximum severity score should be recorded. 
 
Clinically significant laboratory abnormalities of the severity grade 3 and 4 under CTCAE should be 
confirmed by repeated analyzes within 3 calendar days from the moment the results have received (in the 
central laboratory). 
The severity of each AE is not synonymous with its seriousness. The definition of a serious adverse event 
(SAE) is given in Section 7.1. It should be also kept in mind even a SAE does not necessarily have a severe 
intensity. In contrast, a severe AE is not necessarily a serious one (e.g., a full-blown headache is a severe AE, 
but not a SAE). 
To assess the severity of local reactions at the drug injection site, and fever, the recommendations in Sections 
7.4.1.1-7.4.1.2 should be followed. 
7.4.1.1 Evaluation of the severity of local reactions at the drug injection site 
If local reactions occur at the injection site, AE registration and severity Evaluation should be performed 
according to the classification given in Table 3. 
 
Table 3 Evaluation of local reactions at the drug injection site 
Adverse event 
Mild (Grade 
I) 
Moderate 
(Grade II) 
Severe 
(Grade III) 
Extremely severe (life-
threatening) (Grade 
IV) 
Dermatitis at the drug 
injection site  
Reddening, 
itchy skin 
Diffuse 
maculopapular 
rash OR dry 
skin flaking  
Bubbles OR wet 
skin flaking OR 
ulceration  
ANY OF THE 
FOLLOWING: mucosal 
lesions, suspected 
Stevens-Johnson 
syndrome, erythema 
multiform, necrosis 
requiring an operative 
treatment, exfoliative 
dermatitis  
Reaction at the drug 
injection site 
 
Hyperemia 
Induration <10 
mm OR 
inflammation 
OR phlebitis  
Induration ≥10 
mm OR 
ulceration 
Skin necrosis 
 
 
7.4.1.2 Evaluation of the severity of fever 


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If an adverse even 'Fever' occurs, the following classification should be used to assess the AE severity: 
Mild (Grade I) 
Body temperature <38 ° C, a clinically significant change is observed compared 
with the patient's baseline at the time of enrollment. 
Moderate (Grade II) 
Body temperature is ≥ 38°C and < 40°C. 
Severe (Grade III) 
Body temperature is ≥ 40°C, accompanied by hypotension and/or other symptoms 
and signs that are clinically significant. 
 
7.4.2 Evaluation of the causal relationship of an adverse event with the study drug/reference 
product/Tenofovir 
To evaluate the causal relationship of AE with the study drug/reference drug/Tenofovir, all available 
information should be taken into account, which may help in the identifying of this relationship, in particular 
the mode of action of the drug, information on known adverse drug reactions according to the Investigator's 
Brochure/Instructions for medical use, AE characteristics, temporary relation of AEs and drug injection, the 
time of resolution of AEs and other possible causes of AEs that may include: 
• 
Intake of other drugs or exposure to chemicals; 
• 
Natural history of the underlying disease or other conditions; 
• 
Study procedures; 
• 
Impact of other factors. 
Based on the analysis of the information obtained, the investigator defines the causal relationship of the 
adverse event using the following categories: 
 
Definite 
Clinical manifestations of AEs, laboratory abnormalities occur during the period of 
the drug injection, cannot be explained by the presence of existing diseases and the 
influence of other factors; manifestations of AEs regress after withdrawal of the 
drug and develop again with the repeated drug injection. 
Likely 
Clinical manifestations of AEs, laboratory abnormalities are associated with the 
time of the drug injection, are unlikely to be related to concomitant diseases or other 
factors, regress after the drug withdrawal; the response to reassignment is unknown. 
Possible 
Clinical manifestations of AEs, laboratory abnormalities are related to the time of 
the drug injection, but they can be explained by the presence of concomitant 
diseases or by taking other medications and the influence of chemical compounds; 
information on the response to the drug withdrawal is unclear. 
Unlikely 
Clinical manifestations of AEs, laboratory abnormalities occur in the absence of a 
clear temporality with the drug; there are other factors (drugs, diseases, chemicals) 
that can be the cause of their occurrence. 
Non-estimable 
Clinical manifestations of AEs, laboratory abnormalities, attributed to AE, are 
difficult to be evaluated; additional data are needed for evaluation, or these data are 
currently being analyzed. 
There 
is 
no 
relationship 
An AE, in the investigator's opinion, is not related to the drug. 
 
7.4.3 Evaluation of the outcome of an adverse event 
The outcome of an adverse event should be recorded in the original medical records and the patient's case 
report form using the following categories: 
• 
Complete resolution 
• 
In the process of resolution 
• 
No resolution 
• 
Resolution with sequelae 
• 
Fatal outcome 
• 
Unknown 
 
7.5 
Monitoring the dynamics of an adverse event 
If an adverse event or its complications are not resolved, the investigator should conduct follow-up 
monitoring of the patient's condition. The follow-up is performed until the adverse event and its 


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consequences are resolved or stabilized to a state that, in the opinion of the investigator, is acceptable, or 
until the cause of the development of the adverse event not related to the use of the study drug/reference 
product/Tenofovir is identified. 
 
7.6 
Investigator's liability to report a serious adverse event 
The investigator must immediately report the occurrence of a serious adverse event the sponsoring company 
and/or the authorized organization within 24 hours from the date of its detection (or receipt of information on 
the detection). The information is provided in the form of a SAE report. 
The information on SAEs should also be recorded in the source documentation and should coincide with the 
data given in the sections "Adverse event", "Concomitant treatment", "Laboratory test results" of the CRF. 
Before sending the SAE form, the sponsor’s monitor should be informed about that by phone. 
 
If a serious adverse event is detected, it is necessary to 
send the completed SAE report form 
by fax and/or e-mail within 24 hours: 
Sponsor company 
Fax: +7 (495) 726-52-53 
E-mail: pharmacovigilance@ammaxwell.ru  
Authorized organization 
E-mail: safety@smothdd.com 
 
7.7 
The sponsor's liability to provide safety information during the clinical study 
Reporting of suspected unexpected serious adverse reactions (SUSARs) 
The Pharmacovigilance Officer will send expedited reports on suspected unexpected serious adverse 
reactions (SUSARs) to the Institutional Review Board/ Independent Ethics Committee and the appropriate 
regulatory authorities within the time limits established by local regulatory requirements. The requirements 
for reporting of suspected unexpected serious adverse reactions are applied to both the study drug and the 
reference product and Tenofovir. 
The submission of other reports on the treatment safety. 
The Pharmacovigilance Officer will send other safety information that can change the benefit/risk ratio of the 
study drug/reference product/Tenofovir, or serve as a basis for changes in the recommendations for their 
prescription, as well as the basis for reviewing the possibility of further study, to the Institutional Review 
Board/ Independent Ethics Committee and the appropriate regulatory authority. 
In addition to the expedited reporting, throughout the study, the sponsoring company will prepare annual 
reports on the treatment safety, containing all new information obtained during the reporting period. Such 
reports will be sent to the Institutional Review Board/ Independent Ethics Committee and the appropriate 
regulatory authority within the time limits established by local regulatory requirements. 
 
7.8 
Pregnancy 
Pregnancy is not an adverse event as such, except cases when there are reasons to believe that the study 
drug/reference product/Tenofovir led to a decrease in the effectiveness of contraceptives. Congenital 
abnormalities and developmental disorders in patient children are classified as serious adverse events. 
Planned medical abortions, as well as other serious complications of pregnancy (including spontaneous 
abortion) are classified as serious adverse events. Planned artificial abortions in the absence of complications 
are not considered as adverse events. 
All cases of pregnancy identified during the clinical study (including pregnancy of female partners of male 
patients enrolled into the study) should be duly recorded. 
When the pregnancy is confirmed, the investigator must notify the contract research organization/sponsoring 
company thereof in the form of a pregnancy report. Then, information on the pregnancy should be provided. 
Pregnancy in female patients and female partners of male patients is subject to registration, from the first day 
of administration of the study drug/reference product to the completion of the final procedures of the study. 
Each pregnancy outcome (spontaneous abortion, elective abortion, the birth of a healthy child or child with 
congenital anomalies or malformations) should also be recorded. 


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8 
STATISTICAL CONSIDERATIONS 
8.1 
General Information 
The statistical analysis will be carried out under supervision of the responsible biostatistician in accordance 
with the requirements of the ICH GCP and other applicable guidelines and regulatory documents. 
Before the statistical analysis is carried out, data from different centers will be combined into a common data 
set. 
Statistical analysis will be described in the Statistical Analysis Plan in details, which will be finalized before 
the study database lock. All deviations from the Statistical Analysis Plan will be presented in depth in the 
clinical study report. 
Statistical analysis is scheduled to be carried out using IBM SPSS Statistics software (IBM Corporation, 
Armonk, New York, USA), SAS software (Statistical Analysis Software, SAS Institute Inc. Cary, NC, 
USA), or another commercial product with validated algorithms for statistical method implementation and 
with relevant documentation. Calculation of pharmacokinetic parameters will be done in the WinNonlin 
software package or using other applicable software.  
 
8.2 
Populations for the study data analysis 
The following populations will be used for statistical analyses: 
• 
Safety set: all patients who received at least one dose of the study drug/reference product/Tenofovir. 
• 
Full analysis set (FAS): All randomized patients of the Safety set. 
• 
Per protocol set: all FAS patients who completed the study without significant protocol deviations and 
for those who have data about primary efficacy endpoint. 
Significant protocol deviations include, but are not limited to: 
− 
Inclusion of a patient with a violation of inclusion/exclusion criteria, which may affect the treatment 
efficacy 
− 
Administration of concomitant treatment prohibited by this study protocol 
− 
Other deviations from protocol, which will be regarded as significant from point of view of primary 
efficacy endpoint by the decision of Data review meeting 
 
• 
Pharmacokinetic set (PK set): all patients, who had the study drug Myrcludex B injected at least once, 
and for whom data on the blood drug concentration were obtained. 
 
8.3 
Demographic and Baseline Characteristics 
The descriptive statistics will be used to describe demographic and baseline parameters and characteristics 
for the analysis of general population and treatment groups. The arithmetic mean, a 95% confidence interval 
for the mean, standard deviation, medians and quartiles will be calculated for quantitative variables. The 
frequencies of the values, percentages, and 95% confidence intervals for the frequencies under the Clopper-
Pearson method will be calculated for dichotomous variables. 
 
8.4 
Prior and Concomitant Therapy 
Drugs of prior and concomitant treatment will be coded using the WHO Drug dictionary (the latest version at 
the time of the study database lock). The results will be presented for the Safety Set in the form of tables per 
treatment group and the entire population, as well as in the form of listings. 
 
8.5 
Efficacy Analysis 
Efficacy Analysis will be performed for the Full analysis set. Additionally, the efficacy analysis will be 
performed for the per protocol set. 
Primary efficacy endpoint: 
• 
Proportion of patients with a negative PCR finding on HDV RNA (undetectable level of HDV RNA) 
at week 72 (end of the follow up period) 
The frequencies and proportions of participants with HDV RNA response will be presented. The Fisher's 
exact test will be used to compare groups. 
Secondary efficacy endpoints: 
• 
Proportion of patients with a negative PCR finding on HDV RNA (undetectable level of HDV RNA) 


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at weeks 24 and 48 
• 
Proportion of patients with an HDV RNA response (decrease ≥ 2 log10 HDV RNA or an undetectable 
level of HDV RNA) at weeks 24, 48 and 72 
• 
Proportion of patients with ALT normalization in weeks 24, 48 and 72 
• 
Proportion of patients with combined treatment response (negative PCR result of HDV RNA and ALT 
normalization) at weeks 24, 48 and 72 
• 
The proportion of patients with a combined response to therapy ((decrease ≥ 2 log10 HDV RNA or an 
undetectable level of HDV RNA) and normalization of ALT) at weeks 24, 48 and 72 
• 
Proportion of patients with HBsAg response (HBsAg negativation or >1 log10 IU/mL decline) at 
weeks 24, 48 and 72 
• 
Proportion of patients with the HBsAg negativation with the appearance of anti-HBsAg antibodies and 
without it at weeks 48 and 72 
• 
Proportion of patients with a negative PCR result of HBV DNA at weeks 24, 48 and 72 
• 
The intensity of liver fibrosis based on results of transient elastometry at weeks 48 and 72  
• 
Changes in the results of liver biopsy before and after the treatment. 
As part of the study of efficacy, HBV, HDV genotyping, resistance assay and NTCP polymorphism will be 
performed additionally. 
Secondary efficacy endpoints will be analyzed similarly to the primary endpoint if it is applicable. For the 
HBV, HDV genotyping findings, the incidence of the HBV and HDV genotypes is given for the Safety set. 
All data on the efficacy endpoints will be listed in the form of listings. 
 
8.6 
Safety Analysis 
The safety data will be analyzed descriptively in the Safety Set: 
All AEs will be classified using the latest version of the MedDRA dictionary. The analysis will include 
counting the number of AEs and SAEs, the number (proportion) of study subjects with registered AEs and 
SAEs, the number (proportion) of patients with AEs related to the study drug/reference product/Tenofovir, 
the number (proportion) of patients with AEs that required the discontinuation of treatment and the 
premature drop-out of the study. 
Data on AEs will be presented in the tables indicating the system-organ class (SOC) and the preferred term 
(PT) for all treatment groups and the whole population. 
The physical examination findings will be shown in the tables per treatment group with frequency values for 
each organ and system groups by time points of assessment. 
The ophthalmological examination findings will be shown in the listing. 
The analysis results of other safety indicators (vital sings, ECG, hematology, blood chemistry, urine analysis, 
coagulogram, urinalysis, total blood bile acids test, TSH and T4 blood test) will be presented in the tables 
using methods of descriptive statistics (meanings by assessment visits  and changes compared with base 
meanings if it’s applicable. Results on conformity to normal values will also be presented. 
All safety data will additionally be presented in the form of listings. 
 
 
8.7 
Analysis of pharmacokinetic parameters 
The pharmacokinetic analysis will be performed in the PK set (Arms B, C, F). The following indicators will 
be evaluated by the method of non-compartmental analysis: 
• 
Cmax – maximum concentration 
• 
Тmax – time of maximum concentration 
• 
Kel – elimination rate constant 
• 
T1/2 – elimination half-life 
• 
CL/F – total clearance 
• 
AUC0-t – area under the curve "drug concentration-time" from time 0 to the sampling time (t) of the 
last sample 
• 
AUC0-∞ – area under the curve "drug concentration-time" from time 0 to infinity 
The pharmacokinetic analysis results will be presented in the form of tables with descriptive statistics per a 
treatment group. The analysis results and the initial concentrations will also be presented in the form of 
listings. 


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8.8 
Immunogenicity analysis 
Evaluation of immunogenicity will be performed in the treatment groups taking the study drug Myrcludex B. 
These immunogenicity estimates will be analyzed in the Safety Set. The results will be presented in the 
tables using descriptive statistics methods per a treatment group and for the whole population. Values for 
each patient will be presented in the form of listings. 
 
8.9 
Sample size justification 
This clinical study is an exploratory, controlled, parallel-arm study with a control arm, five test arms 
performed to demonstrate differences in the monotherapy of investigational drug, the combination of the 
study drug with standard treatment and the combination investigational drug with Tenofovir versus the 
standard treatment. The study results will be used to select the optimal treatment regimen with Myrcludex B 
in the next phase. 
The primary endpoint (negative result of PCR on HDV RNA at week 72) was used to justify the minimum 
size of treatment arms. 
The calculation of the sample size was carried out according to the method described in the book by Chow 
Sh.-Ch., Sample Size Calculations in Clinical Research [Chow Sh.-Ch., Shao J., Wang H., 2008], by means 
of the TrialSize package for the R programming language. The results of the previous MYR 201 substudy, 
data at the 24 treatment week were used: in Group of peginterferon therapy peginterferon alfa-2a 180 μg for 
48 weeks, the proportion of participants with negative PCR result of HDV RNA was 29% (2 of 7 
participants), in arm of combined therapy Myrcludex B 2 mg + peginterferon alfa-2a 180 μg for 24 weeks, 
followed by peginterferon alfa-2a 180 μg for 24 weeks, the proportion of participants with a negative PCR 
result of HDV RNA was 71% (5 of 7 participants). It is expected that five clinical study groups will 
demonstrate efficacy comparable to combined therapy results in MYR 201 substudy. Under such 
assumptions and a given critical value of the significance level of 0.10, the group size n = 15 will make it 
possible to reach the power of a study more than 60%.  
Considering the exploratory nature of the study, the calculated number of arms can be considered sufficient 
to obtain conclusions about the optimal dosing schedule to be used in clinical studies of the following 
phases. 
 
8.10 Interim analysis 
The interim analysis will be performed when efficacy and safety data are available after the end of follow up 
period of participants in the first phase of the clinical study (Arms A-D).  
Considering the fact that the study is exploratory, there is no provision for adjusting the level of significance 
due to intermediate analysis. Premature termination of the study by results of intermediate analysis is not 
planned. 
 
8.11 Procedures for Accounting Missing Data and Data Queries 
For the statistical safety analysis, the replacement of missing data is not planned. The missing data on the 
primary efficacy criterion will be considered as a treatment non-response. 
 
Recovery missed meanings in analysis of efficacy and pharmacokinetics algorithm is described in details in 
the statistical analysis plan. 


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9 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION 
Source documentation is the original documents, data and records (for example, medical histories, laboratory 
reports, medical records, records of automatic devices, etc.). All information contained in the original 
medical records and their certified copies, describing the results of clinical observations, surveys and other 
activities, allowing to recreate the course of clinical study, is considered as the source data. 
If there is an electronic system of source documentation or laboratory data registration, all relevant data will 
be transferred to the study database or entered into the study database in electronic form directly from the 
source documents. If there is no source documentation, the data will be entered directly into the electronic 
CRF. 
The investigator undertakes to provide direct access to the patient records and source documentation for 
monitoring, auditing or inspections conducted by the sponsor, the sponsor's authorized representatives, or 
control and permission authorities. 


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10 
QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Qualification of the investigator 
The investigator must have the education, occupational training and experience that let him/her claim 
responsibility for the proper conduct of a clinical study. The qualification of the investigator must meet the 
regulatory requirements and be confirmed by his/her curriculum vitae and/or other documents. 
The investigator should know in detail how to use the study drug in accordance with the protocol, the current 
version of the Investigator's Brochure, product information and other sources provided by the sponsoring 
company. 
The investigator should maintain a list of persons with the necessary qualifications who carry out certain 
activities in the study on his/her behalf. 
 
10.2 Study Monitoring 
The monitoring will be carried out by a clinical study specialist (monitor), who will monitor the activities of 
the study from the beginning to the end in accordance with the organization's standard operating procedures 
(SOPs), GCP and relevant regulatory documents. 
The monitoring plan will be described in the Guidance on monitoring in detail. The monitor will monitor the 
study, the filling of the CRFs and the source documentation in, record maintenance and proper accountability 
of the study drugs. For these purposes, the monitor will visit study centers at appropriate time intervals, as 
well as maintain constant communication, oral and written, with the center staff. It is extremely important 
that the monitor is given access to all documents (related to the study and its individual study subjects) at any 
time and immediately upon request. In turn, the monitor will comply with all confidentiality preservation 
requirements, as described in the informed consent form. The principal investigator and his/her team 
members are expected to cooperate with the monitor, to be present for some time during the monitoring visits 
to answer questions and provide missing information. 
 
10.3 Inspection and Audit 
Regulatory authorities, Institutional Review Board/ Independent Ethics Committee and organizations 
authorized by the study's sponsoring company can conduct inspections and audits. The audit objective is to 
perform a comprehensive and independent review of the activities and documentation related to the study 
performed to verify the compliance of these activities, as well as the procedures for collecting, analyzing and 
reporting the data to the protocol, standard operating procedures, good clinical practice and regulatory 
requirements. The principal investigator and authorized study center staff should provide direct access to the 
source documentation, CRFs and other study documents. 
If representatives of control and permission authorities apply to the center with the issue of performance of 
an inspection, investigators should immediately inform Hepatera LLC and the clinical study monitor. 


Hepatera LLC 
PROTOCOL No. MYR 203 
Final version 7.0  
dd. September 24, 2019 
Translation into English,  
dd. October 10, 2019 
 
 
CONFIDENTIAL 
Page 83 of 88 
 
 
11 
ETHICS 
11.1 Declaration of Helsinki 
The investigator will ensure that the study is performed in full compliance with the ethical principles 
described in the current version of the World Medical Association Declaration of Helsinki. 
 
11.2 Good Clinical Practice 
This study will be conducted in accordance with all the requirements of this protocol, the standard operating 
procedures of the sponsoring company and/or the contract research organization, in accordance with 
applicable regulatory requirements and the International Conference on Harmonization Good Clinical 
Practice Guidelines (ICH GCP). 
 
11.3 Study Approval 
Prior to the start of the study, the clinical study protocol, the patient information sheet and the informed 
consent form and other applicable study documents will be submitted for examination to the regulatory 
authority and the Institutional Review Board/ Independent Ethics Committee. The study is possible only after 
a written approval from the authorized regulatory authority and the Institutional Review Board/ Independent 
Ethics Committee has been obtained. 
Changes to the clinical study protocol will be documented in the form of a protocol amendment, and can be 
implemented only after the protocol amendment is considered and approved by the authorized regulatory 
authority and the Institutional Review Board/ Independent Ethics Committee. The procedures for amending 
the clinical study protocol should be in accordance with the applicable regulatory and ethical committee 
requirements. 
 
11.4 Procedure for obtaining the written informed consent 
It is the responsibility of the investigator to obtain the patient's written informed consent before any 
procedures as a part of the study. Before signing, the patient should be informed about the objectives, 
methods, expected benefits and potential risks of the study. The patient should be given one original of the 
patient information sheet and the informed consent form in his/her native language. The second original of 
the signed and dated informed consent form must necessarily be kept in the investigator file. 
Patients will be informed of any new information that may affect their consent to participate in the study. 
The presentation of this information should also be documented in an appropriate manner. 
 
11.5 Confidentiality 
All documents and information, relating to the study, provided to the investigator by the sponsoring company 
are strictly confidential. The investigator and his/her staff undertake to use this information only in this 
study. 
The investigator undertakes to ensure the security of the personal data of patients participating in the study in 
accordance with applicable local regulatory requirements. The necessary personal data of the study subjects 
(e.g., socio-demographic parameters) will be collected solely for the achievement of the study objectives and 
in the minimum amount. The CRF will not record the names, addresses, medical record/out-patient medical 
record numbers. 
No disclosure of information identifying the patient participating in the clinical study is allowed. To protect 
personal data, each patient will be assigned a unique patient number (identification code). If a patient name 
and surname are mentioned in any document, then before submitting a copy of such a document to the 
sponsoring company, that name should be erased. 
Before being enrolled into the study, the patients will be familiarized with the confidentiality policy and the 
use of their personal data, including the need for access to them by the monitor and other authorized persons 
(in case of auditing, inspection, etc.). 


Hepatera LLC 
PROTOCOL No. MYR 203 
Final version 7.0  
dd. September 24, 2019 
Translation into English,  
dd. October 10, 2019 
 
 
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Page 84 of 88 
 
 
12 
DATA HANDLING AND RECORD KEEPING 
12.1 Records Retention 
The Investigator agrees to retain all study records, including original medical records of patients (e.g., 
laboratory test results and instrumental examination findings, out-patient medical records, medical history) in 
accordance with the ICH GCP provisions and the regulatory requirements of the country where the study has 
been performed. These study records should be available for inspection/audit by the study sponsor and/or 
regulatory authorities. 
The destruction of the study records is possible with the written permission of the sponsoring company. 
The main documents that allow to evaluate the study and the quality of the data obtained should be archived 
in such a way as to ensure their integrity and complete safety during the retention period, as well as 
availability upon request of representatives of competent authorities. 
 
12.2 Data Collection 
All data obtained during the study will be recorded in the electronic CRF (eCRF). The investigator is 
responsible for ensuring that all sections of the CRF are correctly filled in and that the data is available for 
verification. 
The validity of data in the CRF will be confirmed by the investigator's dated electronic signature and 
controlled by a data monitoring specialist. 


Hepatera LLC 
PROTOCOL No. MYR 203 
Final version 7.0  
dd. September 24, 2019 
Translation into English,  
dd. October 10, 2019 
 
 
CONFIDENTIAL 
Page 85 of 88 
 
 
13 
SPONSORSHIP AND INSURANCE 
13.1 Sponsorship 
The study is sponsored by the sponsoring company Hepatera LLC. The detailed financial aspects of the study 
are presented in contractual agreement between the sponsoring company, the contract research organization 
and the study centers. 
 
13.2 Insurance 
The life and health of patients participating in this clinical study will be insured in accordance with local 
regulatory requirements. In the Russian Federation, the insurance is performed in accordance with the Decree 
of the Government of the Russian Federation No.714 dd. September 13, 2010 “On establishing standard 
rules for compulsory insurance of the life and health of patients involved in clinical trials of medicinal 
products”. The investigator will provide the patient with information on the terms and conditions of the 
policy of insurance, inform that the use of other treatment types and concomitant medications during the 
study (except for emergency cases) is allowed only with the consent of the investigator. 


Hepatera LLC 
PROTOCOL No. MYR 203 
Final version 7.0  
dd. September 24, 2019 
Translation into English,  
dd. October 10, 2019 
 
 
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14 
PUBLICATION OF THE CLINICAL STUDY RESULTS 
The sponsoring company (Hepatera LLC, Russia) has exclusive rights to the study results. The investigators 
have the right to publish the study results only with the consent of the study's sponsoring company. Prior to 
submission for publication, the investigator is required to submit a copy of the planned publication to the 
representative of Hepatera LLC. All information obtained during the study shall be considered confidential. 


Hepatera LLC 
PROTOCOL No. MYR 203 
Final version 7.0  
dd. September 24, 2019 
Translation into English,  
dd. October 10, 2019 
 
 
CONFIDENTIAL 
Page 87 of 88 
 
15 
REFERENCE LIST 
1. Abbas Z, Ma K, Salih M, Jafri W. Interferon alpha for chronic hepatitis D (Review ). 2011;(12). 
2. Buti, M., Homs, M., Rodriguez-Frias, F., Funalleras, G., Jardí, R., Sauleda, S., … Esteban, R. (2011). 
Clinical outcome of acute and chronic hepatitis delta over time: A long-term follow-up study. Journal of 
Viral Hepatitis, 18, 434–442. doi:10.1111/j.1365-2893.2010.01324.x 
3. Cole S., Gowans E., M. T. (1991). Direct evidence foe cytotoxicity accociated with expression of hepatitis 
delta virua antigen. Hepatology, 13(5), 845–51. 
4. Cornberg, M., Protzer, U., Dollinger, M. M., Petersen, J., Wedemeyer, H., Berg, T., … Manns, M. P. 
(2007). [Prophylaxis, Diagnosis and Therapy of Hepatitis-B-Virus-(HBV-) Infection: upgrade of the 
guideline, AWMF-Register 021/011]. Zeitschrift Für Gastroenterologie, 45(6), 525–74. doi:10.1055/s-2007-
963232 
5. EMA. Guideline on the Clinical Evaluation of Medicinal Product Intended to Treatment of Hepatitis B. 
CHMP/EWP/6172/03, EMEA, 2006. 
6. Gaeta, G. B., Stroffolini, T., Chiaramonte, M., Ascione, T., Stornaiuolo, G., Lobello, S., … Rizzetto, M. 
(2000). Chronic hepatitis D: a vanishing Disease? An Italian multicenter study. Hepatology (Baltimore, 
Md.), 32(4 Pt 1), 824–7. doi:10.1053/jhep.2000.17711 
7. Gheorghe, L., Iacob, S., Simionov, I., Vadan, R., Constantinescu, I., Caruntu, F., … Grigorescu, M. 
(2011). Weight-based dosing regimen of peg-interferon α-2b for chronic hepatitis delta: a multicenter 
Romanian trial. Journal of Gastrointestinal and Liver Diseases : JGLD, 20(4), 377–82. Retrieved from 
http://www.ncbi.nlm.nih.gov/pubmed/22187703 
8. Gish, R. G., Yi, D. H., Kane, S., Clark, M., Mangahas, M., Baqai, S., … Glenn, J. S. (2013). Coinfection 
with hepatitis B and D: epidemiology, prevalence and disease in patients in Northern California. Journal of 
Gastroenterology and Hepatology, 28(9), 1521–5. doi:10.1111/jgh.12217 
9. Glebe, D., Urban, S., Knoop, E. V., Çaǧ, N., Krass, P., Grün, S., … Gerlich, W. H. (2005). Mapping of the 
Hepatitis B Virus Attachment Site by Use of Infection-Inhibiting preS1 Lipopeptides and Tupaia 
Hepatocytes. Gastroenterology, 129(1), 234–245. doi:10.1053/j.gastro.2005.03.090 
10. Gripon, P., Cannie, I., & Urban, S. (2005). Efficient inhibition of hepatitis B virus infection by acylated 
peptides derived from the large viral surface protein. Journal of Virology, 79(3), 1613–22. 
doi:10.1128/JVI.79.3.1613-1622.2005 
11. Heidrich, B., Manns, M. P., & Wedemeyer, H. (2013). Treatment options for hepatitis delta virus 
infection. Curr Infect Dis Rep, 15(1), 31–38. doi:10.1007/s11908-012-0307-z 
12. Heidrich, B., Yurdaydın, C., Kabaçam, G., Ratsch, B. a, Zachou, K., Bremer, B., … Wedemeyer, H. 
(2014). Late HDV RNA relapse after peginterferon alfa-based therapy of chronic hepatitis delta. Hepatology 
(Baltimore, Md.), 2–49. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/24585488 
13. Kucirka, L. M., Farzadegan, H., Feld, J. J., Mehta, H., Winters, M., Glenn, J. S., … Golub, E. T. (2011). 
Prevalence, Correlates and Viral Dynamics of Hepatitis Delta Among Injection Drug Users. J Infect Disease, 
202(6), 845–852. doi:10.1086/655808.Prevalence 
14. Lacombe K., Boyd A., Girard P., et al. (2007). Impact of chronic hepatitis C and/or D on liver fibrosis 
severety, 21(18), 2546–2549. 
15. Lamers MH, Kirgiz ÖÖ, Heidrich B, Wedemeyer H, Drenth JPH. Interferon-α for patients with chronic 
hepatitis delta: a systematic review of randomized clinical trials. Antivir Ther. 2012;17(6):1029-37. 
doi:10.3851/IMP2306. 
16. Man, A. De, Spreyi, R. I., Niesters, H. G. M., Heijtinka, R. A., Zondervan, P. E., Hop, W., & Schalm, S. 
W. (1995). Survival and complications of a cohort of patients with anti-Delta positive liver disese presenting 
in a tertiary referral clinic, 662–667. 
17. Manesis, E. K., Vourli, G., Dalekos, G., Vasiliadis, T., Manolaki, N., Hounta, A., … Touloumi, G. 
(2013). Prevalence and clinical course of hepatitis delta infection in Greece: A 13-year prospective study. 
Journal of Hepatology, 59, 949–956. doi:10.1016/j.jhep.2013.07.005 
18. Niro, G. A., & Smedile, A. (2012). Current concept in the pathophysiology of hepatitis delta infection. 
Current Infectious Disease Reports, 14(1), 9–14. doi:10.1007/s11908-011-0233-5 
19. Niro, G., Gravinese, E., Martini, E., Garrubba, M., Facciorusso, D., Conoscitore, P., … Andriulli, A. 
(2001). Clearance of hepatitis B surface antigen in chronic carriers of hepatitis delta antibodies. Liver, 21(4), 
254–9. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11454188 
20. Radjef, N., Gordien, E., Ivaniushina, V., Gault, E., Anaïs, P., Drugan, T., … De, P. (2004). Molecular 


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Translation into English,  
dd. October 10, 2019 
 
 
CONFIDENTIAL 
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Phylogenetic Analyses Indicate a Wide and Ancient Radiation of African Hepatitis Delta Virus , Suggesting 
a Deltavirus Genus of at Least Seven Major Clades Molecular Phylogenetic Analyses Indicate a Wide and 
Ancient Radiation of African Hepatiti. doi:10.1128/JVI.78.5.2537 
21. 
Rizzetto, 
M. 
(2009). 
Hepatitis 
D: 
Thirty 
years 
after. 
Journal 
of 
Hepatology. 
doi:10.1016/j.jhep.2009.01.004 
22. Romeo, R., Del Ninno, E., Rumi, M., Russo, A., Sangiovanni, A., de Franchis, R., … Colombo, M. 
(2009). A 28-year study of the course of hepatitis Delta infection: a risk factor for cirrhosis and 
hepatocellular carcinoma. Gastroenterology, 136, 1629–1638. doi:10.1053/j.gastro.2009.01.052 
23. Verme, G., Amoroso, P., Lettieri, G., Pierri, P., David, E., Sessa, F., … Rizzetto, M. (1986). A 
histological study of hepatitis delta virus liver disease. Hepatology (Baltimore, Md.), 6(6), 1303–7. Retrieved 
from http://www.ncbi.nlm.nih.gov/pubmed/3793008 
24. Wedemeyer, H. (2010). Re-emerging interest in hepatitis delta: new insights into the dynamic interplay 
between HBV and HDV. Journal of Hepatology, 52(5), 627–9. doi:10.1016/j.jhep.2010.02.001 
25. Wedemeyer, H., & Manns, M. P. (2010). Epidemiology, pathogenesis and management of hepatitis D: 
update and challenges ahead. Nature Reviews. Gastroenterology & Hepatology, 7, 31–40. 
doi:10.1038/nrgastro.2009.205 
26. Wedemeyer, H., Yurdaydìn, C. et al. Prolonged therapy of hepatitis delta for 96 weeks with PEG-IFNa-
2a plus Tenofovir or placebo does not prevent HDV RNA relapse: The HIDIT-2 study. EASL –ILC 2014. 
27. Wedemeyer, H., Yurdaydìn, C., Dalekos, G. N., Erhardt, A., Çakaloğlu, Y., Değertekin, H., … Manns, 
M. P. (2011). Peginterferon plus adefovir versus either drug alone for hepatitis delta. The New England 
Journal of Medicine, 364(4), 322–331. 
28. Yurdaydın, C., Idilman, R., Bozkaya, H., & Bozdayi, a M. (2010). Natural history and treatment of 
chronic delta hepatitis. Journal of Viral Hepatitis, 17(11), 749–56. doi:10.1111/j.1365-2893.2010.01353.x 
29. Zachou, K., Yurdaydin, C., Drebber, U., Dalekos, G. N., Erhardt, A., Cakaloglu, Y., … Wedemeyer, H. 
(2010). Quantitative HBsAg and HDV-RNA levels in chronic delta hepatitis. Liver International : Official 
Journal of the International Association for the Study of the Liver, 30(3), 430–7. doi:10.1111/j.1478-
3231.2009.02140.x 

SAP_001.pdf: 
 
MYR203 Statistical Analysis Plan Final 2.0 2019-01-22 
 
 
 
 
 
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Statistical Analysis Plan 
Study information 
Sponsor study code: 
MYR 203 
Study title: 
A Multicenter, Open-label, Randomized, Comparative, parallel-arm phase II study to 
Assess efficacy and safety of Myrcludex B in combination with Peginterferon alfa-2a 
versus Peginterferon alfa-2a alone in patients with chronic viral hepatitis B with 
delta-agent 
Protocol version and date: 
Version 5.0 May 19, 2018 (Translated into English August 7, 2018) 
PCG study ID: 
MYR003 
 
 


 
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Document control 
Document Name 
Statistical Analysis Plan 
Version 
2.0 
Status 
final  
Author 
Malin Franzon 
LINK Medical Research  
Kungsängsvägen 19 
SE-753 23 Uppsala, Sweden 
e-mail: Malin.Franzon@linkmedical.se 
phone: +46 18 430 31 00 
mobile: +46 73 142 11 89 
Document history 
 
Version 
Modified by (name and role) 
Date 
Description of Changes 
1.0 
Malin Franzon,  
Senior Biostatistician 
2018-12-13 
Initial version 
2.0 
Malin Franzon,  
Senior Biostatistician 
2019-01-22 
Final version 
Updated after comments from the sponsor. 
 
 


 
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Table of contents 
1 
Abbreviations .............................................................................................................................................. 5 
2 
Introduction ................................................................................................................................................ 6 
3 
Study objectives .......................................................................................................................................... 6 
3.1 
Primary objective ............................................................................................................................................................ 6 
3.1.1 
Primary variables ......................................................................................................................................................................... 6 
3.2 
Secondary objectives ...................................................................................................................................................... 6 
3.2.1 
Secondary variables ..................................................................................................................................................................... 6 
3.2.2 
Safety variables ............................................................................................................................................................................ 7 
3.2.3 
Immunogenicity variables ............................................................................................................................................................ 7 
3.2.4 
Pharmacokinetic variables ........................................................................................................................................................... 7 
4 
Study design ................................................................................................................................................ 8 
5 
Study population ......................................................................................................................................... 9 
5.1 
Sample size ..................................................................................................................................................................... 9 
6 
Assessments ................................................................................................................................................ 9 
6.1 
Demographics and other baseline characteristic ........................................................................................................... 9 
6.2 
Efficacy assessments .................................................................................................................................................... 10 
6.3 
Safety assessments ....................................................................................................................................................... 11 
6.4 
Pharmacokinetic assessments ...................................................................................................................................... 11 
6.4.1 
Pharmacokinetics in sub study (PK sub-study) ........................................................................................................................... 11 
6.4.2 
Pharmacokinetics in main study (PK main study) ....................................................................................................................... 11 
6.4.3 
Pharmacokinetics in group F ...................................................................................................................................................... 11 
7 
Method of analysis .................................................................................................................................... 12 
7.1 
General ......................................................................................................................................................................... 12 
7.1.1 
Presentation of results ............................................................................................................................................................... 12 
7.1.2 
Baseline ...................................................................................................................................................................................... 13 
7.1.3 
Analysis relative day................................................................................................................................................................... 13 
7.1.4 
Analysis visit ............................................................................................................................................................................... 13 
7.1.5 
Handling of missing data ............................................................................................................................................................ 13 
7.1.6 
Interim analyses ......................................................................................................................................................................... 13 
7.1.7 
Multiplicity ................................................................................................................................................................................. 13 
7.1.8 
Subgroups .................................................................................................................................................................................. 13 
7.2 
Analysis sets.................................................................................................................................................................. 14 
7.2.1 
Full analysis set .......................................................................................................................................................................... 14 
7.2.2 
Per-protocol analysis set ............................................................................................................................................................ 14 
7.2.3 
Safety analysis set ...................................................................................................................................................................... 14 
7.2.4 
Pharmacokinetic analysis set ..................................................................................................................................................... 14 
7.3 
Disposition of subjects .................................................................................................................................................. 15 
7.4 
Protocol deviations ....................................................................................................................................................... 15 
7.5 
Demographics and baseline characteristics .................................................................................................................. 15 
7.6 
Medical history and concurrent diseases ..................................................................................................................... 16 


 
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7.7 
Prior and concomitant medication ............................................................................................................................... 16 
7.8 
Efficacy evaluation ........................................................................................................................................................ 17 
7.8.1 
Primary efficacy variable: HDV RNA response at Week 72 ........................................................................................................ 17 
7.8.2 
Secondary efficacy variables: proportions ................................................................................................................................. 17 
7.8.3 
Intensity of liver fibrosis ............................................................................................................................................................. 18 
7.8.4 
Change in liver biopsy result ...................................................................................................................................................... 18 
7.8.5 
Other efficacy variables ............................................................................................................................................................. 18 
7.9 
Pharmacokinetic evaluation ......................................................................................................................................... 19 
7.9.1 
Pharmacokinetics in main study (PK main study) ....................................................................................................................... 19 
7.9.2 
Pharmacokinetics in sub studies (group B-C and group F) ......................................................................................................... 19 
7.10 
Safety evaluation .......................................................................................................................................................... 19 
7.10.1 
Extent of exposure ..................................................................................................................................................................... 19 
7.10.2 
Adverse Events........................................................................................................................................................................... 19 
7.10.3 
Laboratory ................................................................................................................................................................................. 20 
7.10.4 
Physical examination ................................................................................................................................................................. 20 
7.10.5 
Vital signs ................................................................................................................................................................................... 21 
7.10.6 
Electrocardiogram...................................................................................................................................................................... 21 
7.10.7 
Immunogenicity ......................................................................................................................................................................... 21 
7.11 
Changes to planned analysis......................................................................................................................................... 21 
8 
Derived variables ....................................................................................................................................... 21 
8.1 
General ......................................................................................................................................................................... 21 
8.1.1 
Change from baseline ................................................................................................................................................................ 21 
8.1.2 
Durations ................................................................................................................................................................................... 21 
8.2 
Disposition of subjects .................................................................................................................................................. 21 
8.3 
Demographics and baseline characteristics .................................................................................................................. 21 
8.3.1 
Age ............................................................................................................................................................................................. 21 
8.3.2 
Body mass index ........................................................................................................................................................................ 22 
8.4 
Efficacy variables .......................................................................................................................................................... 22 
8.4.1 
HDV RNA response (primary efficacy variable) .......................................................................................................................... 22 
8.4.2 
Combined response ................................................................................................................................................................... 22 
8.5 
Safety variables............................................................................................................................................................. 22 
8.5.1 
Exposure .................................................................................................................................................................................... 22 
8.5.2 
Physical examination ................................................................................................................................................................. 22 
8.5.3 
Immunogenicity ......................................................................................................................................................................... 22 
9 
References ................................................................................................................................................ 23 
10 
Signoff ....................................................................................................................................................... 24 
Appendix A: Schedule of assessments .................................................................................................................. 25 
 
 


 
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1 
Abbreviations 
Abbreviation 
Explanation 
AE 
Adverse Event 
ALT 
Alanine transferase 
AST 
Aspartate transferase 
AUC 
Area under the curve 
BMI 
Body mass index 
CI 
Confidence interval 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events  
DDP 
Data display plan 
DRM 
Data Review Meeting 
ECG 
Electrocardiogram 
FAS 
Full analysis set 
HBeAg 
Hepatitis B envelope antigen 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HDV 
Hepatitis delta (D) virus 
IAP 
Interim Analysis Plan 
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effects model for repeated measures 
MXB 
Myrcludex B 
NTCP 
Sodium taurocholate co-transporting polypeptide  
PCR 
Polymerase chain reaction  
PEG-IFN alfa-2a 
Peginterferon alfa-2a 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetic analysis set 
PPAS 
Per-protocol analysis set 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event  
SAP 
Statistical analysis plan 
T4 
Thyroxine  
TSH 
Thyroid-stimulating hormone  
ULN 
Upper limit of Normal 
WHO 
World Health Organisation 


 
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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. 
3 
Study objectives 
3.1 
Primary objective 
To investigate the efficacy of Myrcludex B in monotherapy and in combination with PEG-IFN 
alfa-2a and with Tenofovir compared to monotherapy with PEG-IFN alfa-2a, based on the 
achievement of undetectable viral load at the end of the follow-up period (6 months after the 
end of treatment). 
3.1.1 Primary variables 
The primary variable is the occurrence of (where proportions will be assessed): 
• Negative PCR result of HDV RNA (HDV RNA negativation) at Week 72 (end of the follow up 
period). 
3.2 
Secondary objectives 
• To investigate the efficacy of Myrcludex B in monotherapy and in combination with PEG-
IFN alfa-2a and with Tenofovir as compared with monotherapy with PEG-IFN alfa-2a, 
based on the secondary efficacy endpoints; 
• To investigate the safety of Myrcludex B in monotherapy and in combination with PEG-
IFN alfa-2a and with Tenofovir compared with PEG-IFN alfa-2a monotherapy; 
• To investigate the pharmacokinetics of Myrcludex B when administered in combination 
with PEG-IFN alfa-2a and with Tenofovir; 
• To investigate the immunogenicity of Myrcludex B. 
3.2.1 Secondary variables 
The secondary variables are the occurrence of (where proportions will be assessed): 
• Negative PCR result of HDV RNA (HDV RNA negativation) at Weeks 24 and 48; 
• ALT normalization at Weeks 24, 48 and 72; 
• Combined treatment response (negative PCR result of HDV RNA and ALT normalization) at 
Weeks 24, 48 and 72; 
• HBsAg response HBsAg negativation or >1 log10 IU/mL decline) at Weeks 24, 48 and 72; 
• HBsAg negativation with the appearance of anti-HBsAg antibodies at Weeks 48 and 72; 
• HBsAg negativation without appearance of anti-HBsAg antibodies at Weeks 48 and 72; 
• Negative PCR result of HBV DNA at Weeks 24, 48 and 72. 


 
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Additionally, the following secondary variables will be assessed: 
• The intensity of liver fibrosis based on results of transient elastometry of liver at Weeks 48 
and 72; 
• Changes in the results of liver biopsy before and after the treatment as part of the study 
of efficacy; 
• HBV, HDV genotyping, resistance assay and study of NTCP polymorphism. 
3.2.2 Safety variables 
The safety variables are: 
• Adverse events, serious adverse events;  
• Physical examination;  
• Ophthalmological examination; 
• Vital signs;  
• 12-lead ECG;  
• Haematology; 
• Blood chemistry;  
• Total bile acids;  
• Coagulogram;  
• Urinalysis;  
• Blood test for TSH, T4.  
 
3.2.3 Immunogenicity variables 
The level of antibodies to Myrcludex B (arms B - F). 
 
3.2.4 Pharmacokinetic variables 
Plasma concentrations for Myrcludex B for main-study and sub-study (B-D) and sub-study (E-F). 
Pharmacokinetic parameters for Myrcludex B for the sub-studies: 
• Cmax – maximum concentration;  
• Тmax – time of maximum concentration; 
• Kel – elimination rate constant;  
• T1/2 – elimination half-life;  
• CL/F – total clearance;  
• AUC0-t – area under the curve "drug concentration-time" from time 0 to the sampling time 
(t) of the last sample;  
• AUC0-∞ – area under the curve "drug concentration-time" from time 0 to ∞. 
PCG will receive the PK parameters to be included in descriptive analyses. 


 
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4 
Study design 
This study is a multicenter, open-label, randomized, comparative, parallel-arm phase II study. 
It is planned that a total of 90 patients will be randomized using two separate randomisation lists 
in two phases of the study. 
 
In Phase I, 60 patients will be randomized to the following groups: 
• Arm A (n=15): PEG-IFN alfa-2a 180 μg during 48 weeks  
• Arm В (n=15): Myrcludex B 2 mg + PEG-IFN alfa-2a 180 μg during 48 weeks  
• Arm С (n=15): Myrcludex B 5 mg + PEG-IFN alfa-2a 180 μg during 48 weeks  
• Arm D (n=15): Myrcludex B 2 mg during 48 weeks  
 
In Phase II, 30 patients will be randomised to the following groups: 
• Arm E (n=15): Myrcludex B 10 mg (10 mg once a day) + PEG-IFN alfa-2a 180 μg during 48 
weeks  
• Arm F (n=15): Myrcludex B 10 mg (5 mg twice a day) + Tenofovir during 48 weeks 
 
All treatment groups will have a treatment period of 48 weeks with a follow-up period of 24 
weeks after the treatment. Patients from group F will continue Tenofovir treatment during 
follow-up period. 
The treatment arms are grouped into 2 phases: 
Phase I – patients randomised to groups A – D 
Phase II – patients randomised to groups E – F 
It is planned to perform a pharmacokinetic study of Myrcludex B during the study: 
1. Pharmacokinetic sub study (PK sub study) 
10 patients randomized to each of treatment arms B and C (20 patients in total) will be 
enrolled, where blood sample will be collected at Day 1, 2 and at Day 14, 15 (where the 
patients will be hospitalized during the collection).  
 
2. Pharmacokinetic main study (PK main study) 
All patients of each MXB arm (Arm B, C, D, E and F) will be included. 
For the patients not participating in the pharmacokinetic sub study, a blood sampling 
point at a randomization visit (in 1hour +/-15 min after the drug injection) is assigned. 
Blood sample will be collected 1h±15min after injection at visits Week 4, 8, 12, 16, 20, 24, 
28, 32 and 40 and at Week 48 for groups E and F only.  
 
3. Pharmacokinetic study in group F (second part of study) 
10 patients of group F will take part, where blood samples will be collected at Day 1, 2 
and Day 14, 15 (where the patients will be hospitalized during collection). 
 


 
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5 
Study population 
The study plans to randomize 90 male and female patients aged 18 through 65 years of age with 
chronic viral hepatitis B with delta-agent. To account for drop-outs during the randomization 
period, 123 patients are planned to be screened for the study.  
The study selection criteria suggest the enrolment of patients with a positive result of HDV RNA, 
anti-HDV antibodies, HBeAg-positive or negative chronic hepatitis B, ALT level ≥ 1 ULN and <10 
ULN, and with no co-infection with the hepatitis C virus or HIV.  
 
5.1 
Sample size 
The primary endpoint (negative result of PCR on HDV RNA at Week 72) was used to justify the 
minimum size of treatment arms.  
The calculation of the sample size was carried out according to the method described in the book 
by Chow Sh.-Ch., Sample Size Calculations in Clinical Research [Chow Sh.-Ch., Shao J., Wang H., 
2008], by means of the TrialSize package for the R programming language.  
 
The results of the previous MYR 201 substudy, data at the 24 treatment week were used: in 
Group of peginterferon therapy peginterferon alfa-2a 180 μg for 48 weeks, the proportion of 
participants with negative PCR result of HDV RNA was 29% (2 of 7 participants), in arm of 
combined therapy Myrcludex B 2 mg + peginterferon alfa-2a 180 μg for 24 weeks, followed by 
peginterferon alfa-2a 180 μg for 24 weeks, the proportion of participants with a negative PCR 
result of HDV RNA was 71% (5 of 7 participants).  
 
It is expected that five clinical study groups will demonstrate efficacy comparable to combined 
therapy results in MYR 201 substudy. Under such assumptions and a given critical value of the 
significance level of 0.10, the group size n = 15 will make it possible to reach the power of a study 
more than 60%.  
Considering the exploratory nature of the study, the calculated number of arms can be 
considered sufficient to obtain conclusions about the optimal dosing schedule to be used in 
clinical studies of the following phases. 
 
6 
Assessments 
A schedule of assessments from the protocol is presented in Appendix A: Schedule of 
assessments. 
6.1 
Demographics and other baseline characteristic 
Demographic data 
• Date of birth;  
• Sex; 
• Race;  
• Data on bad health habits: smoking, drinking and drug use, drug abuse.  


 
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Medical history 
• Diagnosis/symptom; 
• Degree of severity of the disease according to CTCAE; 
• Start and end date; 
• Information if the disease is resolved. 
Previous and concomitant medication 
• Drugs; 
• Non-medicinal methods of treatment. 
Body height and weight 
• Body height (cm); 
• Body weight (kg); 
• BMI. 
Urine pregnancy test 
Urine drug screening 
Alcohol-breath test 
Alpha-fetoprotein blood test 
Abdominal ultrasound 
 
Serologic assay 
• Anti-HIV antibodies; 
• Anti-HCV antibodies and HCV RNA; 
• Anti-HDV antibodies; 
• Non-quantitative HBsAg analysis to assess the acceptability of the patient to participate in 
the study; 
• Non-quantitative HBeAg analysis; 
• Anti-HBsAg antibodies; 
• Anti-HBeAg antibodies. 
6.2 
Efficacy assessments 
Virology parameters: 
• HDV RNA by a quantitative PCR method; 
• HBsAg level by a quantitative EIA method; 
• HBV DNA by a quantitative PCR method; 
• Anti-HBsAg antibodies (only in patients with undetectable quantitative HBsAg). 
Fibroscan (transient elastometry of the liver)  
 
• To assess fibrosis. 
The liver biopsy 
ALT 


 
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6.3 
Safety assessments 
• Adverse events, serious adverse events; 
• Physical examination; 
• Ophthalmological examination; 
• Vital signs;  
• 12-lead ECG;  
• Hematology; 
• Blood chemistry;  
• Coagulogram;  
• Urinalysis;  
• Total bile acids;  
• Blood test for TSH, T4.  
 
6.4 
Pharmacokinetic assessments 
6.4.1 Pharmacokinetics in sub study (PK sub-study) 
Blood sample for estimation of drug concentration will be collected at Day 1, 2 and at Day 14, 15 
at the following timepoints:  
• Day 1 – before the first injection of Myrcludex B, in 00:30, 1:00, 1:30, 2:00, 2:30, 3:00, 
4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 14:00 (hh:min) after the drug injection; 
• Day 2 – in 24:00 (hh:min) after the drug injection;  
• Day 14 – before injection of Myrcludex B, in 00:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 
6:00, 8:00, 10:00, 12:00, 14:00 (hh:min) after the drug injection;  
• Day 15 – in 24:00 (hh:min) after the drug injection.  
 
6.4.2 Pharmacokinetics in main study (PK main study) 
Blood sampling points for the pharmacokinetic study are assigned: Week 4, 8, 12, 16, 20, 24, 28, 
32, 40, 481 (in 1hour +/-15 min after the drug injection)  
 
6.4.3 Pharmacokinetics in group F  
Blood samples for estimation of drug concentration will be collected at Day 1, 2 and Day 14, 15 at 
the following timepoints:  
• Day 1 – before the first injection of Myrcludex B, in 00:30, 1:00, 1:30, 2:00, 2:30, 3:00, 
4:00, 5:00, 6:00, 8:00, 10:00, 12:00 (hh:min) after the drug injection;  
• Day 2 – in 12:00 after the second injection in Day 1;  
• Day 14 - before injection of Myrcludex B, in 00:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 
6:00, 8:00, 10:00, 12:00 (hh:min); 
• Day 15 - in 12:00 (hh:min) after the second injection in Day 14.  
 


 
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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). 
The groups B-D in Phase I will be compared with the control group A. Group A will also work as a 
control group for the Phase II of the study (2). 
7.1.1 Presentation of results 
All results will be presented by treatment group and in total, unless stated otherwise. It should 
be clearly stated which unit applies to each presented variable. 
Continuous data will be summarised using descriptive statistics, and the following parameters 
will be reported: 
• number of subjects with evaluable observations and missing observations; 
• arithmetic mean and standard deviation; 
• median; 
• first and third quartiles; 
• 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 in this study will be two-sided and performed in the framework of explorative 
analysis. When reporting the results of significance tests, p-values will be presented. 
All confidence intervals presented will be two-sided with a nominal confidence level of 95%. 
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. 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 (3), unless stated otherwise. 


 
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7.1.2 Baseline 
Unless stated otherwise, the baseline value for a parameter is defined as the last non-missing value 
before the first dose of the study 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 
randomisation to the date of the assessment. The date of randomisation 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 vari-
able into temporal or conceptual groups used for analyses. 
The visits as defined in the case report form, CRF, will be used as analysis visits. 
In general, data from unscheduled visits will be presented in data listings only and not included in 
analysis or summary tables. An exception to this is data used to confirm eligibility in association 
with screening or randomisation where the last assessment will be considered in summaries of 
screening data. 
7.1.5 Handling of missing data 
In general, no imputations of missing data will be performed, and the analyses will be performed 
on the observed cases, unless stated otherwise.  
For all response variables, the missing equals failure (MEF) approach will be used for the main 
analysis (i.e., subjects with missing data will be considered as non-responders). 
Data listings will include the observed values. For derived variables, values based on imputed 
data can be presented in listings. 
7.1.6 Interim analyses 
The two parts Phase I and Phase II of the study will be finalised and analysed at separate time 
points. 
• Final Phase I: When groups A-D have finished, final analysis will be performed for these 
groups; 
• Final Phase II: When group E-F (which started after group A-D) have finished, final 
analyses for all groups (A-F) will be performed. 
For Phase II (group E-F), there will be an interim after 24 weeks which will be described 
separately in an Interim Analysis Plan (IAP). 
7.1.7 Multiplicity 
Considering the explorative nature of this study no adjustment for multiple testing will be 
performed.  
7.1.8 Subgroups 
Analysis of ALT normalization will be repeated for subjects with abnormal ALT values at baseline. 


 
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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 Full analysis set 
The full analysis set (FAS) is defined as all randomised subjects who received at least one dose of 
the study medication. 
Analysis of the full analysis set will be based on the planned treatment (i.e. subjects will be 
analysed ‘as randomised’). 
7.2.2 Per-protocol analysis set 
The per-protocol analysis set (PPAS) is defined as the subset of subjects in 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 DRM and documented in the DRM report. 
Analysis on the per-protocol analysis set will be based on the actual treatment (i.e. subjects will 
be analysed ‘as treated’). 
7.2.3 Safety analysis set 
The safety analysis set is defined as all subjects who received at least one dose of the study 
medication. 
Analysis on the safety analysis set will be based on the actual treatment (i.e. subjects will be 
analysed ‘as treated’). 
7.2.4 Pharmacokinetic analysis set 
Generally, the pharmacokinetic analysis set (PKAS) is defined as the subset of subjects in the 
safety analysis set for whom data on the blood drug concentration were obtained. 
As there are separate PK studies involved, one PK analysis set will be formed for each PK study: 
• PKAS – sub-study 
Subjects in the safety analysis set who also are included in the PK sub-study (group B and C)  
• PKAS – main study 
Subjects in the safety analysis set who also are included in the PK main-study (any MXB 
group)  
• PKAS – group F 
Subjects in the safety analysis set who also are included in the PK Group F sub-study  
 


 
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7.3 
Disposition of subjects 
The following will be presented: 
• Number of screened subjects, in total; 
• Number of screening failures, in total; 
• Number of randomised subjects, by treatment group and in total. 
Based on the number of randomised subjects, the following will also be presented, by treatment 
group and in total: 
• Number and percentage of subjects who did not receive any dose of study medication; 
• Number and percentage of subjects who received at least one dose of study medication; 
• Number and percentage of subjects who completed the study; 
• Number and percentage of subjects who withdrew prematurely from the study; 
• 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 with at least one major protocol deviation 
leading to exclusion from an analysis set will be presented. 
7.5 
Demographics and baseline characteristics 
Summary statistics and frequencies on demographic data will be presented for the Safety and 
FAS datasets. 
The following variables will be summarised descriptively: 
Demographic data: 
• Demographics: Age, sex, and race; 
• Data on bad health habits: smoking, drinking and drug use, drug abuse; 
• Baseline anthropometrics: height, body weight, body mass index (BMI) and BMI categories 
('<30 kg/m²' and '≥30 kg/m²'). 
Baseline data (collected at screening and/or randomisation visit): 
• Urine drug test: amphetamine, barbiturates, benzodiazepine, cocaine, marijuana, 
methadone, opiates, tricyclic antidepressants; 
• Alcohol breath test; 
• Serum alpha fetoprotein (AFP) test [IU/mL]; 
• Abdominal ultrasound 
• Serology test: anti-HIV antibodies, HCV RNA and anti-HCV antibodies, anti-HDV antibodies, 
HBsAg, HBeAg, anti-HBsAg antibodies, anti-HBeAg antibodies. 
The arithmetic mean, standard deviation, medians and quartiles will be calculated for 
quantitative variables. The frequencies of the values and percentages will be calculated for 
dichotomous variables. 


 
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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 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 Organisation (WHO) Drug Dictionary 
and summarised 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 summarised in separate tables, based on the safety 
analysis set. 
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. 


 
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7.8 
Efficacy evaluation 
All analyses of efficacy variables will be performed on both the full analysis set (main analysis) 
and the per-protocol analysis set (supportive analysis). 
For response variables, the missing equals failure (MEF) approach will be used as also described 
in paragraph 7.1.5 (handling of missing data). 
In addition to the statistical hypothesis testing described in the subsections below, all efficacy 
variables will be summarised descriptively by treatment group and visit, for both the FAS analysis 
set and the per-protocol analysis set. 
The arithmetic mean, a 95% confidence interval for the mean, standard deviation, medians and 
quartiles will be calculated for quantitative variables. The frequencies of the values, percentages, 
and 95% confidence intervals for the frequencies under the Clopper-Pearson method will be 
calculated for dichotomous variables. 
 
7.8.1 Primary efficacy variable: HDV RNA response at Week 72 
The proportions of negative HDV RNA response at Week 72 in each of the Myrcludex treatment 
groups (B-F) will be compared with the control group of Peginterferon alfa-2a by using Fisher’s 
exact test and by presenting exact unconditional 95%-confidence intervals based on scores for 
the proportion differences.  
The frequencies and proportions of participants with HDV RNA response at Week 72 will be 
presented by treatment group along with the p-values and confidence intervals for the 
comparison versus group A.  
In addition to FAS using MEF approach for main analysis and PPAS as supportive, the following 
sensitivity analysis will be performed for the primary efficacy variable: 
• FAS with observed cases (excluding missing values); 
 
7.8.2 Secondary efficacy variables: proportions 
The following secondary efficacy variables involving proportions will be analysed in the same way 
as for the primary efficacy variable. For each comparison Arm B-F versus Arm A, the hypotheses 
of equal proportions will be tested using Fisher’s exact test and by presenting exact unconditional 
95%-confidence intervals based on scores for the proportion differences.  
• HDV RNA response at Week 24 and Week 48; 
• ALT normalization at Weeks 24, 48 and 72; 
• Combined response of negative HDV RNA and ALT normalization at Weeks 24, 48 and 72; 
• HBsAg negativation with the appearance of anti-HBsAg antibodies at Weeks 48 and 72; 
• HBsAg negativation without appearance of anti-HBsAg antibodies at Weeks 48 and 72; 
• HBV DNA response at Weeks 24, 48 and 72; 
 


 
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7.8.3 Intensity of liver fibrosis  
Summary statistics of Intensity of liver fibrosis at baseline (screening), Weeks 48 and 72 (as 
measured in kPa using transient elastometry/FibroScan) will be presented as well as change from 
baseline. Wilcoxon Mann-Witney test (also called Wilcoxon rank-sum test) will be used to 
compare change from baseline at week 48 and 72 between each of Arm B-F versus Arm A. 
7.8.4 Change in liver biopsy result 
The number and percentage of subjects with an improvement (decrease) or worsening (increase) 
of at least 1 point will be presented for the following parameters: 
• 
Fibrosis: 
o Ishak fibrosis score 
o Knodell fibrosis score 
o METAVIR fibrosis stage 
• 
Histological activity stage: 
o Histological activity index 
o METAVIR activity grade 
Descriptive statistics for the following molecular analysis and gene expression parameters will be 
presented based on log-10 transformed data as well as non-transformed data, including the 
change from baseline for the transformed data: 
• Molecular analysis: 
o Relative HDV RNA expression 
o relative HBV pregenomic expression 
o relative total HBV RNA expression (X region) 
o relative HBV RNA expression (S region) 
o total HBV DNA (X region) copies/cell 
o HBV DNA (S region) copies/cell 
o cccDNA copies/cell 
o HDAg positive Hepatocytes % 
 
• Gene expression: 
o CXCL10 relative expression 
o NTCP relative expression 
o CYP7A1 relative expression 
o ISG15 relative expression 
7.8.5 Other efficacy variables 
HDV RNA levels and HBV DNA levels (on log-10 scale) will be analysed using mixed-effects model 
for repeated measures (MMRM) with time-point estimates. The MMRM analysis for HDV RNA 
will be used as a sensitivity analysis. 
HDV RNA levels and HBV DNA levels (on log-10 scale) will also be presented descriptively. For 
Week 72 (follow-up visit), the change from Week 48 to Week 72 will be included as well.  
Data will also be presented graphically, in line charts displaying the mean log-transformed levels 
over time. 
HBV and HDV genotyping will be presented descriptively by visit. 


 
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7.9 
Pharmacokinetic evaluation 
All analyses and summaries of PK data will be based on the PK analysis set. 
7.9.1 Pharmacokinetics in main study (PK main study) 
For Myrcludex B plasma concentrations, summary statistics (including the geometric mean, and 
the arithmetic and geometric coefficients of variation [CV%]) will be presented by visit. Data will 
also be presented graphically, in line charts where the mean plasma concentration is plotted 
against time. 
7.9.2 Pharmacokinetics in sub studies (group B-C and group F) 
For plasma concentrations, summary statistics, including the geometric mean and arithmetic and 
geometric CV%, will be presented by visit and timepoint. 
For the PK parameters, summary statistics (including the geometric mean, and the arithmetic and 
geometric coefficients of variation [CV%]) will be presented by Day (1, 2, 14 and 15).  
7.10 Safety evaluation 
All evaluations of safety data will be performed on the safety analysis set. 
7.10.1 Extent of exposure 
Exposure to Myrcludex B will be presented for each of the MXB groups (Arm B, C, D, E and F) 
separately and in total. Summary statistics will be presented for: 
- 
treatment duration (weeks); 
- 
total dose (mg); 
- 
dose intensity (mg/week); 
- 
compliance (%). 
Exposure to PEG-IFN alfa-2a will be presented for each of the groups A, B, C and E separately and 
in total. Exposure to Tenofovir will be presented for group F. For PEG-IFN alfa-2a and Tenofovir 
exposure, summary statistics will be presented for: 
- 
treatment duration (weeks); 
- 
total dose (mg); 
- 
compliance (%). 
 
7.10.2 Adverse Events 
Adverse events will be coded according to MedDRA. 
An overview of all adverse events will be presented, including the number and percentage of 
subjects with at least one, and the total number, of the following: 
• Adverse events; 
• Serious adverse events; 
• Adverse events leading to withdrawal of the study medication or dose reduction; 
• Fatal adverse events; 
• Adverse events, broken down by severity; 
• Adverse events, broken down by causality assessment. 


 
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The incidence of adverse events will be presented by system organ class and preferred term. For 
each system organ class and preferred term, the total number of adverse events as well as the 
number and percentage of subjects with at least one adverse event in that system organ class or 
preferred term will be presented. The incidence of serious adverse events will be presented in 
the same way. 
Separate tables for the incidence of adverse events broken down by severity and the incidence of 
adverse events broken down by causality assessment will also be presented by system organ 
class and preferred term. 
There will also be tables on the most frequently reported adverse events, 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 adverse events data in consultation with the author of the clinical 
study report and could be influenced by factors such as the overall number of adverse events, 
study design, and the nature of the indication. The frequency cut-off should be mentioned in a 
table note. 
7.10.3 Laboratory 
For the purpose of summary tables on laboratory test results, any value reported as below the 
lower limit of quantification or as undetectable will be considered as missing, and any value 
reported as above the upper limit of quantification will be considered as being equal to the upper 
limit. In data listings, the reported value will be presented. 
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 
following parameters: 
• 
Haematology: Haematocrit [%], haemoglobin [g/dL], red blood cells, reticulocytes [‰], 
platelets [10^9/L], leucocytes [10^9/L], White blood cell differentials for neutrophils, 
eosinophils, monocytes, basophils and lymphocytes, erythrocyte sedimentation rate (ESR); 
• 
Blood chemistry: total protein [g/L], albumin [g/L], aminotransferase (ALT) [U/L], aspartate 
aminotransferase (AST) [U/L], gamma glutamyl transferase (GGT) [U/L], Lactate 
dehydrogenase (LDH) [U/L], pancreatic amylase [U/L], alkaline phosphatase [U/L], lipase 
[U/L], triglycerides [mmol/L], total bilirubin [umol/L], direct bilirubin [umol/L], total 
cholesterol [mmol/L], creatinine [umol/L], urea [mmol/L], glucose [mmol/L], potassium 
[mmol/L], sodium [mmol/L], calcium [mmol/L], chloride [mmol/L], phosphate [mmol/L], C-
reactive protein [mg/L]; 
• 
Blood bile acids: total bile acids [umol/L]; 
• 
Coagulogram:  Activated partial thromboplastin time [aPTT], Prothrombin time.  
 
Blood test for TSH, T4 
Urinalysis data will be presented in listings only. 
 
7.10.4 Physical examination 
For all body systems examined, frequency tables on the investigator’s assessment will be 
presented by visit. For post-baseline visits, the shift from baseline will also be presented. 


 
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7.10.5 Vital signs 
For vital signs parameters, summary statistics will be presented by visit. For post-baseline visits, 
summary statistics on the change from baseline will also be presented. 
7.10.6 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. 
7.10.7 Immunogenicity 
Summary statistics for the anti-MXB antibodies concentration values and change from baseline 
will be presented by visit for the groups receiving Myrcludex B (Arm B-F). The number and 
percentage of positive subjects will also be presented. 
7.11 Changes to planned analysis 
This SAP is based on protocol version 5.0 May 19, 2018 (Translated into English August 7, 2018). 
A protocol amendment will be written, which imply that this SAP may need to be updated after 
approval. 
The suggested changes are that there will two final analyses, one for Phase I and for Phase II 
(+Phase I) and one interim after 24 weeks for Phase II (group E-F).  
 
8 
Derived variables 
8.1 
General 
8.1.1 Change from baseline 
Change from baseline will be computed as the difference between a post-baseline value and the 
corresponding baseline value. 
Percentage change from baseline will be computed as 100 times the change from baseline 
divided by the baseline value. 
8.1.2 Durations 
In general, the duration of a time period will be computed as the time in days from the start date 
to the end date plus 1 day. The duration in weeks is derived by division by 7 days/week. 
8.2 
Disposition of subjects 
A screening failure is defined as a screened but not randomised subject. 
8.3 
Demographics and baseline characteristics 
8.3.1 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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8.3.2 Body mass index 
BMI will be computed as the body weight in kg divided by the squared height in metres. 
 
8.4 
Efficacy variables 
8.4.1 HDV RNA response (primary efficacy variable) 
HDV RNA response is defined as HDV negativation (i.e., HDV RNA level of zero). 
 
8.4.2 Combined response 
Combined response is defined as fulfilment of both of the following two conditions 
simultaneously: 
• Response, as defined in section 8.4.1; 
• Normalisation of ALT (i.e., ALT value is within the normal range). 
 
8.5 
Safety variables 
8.5.1 Exposure 
The Myrcludex B treatment duration (in weeks) will be computed based on the dates of the first 
and last injections. 
The cumulative dose of MXB (in mg) will be computed as the sum of all injected doses of MXB. 
The MXB dose intensity (in mg/week) will be computed as the cumulative dose of MXB divided by 
the duration of exposure to MXB. 
Compliance with MXB treatment (in %) will be computed as the ratio of the cumulative dose of 
MXB to the planned total dose of MXB (planned daily dose multiplied by 24×7 days) multiplied by 
100. 
The duration of exposure to tenofovir (in weeks) will be computed based on the first date of drug 
dispensation and the last date of drug return. If the date of last drug return has not been 
reported, the duration will be considered as missing. 
The durations will be computed according to section 8.1.2. 
8.5.2 Physical examination 
The analysis parameters will be dichotomous variables categorising the examination results as 
'Normal' or 'Abnormal' (findings not reported as normal). For examinations reported as not done, 
the analysis value will be missing. 
8.5.3 Immunogenicity 
A subject will be considered as positive at a post-baseline visit if there was >2-fold increase in the 
concentration of antibodies compared to baseline (i.e., if the ratio to baseline was > 2). 
 


 
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9 
References 
1. ICH Harmonised Tripartite Guideline for Statistical Principles for Clinical Trials E9. February 
1998. 
2. ICH Harmonised Tripartite Guideline for choice of control group and related issues in clinical 
trials E10. 2000. 
3. ICH Harmonised Tripartite Guideline for Structure and Content of Clinical Trial Reports E3. 
November 1995. 
4. Guideline on missing data in confirmatory trials. EMA; Committee for Medicinal Products for 
Human Use. 2010. 
5. Clinical Study Protocol MYR 203, version 5.0 May 19, 2018 (translated into English August 7, 
2018).  
 
 


 
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10 Signoff 
We have read this SAP for the MYR 203 study and confirm that, to the best of our knowledge, the 
statistical analyses to be performed in this study are accurately described. 
Hepatera LLC: Yana Deloveri, CEO 
SIGNATURE AND DATE 
Klaus Junge, External Biostatistician 
SIGNATURE AND DATE 
LINK Medical Research SAP Author: Malin Franzon, Senior Biostatistician 
SIGNATURE AND DATE 
 


 
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25 (28) 
Appendix A: Schedule of assessments 
 
 


 
MYR203 Statistical Analysis Plan Final 2.0 2019-01-22 
 
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26 (28) 
 
 


 
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27 (28) 
 
 


 
MYR203 Statistical Analysis Plan Final 2.0 2019-01-22 
 
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28 (28) 
 
 
 
 
 
 
 
 




 
MYR203 Statistical Analysis Plan Amendment_2019-05-17 
 
 
1 (6) 
Amendment to 
Statistical Analysis Plan 
Study information 
Sponsor study code: 
MYR 203 
Study title: 
A Multicenter, Open-label, Randomized, Comparative, parallel-arm phase II study to 
Assess efficacy and safety of Myrcludex B in combination with Peginterferon alfa-2a 
versus Peginterferon alfa-2a alone in patients with chronic viral hepatitis B with delta-
agent 
Protocol version and date: 
Amended protocol version 6.0 dated January 21, 2019 
PCG study ID: 
MYR003 
 
 


 
MYR203 Statistical Analysis Plan Amendment_2019-05-17 
 
 
2 (6) 
Document control 
Document Name 
Statistical Analysis Plan Amendment 
Version 
1.0 
Status 
final  
Author 
Malin Franzon 
LINK Medical Research  
Kungsängsvägen 19 
SE-753 23 Uppsala, Sweden 
e-mail: Malin.Franzon@linkmedical.se 
phone: +46 18 430 31 00 
mobile: +46 73 142 11 89 
Document history 
 
Version 
Modified by (name and role) 
Date 
Description of Changes 
1.0 
Malin Franzon,  
Senior Biostatistician 
2019-05-17 
Final version 
 
 
 
 
 
 
 
 
 
 


 
MYR203 Statistical Analysis Plan Amendment_2019-05-17 
 
 
3 (6) 
Table of contents 
1 
Purpose ....................................................................................................................................................... 4 
2 
Handling of randomisation issues ............................................................................................................... 4 
3 
Amendment to sections in SAP ................................................................................................................... 4 
3.1 
Handling of missing data and non-quantifiable values ................................................................................................... 4 
3.2 
Interim analyses ............................................................................................................................................................. 4 
3.3 
Secondary efficacy variables: proportions ...................................................................................................................... 5 
3.4 
Biopsy results.................................................................................................................................................................. 5 
3.5 
Laboratory ...................................................................................................................................................................... 5 
3.6 
HDV RNA response ......................................................................................................................................................... 5 
3.7 
Exposure to MXB and PEG-IFN ....................................................................................................................................... 6 
4 
Presentation of results ................................................................................................................................ 6 
5 
Signoff......................................................................................................................................................... 6 
 
 


 
MYR203 Statistical Analysis Plan Amendment_2019-05-17 
 
 
4 (6) 
1 
Purpose 
The purpose of this amendment to the statistical analysis plan (SAP) is to describe changes to the final 
SAP version 2.0 after amendment protocol 6.0. Furthermore, handling of randomisation issues is also 
mentioned.  
2 
Handling of randomisation issues  
There are uncertainties regarding how randomisation has been performed in this study. This will be 
considered when interpreting the results in the clinical study report.  
 
3 
Amendment to sections in SAP 
3.1 
Handling of missing data and non-quantifiable values 
Handling of missing data described in section 7.1.5 of final SAP v2.0 is amended to handle values 
below LLOD and LLOQ in the same way as study MYR202. 
For the virology results and other parameters using LLOQ and/or LLOD values, the following rules will 
be applied: 
 
• Values below the limit of detection (LLOD) will be imputed as zero values. 
• Values reported as '<x' (below the lower limit of quantification, LLOQ), will be imputed as half 
the LLOQ value. 
• 'Non-measurable' data will be considered as missing data. 
• Values reported as '>x' (above the upper limit of quantification, ULOQ), will be imputed as the 
ULOQ value. 
For the log-10 transformed data, missing values due to untransformed values of zero will be imputed 
as zero. 
 
3.2 
Interim analyses 
Planned interim analyses were described in section 7.1.6 of final SAP v2.0. Below is a clarification of 
the interim analyses in accordance with amended protocol v 6.0. 
There will be two interims in the study before the final analysis of all treatment arms. 
1) Phase I: When groups A-D have finished, final analysis will be performed for these groups; 
2) 24 weeks interim for Phase II (groups E-F). 
The 24 weeks interim analysis for groups E-F in Phase II of the study (number 2) above) will be 
described separately in an Interim Analysis Plan (IAP). 


 
MYR203 Statistical Analysis Plan Amendment_2019-05-17 
 
 
5 (6) 
3.3 
Secondary efficacy variables: proportions 
Section 7.8.2 of the final SAP v2.0 is amended to include the following the following secondary 
variable:  
• HBsAg response (HBsAg negativation or >1 log10 IU/mL decline) at Weeks 24, 48 and 72.  
 
The variable is included in section 3.2.1 of the final SAP v2.0, but not in section 7.8.2. 
 
Analysis of this variable will be performed in the same way as for the other variables as described in 
section 7.8.2 of the final SAP v2.0.  
3.4 
Biopsy results 
The following molecular analysis and gene expression parameters will be added to the list of 
parameters in section 7.8.4 of the final SAP v2.0: 
 
• Molecular analysis: 
o HBsAg (from biopsy) 
 
• Gene expression: 
o MX1 relative expression 
o OAS relative expression 
o HLA-E relative expression 
o TAP1 relative expression 
o USP18 relative expression 
 
Furthermore, RNA content and DNA content (molecular analysis) will be listed. 
 
3.5 
Laboratory 
The following amendments will be applied to section 7.10.3 of final SAP v2.0: 
Missing data for laboratory will be handled as described in section 3.1 above. 
For Haematology, summary statistics will be presented by visit for the following parameters: 
• 
Haematology: leukocytes [10^9/L] with absolute [10^9/L] and relative [%] differentials: 
basophils, eosinophils, lymphocytes, monocytes, neutrophils; erythrocyte sedimentation rate 
(mm/h), haematocrit [%], haemoglobin [g/dL], platelets [10^9/L], red blood cells, reticulocytes 
(absolute10^9/L and relative ‰);  
 
3.6 
HDV RNA response  
In section 8.4.1 of final SAP v2.0, HDV RNA response is defined as “HDV negativation (i.e., HDV RNA 
level of zero)”. However, as described in section 3.1 above values below the limit of detection (LLOD) 
will be imputed as zero values. Hence, HDV negativation is defined as HDV RNA level of zero or below 
the limit of detection (LLOD). 
 


 
MYR203 Statistical Analysis Plan Amendment_2019-05-17 
 
 
6 (6) 
 
3.7 
Exposure to MXB and PEG-IFN 
The following amendments will be applied to section 8.5.1 of final SAP v2.0: 
Compliance with MXB treatment (in %) will be computed as the ratio of the cumulative dose of MXB 
to the planned total dose of MXB, where planned total dose of MXB will be calculated as planned 
daily dose multiplied by 48×7 days multiplied by 100 (as MXB is administrated daily for 48 weeks). 
Compliance with PEG-IFN treatment (in %) will be computed as the ratio of the cumulative dose of 
PEG-IFN to the planned total dose of PEG-IFN, where planned total dose of PEG-IFN will be calculated 
as planned daily dose multiplied by 48 multiplied by 100 (as PEG-IFN is administrated once a week for 
48 weeks). 
4 
Presentation of results 
The updated version of the DDP Final 3.0 incorporates the changes described in this SAP amendment. 
5 
Signoff 
We have read this SAP Amendment for the MYR 203 study and confirm that, to the best of our know-
ledge, the statistical analyses to be performed in this study are accurately described. 
Hepatera LLC: Yana Deloveri, CEO 
SIGNATURE AND DATE 
Klaus Junge, External Biostatistician 
SIGNATURE AND DATE 
LINK Medical Research SAP Author: Malin Franzon, Senior Biostatistician 
SIGNATURE AND DATE 
 




 
MYR203 Statistical Analysis Plan Amendment 2_Final_2019-08-13 
 
 
1 (8) 
Amendment 2 to 
Statistical Analysis Plan 
Study information 
Sponsor study code: 
MYR 203 
Study title: 
A Multicenter, Open-label, Randomized, Comparative, parallel-arm phase II study to 
Assess efficacy and safety of Myrcludex B in combination with Peginterferon alfa-2a 
versus Peginterferon alfa-2a alone in patients with chronic viral hepatitis B with delta-
agent 
Protocol version and date: 
Amended protocol version 6.0 dated January 21, 2019 
PCG study ID: 
MYR003 
 
 


 
MYR203 Statistical Analysis Plan Amendment 2_Final_2019-08-13 
 
 
2 (8) 
Document control 
Document Name 
Statistical Analysis Plan Amendment 2 
Version 
1.0 
Status 
final 
Author 
Malin Franzon 
LINK Medical Research  
Kungsängsvägen 19 
SE-753 23 Uppsala, Sweden 
e-mail: Malin.Franzon@linkmedical.se 
phone: +46 18 430 31 00 
mobile: +46 73 142 11 89 
Document history 
 
Version 
Modified by (name and role) 
Date 
Description of Changes 
0.1 
Malin Franzon,  
Senior Biostatistician 
2019-08-06 
Initial version 
1.0 
Malin Franzon,  
Senior Biostatistician 
2019-08-13 
Final version. 
Updates with comments from sponsor.  
 
 
 
 
 
 


 
MYR203 Statistical Analysis Plan Amendment 2_Final_2019-08-13 
 
 
3 (8) 
Table of contents 
1 
Purpose ....................................................................................................................................................... 4 
2 
Amendment to SAP and first SAP Amendment ........................................................................................... 4 
2.1 
Handling of missing data and non-quantifiable values ................................................................................................... 4 
2.2 
Post hoc variables ........................................................................................................................................................... 4 
3 
Presentation of results ................................................................................................................................ 5 
14.2.12 Post hoc analyses ........................................................................................................................................................................ 5 
4 
Signoff......................................................................................................................................................... 8 
 
 


 
MYR203 Statistical Analysis Plan Amendment 2_Final_2019-08-13 
 
 
4 (8) 
1 
Purpose 
The purpose of this amendment to the statistical analysis plan (SAP) is to describe changes to the final 
SAP version 2.0 and the first SAP Amendment dated 2019-05-17.  
The rules for handling parameters using LLOD was stated in the first SAP Amendment, where values 
below the limit of detection (LLOD) will be imputed as zero values. 
According to the first SAP Amendment: for the log-10 transformed data, log10(0) was then to be 
imputed as zero. 
However, when LLOD<1 this may result in log10(<LLOD) being greater log(>LLOD) when log(>LLOD) is 
negative and log10(<LLOD) is imputed as zero. 
This SAP Amendment 2 is a description of the correction of this, by imputing log(0) with log(LLOD/2) 
when LLOD<1. 
 
This SAP Amendment 2 also describes adding of variables for post hoc analyses. 
 
2 
Amendment to SAP and first SAP Amendment 
2.1 
Handling of missing data and non-quantifiable values 
Values below the limit of detection (<LLOD) will still be imputed as zero values, as described in the 
first SAP Amendment. 
However, for the log-10 transformed data, the imputation is amended to the following: 
• For the log-10 transformed data for parameters using LLOD values where LLOD>1, missing 
values due to untransformed values of zero will be imputed as 0 
• For the log-10 transformed data for parameters using LLOD values where LLOD<1, missing 
values due to untransformed values of zero will be imputed as log10(LLOD/2). 
 
2.2 
Post hoc variables 
The following the following post hoc variables will be added:  
• 
Adjusted HDV RNA response: (>2log10 HDV RNA reduction or HDV RNA negativation) at Weeks 
24, 48 and 72 
• Adjusted combined response: ((>2log10 HDV RNA reduction or HDV RNA negativation) and ALT 
normalisation) at Weeks 24, 48 and 72 
 
Analysis of these variables will be performed in the same way as for the other variables as described 
in section 7.8.2 of the final SAP v2.0. Mock tables are included in paragraph 3 below. 
 
 


 
MYR203 Statistical Analysis Plan Amendment 2_Final_2019-08-13 
 
 
5 (8) 
3 
Presentation of results 
The results will be presented in accordance with DDP Final 3.0 but with the following tables added for the Post hoc variables.  
14.2.12 Post hoc analyses 
14.2.12.1 
Adjusted HDV RNA response: (>2log10 HDV RNA reduction or HDV RNA negativation) at Week 24, 48 and 72 
Table 14.2.12.1-1. Adjusted HDV RNA response (>2 log10 HDV RNA reduction or HDV RNA negativation) at Week 24, 48 and 72. Statistical analysis of 
difference in proportions, using Fisher’s exact test. Full analysis set 
Table 14.2.12.1-2. Adjusted HDV RNA response (>2 log10 HDV RNA reduction or HDV RNA negativation) at Week 24, 48 and 72. Statistical analysis of 
difference in proportions, using Fisher’s exact test. Per protocol analysis set 
Adjusted HDV RNA response 
PEG-IFN 
(N=xx) 
MXB 2mg + 
PEG-IFN 
(N=xx) 
MXB 5mg + 
PEG-IFN 
(N=xx) 
MXB 2mg 
(N=xx) 
MXB 10mg + 
PEG-IFN 
(N=xx) 
MXB 5mg bid + 
Tenofovir 
(N=xx) 
Week 24 
 
 
 
 
 
 
 
Number of subjects included in analysis 
xx 
xx 
xx 
xx 
xx 
xx 
 
Proportion Response (95% CI) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x)  
xx.x (xx.x, xx.x) 
xx.x(xx.x, xx.x) 
 
Difference in proportions (95% CI) 
 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
 
p-value 
 
0.xxxx 
0.xxxx 
0.xxxx 
0.xxxx 
0.xxxx 
 
 
 
 
 
 
 
Week 48 
 
 
 
 
 
 
 
Number of subjects included in analysis 
xx 
xx 
xx 
xx 
xx 
xx 
 
Proportion Response (95% CI) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x)  
xx.x (xx.x, xx.x) 
xx.x(xx.x, xx.x) 
 
Difference in proportions (95% CI) 
 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
 
p-value 
 
0.xxxx 
0.xxxx 
0.xxxx 
0.xxxx 
0.xxxx 
 
 
 
 
 
 
 
Week 72 
 
 
 
 
 
 
 
Number of subjects included in analysis 
xx 
xx 
xx 
xx 
xx 
xx 
 
Proportion Response (95% CI) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x)  
xx.x (xx.x, xx.x) 
xx.x(xx.x, xx.x) 
 
Difference in proportions (95% CI) 
 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
 
p-value 
 
0.xxxx 
0.xxxx 
0.xxxx 
0.xxxx 
0.xxxx 
 
 
 
 
 
 
 
CI = Confidence interval, calculated using Clopper–Pearson (exact) for within group proportions and exact unconditional for difference in proportions. 
Fisher's exact tests were used for the comparison of respective MXB group and PEG-IFN alfa-2 only group.  
Source: <program name>.sas Date and time program was run: YYYY-MM-DDTHH:MM. Date and time analysis database was run: YYYY-MM-DDTHH:MM 
For final Phase I, the table will only include the groups: “PEG-IFN”, “MXB 2mg + PEG-IFN”, “MXB 5mg + PEG-IFN”, “MXB 2mg”. 


 
MYR203 Statistical Analysis Plan Amendment 2_Final_2019-08-13 
 
 
6 (8) 
 
 
Table 14.2.12.1-3. Frequency table for Adjusted HDV RNA response (>2 log10 HDV RNA reduction or HDV RNA negativation) at Week 24, 48 and 72. Full 
analysis set 
Table 14.2.12.1-4. Frequency table for Adjusted HDV RNA response (>2 log10 HDV RNA reduction or HDV RNA negativation) at Week 24, 48 and 72. Per 
protocol analysis set 
Adjusted HDV RNA response 
PEG-IFN 
(N=xx) 
MXB 2mg + 
PEG-IFN 
(N=xx) 
MXB 5mg + 
PEG-IFN 
(N=xx) 
MXB 2mg 
(N=xx) 
MXB 10mg + 
PEG-IFN 
(N=xx) 
MXB 5mg bid + 
Tenofovir 
(N=xx) 
Week 24 
 
 
 
 
 
 
 
Responder 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Non-responder 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Missing 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
Week 48 
 
 
 
 
 
 
 
Responder 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Non-responder 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Missing 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
Week 72 
 
 
 
 
 
 
 
Responder 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Non-responder 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Missing 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
Percentages are based on the number of subjects within each treatment group. 
Source: <program name>.sas Date and time program was run: YYYY-MM-DDTHH:MM. Date and time analysis database was run: YYYY-MM-DDTHH:MM 
For final Phase I, the table will only include the groups: “PEG-IFN”, “MXB 2mg + PEG-IFN”, “MXB 5mg + PEG-IFN”, “MXB 2mg”. 
 
 


 
MYR203 Statistical Analysis Plan Amendment 2_Final_2019-08-13 
 
 
7 (8) 
14.2.12.2 
Adjusted combined response: ((>2log10 HDV RNA reduction or HDV RNA negativation) and ALT normalisation) at Week 24, 48 and 72 
 
Table 14.2.12.2-1. Adjusted combined response ((>2 log10 HDV RNA reduction or HDV RNA negativation) and ALT normalisation) at Week 24, 48 and 72. 
Statistical analysis of difference in proportions, using Fisher’s exact test. Full analysis set 
Table 14.2.12.2-2. Adjusted combined response ((>2 log10 HDV RNA reduction or HDV RNA negativation) and ALT normalisation) at Week 24, 48 and 72. 
Statistical analysis of difference in proportions, using Fisher’s exact test. Per protocol analysis set 
Same as Table 14.2.12.1-1 
 
Table 14.2.12.2-3. Frequency table for Adjusted combined response ((>2 log10 HDV RNA reduction or HDV RNA negativation) and ALT normalisation) at 
Week 24, 48 and 72. Full analysis set 
Table 14.2.12.2-4. Frequency table for Adjusted combined response ((>2 log10 HDV RNA reduction or HDV RNA negativation) and ALT normalisation) at 
Week 24, 48 and 72. Per protocol analysis set 
Same as Table 14.2.12.1-3 
 
 
 
 
 
 


 
MYR203 Statistical Analysis Plan Amendment 2_Final_2019-08-13 
 
 
8 (8) 
4 
Signoff 
We have read this SAP Amendment 2 for the MYR 203 study and confirm that, to the best of our 
knowledge, the statistical analyses to be performed in this study are accurately described. 
Hepatera LLC: Yana Deloveri, CEO 
SIGNATURE AND DATE 
Klaus Junge, External Biostatistician 
SIGNATURE AND DATE 
LINK Medical Research SAP Author: Malin Franzon, Senior Biostatistician 
SIGNATURE AND DATE 
 




 
$210a0dae238e$49F0ED3D6DBF426D8386AF0A8D83C2B9.docx 
 
 
1 (6) 
Amendment 3 to 
Statistical Analysis Plan 
Study information 
Sponsor study code: 
MYR 203 
Study title: 
A Multicenter, Open-label, Randomized, Comparative, parallel-arm phase II study to 
Assess efficacy and safety of Myrcludex B in combination with Peginterferon alfa-2a 
versus Peginterferon alfa-2a alone in patients with chronic viral hepatitis B with delta-
agent 
Protocol version and date: 
Amended protocol version 6.0 dated January 21, 2019 
LINK study ID: 
MYR003 
 
 
DocuSign Envelope ID: B059DDCE-EB15-48B9-BC44-414EA041A5AD


 
$210a0dae238e$49F0ED3D6DBF426D8386AF0A8D83C2B9.docx 
 
 
2 (6) 
Document control 
Document Name 
Statistical Analysis Plan Amendment 3 
Version 
1.0 
Status 
final 
Author 
Malin Franzon 
LINK Medical Research  
Kungsängsvägen 19 
SE-753 23 Uppsala, Sweden 
e-mail: Malin.Franzon@linkmedical.se 
phone: +46 18 430 31 00 
mobile: +46 73 142 11 89 
Document history 
 
Version 
Modified by (name and role) 
Date 
Description of Changes 
0.1 
Malin Franzon,  
Senior Biostatistician 
2020-05-29 
Initial version 
1.0 
Malin Franzon,  
Senior Biostatistician 
2020-06-04 
Final version. 
Updated with comments from sponsor 
 
 
 
 
 
 
DocuSign Envelope ID: B059DDCE-EB15-48B9-BC44-414EA041A5AD


 
$210a0dae238e$49F0ED3D6DBF426D8386AF0A8D83C2B9.docx 
 
 
3 (6) 
Table of contents 
1 
Purpose ....................................................................................................................................................... 4 
2 
Amendment to SAP and prior SAP Amendments (1st SAP Amendment and SAP Amendment 2) ................. 4 
2.1 
Presentation of Adverse Events ...................................................................................................................................... 4 
2.2 
Other changes and updated DDP ................................................................................................................................... 5 
3 
Signoff......................................................................................................................................................... 6 
 
 
DocuSign Envelope ID: B059DDCE-EB15-48B9-BC44-414EA041A5AD


 
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4 (6) 
1 
Purpose 
The purpose of this amendment (Amendment 3) to the statistical analysis plan (SAP) is to describe 
changes to the final SAP version 2.0 and the first SAP Amendment dated 2019-05-17 and SAP 
Amendment 2 dated 2019-08-13. 
This SAP Amendment 3 mainly describes tables to be added based on requests during EMA’s CHMP 
assessment of the MAA, which included the report of Interim 1 A-D. 
The additional mock tables are included in the updated Data Display Plan (DDP), Final DDP v4.0. 
 
2 
Amendment to SAP and prior SAP Amendments (1st SAP 
Amendment and SAP Amendment 2) 
2.1 
Presentation of Adverse Events 
Adverse Events will be presented as described in the SAP. 
However, Overview of Adverse Events, the incidence of Adverse Events and Serious Adverse Events 
will also be presented by study period (total, during treatment and follow-up) and by subgroups ADA 
positive/negative. 
 
The following groups of adverse events will be used: 
 Adverse events started during the study (both the treatment and FU period) 
 Adverse events started during the treatment period  
 Adverse events started after the end of treatment period 
 Adverse events started during the study (both the treatment and FU period) for the subgroup 
of ADA positive subjects. 
 Adverse events started during the study (both the treatment and FU period) for the subgroup 
of ADA negative subjects. 
 Adverse events started during the treatment period for the subgroup of ADA positive subjects. 
 Adverse events started during the treatment period for the subgroup of ADA negative subjects. 
 Adverse events started after the end of treatment period for the subgroup of ADA positive 
subjects. 
 Adverse events started after the end of treatment period for the subgroup of ADA negative 
subjects. 
 
A table with descriptive statistics for time to first injection site reaction in patients with at least one 
injection site reaction will also be presented by treatment group and Total. 
 
 
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2.2 
Other changes and updated DDP  
In the amended protocol v 6.0, two interims were planned before the final analysis of all treatment 
arms.  
1) Phase I: When groups A-D have finished, final analysis will be performed for these groups; 
2) 24 weeks interim for Phase II (groups E-F); 
3) Final analysis: When group E-F (which started after group A-D) have finished, final analyses for all 
groups (A-F) will be performed. 
In the end, the interim 2) with 24 weeks data for E-F was not performed. This is described in an 
amended protocol v7.0. As the final analysis of groups A-D was based on protocol 6.0, the final analysis for  
this study will be presented using the endpoints in protocol v6.0. 
The DDP has been updated with the changes described in section 2.1 above and the post-hoc analyses 
described in SAP Amendment 2.  
 
 
 
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3 
Signoff 
We have read this SAP Amendment 3 for the MYR 203 study and confirm that, to the best of our 
knowledge, the statistical analyses to be performed in this study are accurately described. 
Hepatera LLC: Yana Deloveri, CEO 
SIGNATURE AND DATE 
Klaus Junge, External Biostatistician 
SIGNATURE AND DATE 
LINK Medical Research SAP Author: Malin Franzon, Senior Biostatistician 
SIGNATURE AND DATE 
 
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2020-06-12 | 10:54 CEST
2020-06-11 | 13:54 CEST