Clinical trial NCT03546621
Conditions: Chronic Hepatitis D Infection With Hepatitis B
Keywords: Hepatitis D
Sponsor: Hepatera Ltd.
Start date: 2016-02-16; Completion date: 2018-01-31
Enrollment: 120 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, open-label, randomized clinical trial to Assess Efficacy and Safety of 3 Doses of Myrcludex B for 24 Weeks in Combination with Tenofovir Compared to Tenofovir Alone to Suppress HBV Replication in Patients with Chronic Hepatitis D

Detailed description:
This is a multicenter, open-label, randomised, phase II study.

The study will be conducted in Russia and Germany. The study is designed to evaluate the benefit of 3 MXB doses versus observation in patients on background therapy with tenofovir, suffering from hepatitis delta with very limited therapeutic options; the patients will be randomized 1:1:1:1 into 3 treatment arms and an observation arm. Patients with compensated cirrhosis at screening will be stratified to allow similar distribution into each treatment arm. If patients were not receiving treatment with nucleoside/nucelotide analogue, the comparator/background drug will be initiated after the eligibility confirmation, for 12 weeks prior to randomization visit; patients who previously received tenofovir will continue the dosing; patients on different nucleoside/nucleotide analogue will be switched to tenofovir. Observation is considered an adequate control group, as daily placebo injections for 24 weeks are regarded not feasible and ethically questionable.

It is planned to screen 200 patients, and 120 patients will be randomised into four treatment arms in the 1:1:1:1 ratio.

* Arm A (30 patients): Myrcludex B, 2 mg/day subcutaneously (s.c.) for 24 weeks + tenofovir with a further follow-up period of 24 weeks of continued tenofovir therapy.
* Arm B (30 patients): Myrcludex B, 5 mg/day subcutaneously (s.c.) for 24 weeks + tenofovir with a further follow-up period of 24 weeks of continued tenofovir therapy.
* Arm C (30 patients): Myrcludex B, 10 mg/day subcutaneously (s.c.) for 24 weeks + tenofovir with a further follow-up period of 24 weeks of continued tenofovir therapy.
* Arm D (30 patients): tenofovir treatment for 48 weeks.

Arms: arm 1: Myrcludex B, 2 mg/day subcutaneously (s.c.) for 24 weeks + tenofovir with a further follow-up period of 24 weeks of continued tenofovir therapy. arm 2: Myrcludex B, 5 mg/day subcutaneously (s.c.) for 24 weeks + tenofovir with a further follow-up period of 24 weeks of continued tenofovir therapy. arm 3: Myrcludex B, 10 mg/day subcutaneously (s.c.) for 24 weeks + tenofovir with a further follow-up period of 24 weeks of continued tenofovir therapy. arm 4: tenofovir treatment for 48 weeks
Interventions: intervention 1: Myrcludex B intervention 2: Myrcludex-B intervention 3: Myrcludex-B intervention 4: Tenofovir
Intervention descriptions: intervention 1: 2 mg, once daily, subcutaneously intervention 2: 5 mg, once daily, subcutaneously intervention 3: 10 mg, once daily, subcutaneously intervention 4: tenofovir disoproxil 245 mg, equivalent to tenofovir disoproxil fumarate 300 mg

Protocol documents:
Prot_001.pdf: 
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Protocol # MYR 202, version 3.0                                                                                            Date: 25 Dec 2017 
 
Confidential 
 
CLINICAL STUDY PROTOCOL  
MYR 202 
A Multicenter, Open-label, Randomized Clinical Study to Assess Efficacy and Safety of 
3 Doses of Myrcludex B for 24 Weeks in Combination with Tenofovir Compared to 
Tenofovir Alone to Suppress HBV Replication in Patients with Chronic Hepatitis D 
Version: 3.0 
Including Amendment(s): N/A  
Date: 25 December 2017  
Investigational Product: Myrcludex B, lyophilized powder for solution for injection 
Study Sponsor: Hepatera LLC, Russia 
Sponsor’s Address: 12/19 Verkhnyaya Radischevskaya Ul, Bld. 1, Moscow, 109240 
Sponsor`s legal representative: MYR GmbH 
Sponsor`s legal representative address: Weinbergsweg 66, 61348 Bad Homburg, Germany 
Phase: II 
 
 
EudraCT number: 2016-000395-13 
 
Replaces all previous versions of this protocol 
Confidentiality Statement  
This document is intended to be used by authorized parties only. The document contains 
confidential information and/or trade secrets protected by law and cannot be disclosed.  By 
accepting this document, you acknowledge its confidentiality and agree not to disclose it to any 
third parties or persons without prior written authorization of OOO Hepatera or MYR GmbH and 
not to use it for any non-authorized purposes.  
 
 
 


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Table of Contents  
Protocol Synopsis ............................................................................................................................ 7 
List of Abbreviations ..................................................................................................................... 14 
1. Administrative Study Structure ................................................................................................. 17 
1.1. Protocol Identification ........................................................................................................ 17 
1.2. Sponsor’s and Authorized Representatives’ Contact Information ..................................... 18 
1.3. Signature Page .................................................................................................................... 19 
1.4. 
Sites contact list and Principal Investigators ........................................................... 20 
1.5. 
Investigator’s Signature ........................................................................................... 22 
1.6 Central Laboratories Contact List ........................................................................................ 23 
2. Study Rationale ......................................................................................................................... 25 
2.1. Study Drug Name and Description ..................................................................................... 26 
2.1.1. General Properties ........................................................................................................ 26 
2.2. Summary of Pre-clinical and Clinical Data ........................................................................ 27 
2.2.1. Pre-clinical Studies ....................................................................................................... 27 
2.2.2. Clinical Experience with Myrcludex B ........................................................................ 28 
2.3. Information About Comparator / Background medication ................................................. 31 
2.4. Rational for the study, dose selection and risk-benefit assessment .................................... 31 
2.6. Study Population ................................................................................................................. 33 
3. Study Objectives and Endpoints ................................................................................................ 33 
4. Study Design ............................................................................................................................. 34 
4.1. Summary of Study Design .................................................................................................. 34 
4.2. Pharmacokinetic Study ....................................................................................................... 39 
4.3. Randomization .................................................................................................................... 39 
4.4. Study Periods and Procedures ............................................................................................. 39 
4.4.1. Screening Procedures ................................................................................................... 40 
4.4.2. Tenofovir Pre-Treatment Period Procedures and Assessments ................................... 41 
4.4.3. Randomization Visit ..................................................................................................... 42 
4.4.4. Treatment Period Procedures and Assessments ........................................................... 43 
4.4.5. Post-treatment Assessments ......................................................................................... 48 
4.5. Premature Discontinuation, Study Drug Interruption, Dose Adjustments ......................... 51 
4.6. Management of Hepatitis Exacerbations ............................................................................ 52 
4.7. Description of Study Procedures ........................................................................................ 52 


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4.8. Study Completion, Interruption and Termination, Individual Study Site Termination and 
Subject Withdrawal .................................................................................................................... 57 
4.8.1. Study Completion ......................................................................................................... 57 
4.8.2. Study Suspension or Early Termination....................................................................... 57 
4.8.3. Premature Discontinuation of Study Site by the Sponsor ............................................ 58 
4.8.4. Early Termination of Patient’s Participation ................................................................ 58 
4.9. List of Data Entered Directly into CRF .............................................................................. 58 
5. Selection and Withdrawal of Study Participants ....................................................................... 59 
5.1. Inclusion Criteria ................................................................................................................ 59 
5.2. Exclusion Criteria ............................................................................................................... 60 
5.3. Subject Withdrawal Criteria ............................................................................................... 61 
5.3.1. Withdrawal Criteria ...................................................................................................... 61 
5.3.2. Withdrawn Subject Data .............................................................................................. 62 
5.3.3. Replacement of Subjects .............................................................................................. 62 
5.3.4. Follow-Up of Withdrawn Subjects .............................................................................. 63 
6. Treatment of Patients ................................................................................................................. 63 
6.1. Myrcludex B ....................................................................................................................... 63 
6.1.1. Formulation .................................................................................................................. 63 
6.1.2. Container Closure System ............................................................................................ 63 
6.1.3. Drug Storage and Handling .......................................................................................... 63 
6.2. Dosing and Administration of Myrcludex B ...................................................................... 64 
6.3. Previous and Concomitant Medications ............................................................................. 65 
6.4. Prohibited Products ............................................................................................................. 66 
6.5. Methods to Control Patients’ Compliance with Study Procedures ..................................... 66 
7. Efficacy Assessments ................................................................................................................ 66 
7.1. Efficacy Endpoints .............................................................................................................. 66 
7.2. Efficacy Assessment Methods and Time Points ................................................................. 67 
8. Safety Assessment ..................................................................................................................... 68 
8.1. Safety Endpoints ................................................................................................................. 68 
8.2. Adverse Events ................................................................................................................... 68 
8.2.1. Definitions .................................................................................................................... 69 
8.2.2. Suspected Unexpected Serious Adverse Reaction (SUSAR) ...................................... 70 
8.2.3. Follow-Up Period and Documentation ........................................................................ 70 
8.2.4. Characteristics of Adverse Events................................................................................ 71 


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8.2.5. Investigator’s Notifications of Serious Adverse Events .............................................. 72 
8.2.6. Second Assessment ...................................................................................................... 72 
8.2.7. Expedited Reporting ..................................................................................................... 73 
8.2.8. Pregnancy ..................................................................................................................... 73 
8.2.9. Reporting Requirements after the Study ...................................................................... 73 
8.3. Clinical Laboratory Abnormalities and Other Abnormalities Considered AEs or SAEs
 ................................................................................................................................................ 73 
8.4. Toxicity Management ......................................................................................................... 74 
Grades 1 and 2 Laboratory Abnormality or Clinical Event ................................................... 75 
Grade 3 Laboratory Abnormality or Clinical Event............................................................... 75 
Grade 4 Laboratory Abnormality or Clinical Event............................................................... 75 
8.5. Risks for Females of Childbearing Potential and Risk during Pregnancy .......................... 75 
9. Statistical Analysis .................................................................................................................... 77 
9.1. Analytical Methods ............................................................................................................. 77 
9.1.1. General Information ..................................................................................................... 77 
9.1.2. Demographics and Baseline Characteristics ................................................................ 77 
9.1.3. Efficacy Analysis ......................................................................................................... 77 
9.1.4. Safety Analysis ............................................................................................................. 78 
9.2. Planned Number of Subjects ............................................................................................... 78 
9.3. Significance Level .............................................................................................................. 80 
9.4. Interim and Final Data Analysis ......................................................................................... 80 
9.5. Handling of Missing and Non-Evaluable Data ................................................................... 80 
9.6. Reporting of Any Deviations from Initial Statistical Plan .................................................. 80 
9.7. Selection of Subjects for Statistical Analysis ..................................................................... 80 
10. Direct Access to Source Data/ Documents .............................................................................. 81 
10.1. Access and Review of Source Data and Records ............................................................. 81 
10.2. Additional Information ..................................................................................................... 81 
11. Quality Control and Assurance ............................................................................................... 81 
11.1. Periodic Monitoring .......................................................................................................... 81 
11.2. Audit and Inspection ......................................................................................................... 81 
12. Ethical and Legal Issues .......................................................................................................... 81 
12.1. Good Clinical Practice ...................................................................................................... 81 
12.2. Patient information leaflet and informed consent form .................................................... 82 
12.3. Confidentiality .................................................................................................................. 82 


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12.4. Responsibilities of Principal Investigator ......................................................................... 82 
12.5. Approval of Trial Protocol and Amendments ................................................................... 83 
12.6. Notification of Regulatory Authorities ............................................................................. 83 
12.7. Continuous Information to Independent Ethics Committee ............................................. 83 
13. Data Management .................................................................................................................... 83 
13.1. Data collection .................................................................................................................. 83 
13.2. Data handling .................................................................................................................... 84 
13.3. Storage and archiving of data ........................................................................................... 84 
14. Insurance .................................................................................................................................. 84 
15. Publication and Other Use of Study Results ........................................................................... 85 
16. Confidentiality ......................................................................................................................... 85 
17. Protocol Amendments and/or Revisions ................................................................................. 85 
18. References ............................................................................................................................... 86 
 
 
 


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List of Figures  
Figure 1а. Phase II Study Scheme ................................................................................................. 35 
 
List of Tables  
Table 1. Study Flowchart .............................................................................................................. 36 
 
 
 


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Protocol Synopsis  
Protocol Code: MYR 202 
 
 
 
Investigational Product: Myrcludex B 
Study Title:  
A Multicenter, Open-label, Randomized Clinical Study to Assess 
Efficacy and Safety of 3 Doses of Myrcludex B for 24 Weeks in 
Combination with Tenofovir Compared to Tenofovir Alone to 
Suppress HBV Replication in Patients with Chronic Hepatitis D 
Clinical Phase  
Phase II 
Background 
Information:  
HDV is a small RNA virus, which requires helper functions from 
HBV for virion assembly and propagation, and uses the HBV 
envelope for virus release and infection of new cells.  
About 5-15% of chronically HBV infected are co-infected with 
HDV. Several studies have shown that chronic HDV infection leads 
to more severe liver disease than chronic HBV mono-infection, with 
an accelerated course of fibrosis progression, an increased risk of 
hepatocellular carcinoma and early decompensation in the setting of 
cirrhosis. A recent 28 years follow-up study on hepatitis delta 
patients from Italy showed that 25% of patients with cirrhosis 
developed HCC and that liver failure was the cause of death in about 
three fifths of patients (Romeo et al, 2009). Liver cirrhosis and 
cancer occur 10-15 years earlier in HBV/HDV co-infection, and the 
5-year mortality of co-infected individuals is twice that of HBV 
mono-infection (German Guideline for Prophylaxis, Diagnostics and 
Treatment of HBV infection, Cornberg et al. 2007).  
Current treatment options for patients with delta hepatitis are very 
limited as interferon alfa is able to clear HDV only in very few 
patients and is associated with significant side-effects. PEG-INF-a 
has also been used in small trials to treat delta hepatitis with 
sustained virological response rates of about 20%. Moreover, 
nucleoside and nucleotide analogues used for the treatment of HBV 
infection have been shown to be ineffective against HDV. A huge 
medical need remains for treating of chronic HDV infection as 75% 
of HBV/HDV co-infected individuals lack therapeutic options 
entirely.  
Trial Population:  
The study will enroll patients with chronic HDV infection, positive 
HDV RNA test at Screening, Patients who failed previous interferon 
therapy or for whom, in the opinion of the investigator, such therapy 
is contraindicated (including history of interferon intolerance), as 
well as cirrhotic patients are allowed. Cirrhotic patients will be 
included after an interim safety evaluation and upon a separate 
notification by the sponsor. 
Number of Subjects  
It is planned to screen up to 200 patients, and randomize 120 patients 
in the 1:1:1:1 ratio to one of the four treatment arms. This is a 
multinational trial. In Germany, it is planed to include up to 30 
patients.  
Study Design:  
This is a multicenter, open-label, randomized clinical trial.  
Taking into consideration the screening failure rate, approximately 


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up to 200 patients will be screened, and 120 patients will be 
randomized in the 1:1:1:1 ratio to one of the four treatment arms:  
Arm A (30 patients): Myrcludex B, 2 mg/day subcutaneously (s.c.) 
for 24 weeks + tenofovir with a further follow-up period of 24 weeks 
of continued tenofovir therapy.  
Arm B (30 patients): Myrcludex B, 5 mg/day subcutaneously (s.c.) 
for 24 weeks + tenofovir with a further follow-up period of 24 weeks 
of continued tenofovir therapy.  
Arm C (30 patients): Myrcludex B, 10 mg/day subcutaneously (s.c.) 
for 24 weeks + tenofovir with a further follow-up period of 24 weeks 
of continued tenofovir therapy.  
Arm D (30 patients): tenofovir treatment for 48 weeks.  
The main part of the study includes Screening period of 28 days 
(Days -28/-1), pre-treatment period for patients, for whom a 
preliminary therapy with tenofovir of up to 84 days is indicated, 
baseline randomization visit (Day 1), and study period of 24 weeks. 
Follow-up period will be 24 weeks for all treatment arms.  
Screening 
The following procedures will be done during screening (up to 
28 days before the first dose of the study drug or pre-treatment 
phase): informed consent form signing, physical examination 
(including weight), safety laboratory tests, serology tests (HIV, 
HCV, HBsAg and HBeAg antibodies, HBsAg, HBeAg), HCV RNA 
in patients with HCV antibodies, antibodies to HDV, HDV RNA, 
transient liver elastometry (Fibroscan), abdominal ultrasound, urine 
pregnancy test, breath alcohol test, urine drug screening (test strips), 
evaluation of inclusion/ exclusion criteria.  
Tenofovir Pre-treatment Period  
All patients, who meet all inclusion and none of the exclusion criteria 
and who have not received treatment with nucleoside/ nucleotide 
analogues for at least 12 weeks before the planned start of study 
treatment, will be receiving protocol-defined nucleotide analogue 
(tenofovir) for 12 weeks prior to randomization.  
Randomization Visit  
All patients, who meet inclusion/ exclusion criteria and who received 
treatment with nucleoside/ nucleotide analogues for at least 12 weeks 
before the planned start of study treatment or underwent protocol-
specified tenofovir pre-treatment, will be asked to attend 
Randomization Visit. The following tests and procedures are 
performed at this visit: physical examination (including weight), 
safety laboratory tests, virology parameters, serum fibrosis marker, 
immunogenicity, HBV and HDV genotyping and resistance analysis 
(in patients who have not underwent prior treatment with tenofovir).  
All assessments at this visit will be regarded as baseline for safety 
monitoring. Upon completion of all protocol-defined procedures, 
patients are randomly assigned to one of the 4 treatment arms and 


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receive study medication for the first 28 days of use.  
Treatment Period 
Treatment with the study medication in combination with tenofovir 
or tenofovir alone will last for 24 weeks, followed by a 24-week 
follow-up period.  Treatment will be performed in the outpatient 
settings.  
Follow-up Period  
Follow-up period lasts for 24 weeks. During this period, patients will 
receive treatment with tenofovir.  
Assessments  
Time points for study assessments are shown in Study Schedule. 
1. Pharmacokinetics  
For a more precise investigation of the possible study drug 
accumulation all the patients of each Myrcludex B treatment arm 
will be included in this sub-study. 
Blood samples for pharmacokinetic study are to be collected at 
Week 4, 8, 12, 16, 20, 24 (1 hour +/- 15 min after Myrcludex B 
administration).  
Blood samples from the patients are to be collected on at 
randomization visit (1 hour +/- 15 min after Myrcludex B 
administration).  
 
Study Duration  
Up to 64 weeks, including Screening.  
Interim and Final Data Analysis  
When the last patient completes 24-week treatment period, viral load 
data from all treatment arms, obtained up to Week 24, will be 
analyzed based on PCR results for HDV RNA (negative PCR results 
for HDV RNA or decrease by ≥2 log from baseline at Week 24 will 
be the endpoint).  These data will be included into the Interim Report 
of this clinical trial.  
When the last patient completes follow-up period, study data will be 
analyzed for all subjects completing 48-week treatment period, Final 
Study Report will be prepared and submitted to regulatory 
authorities.  
  
Study Endpoints:  
Efficacy Endpoints  
Primary Efficacy Endpoint:  
 HDV RNA negativation or decrease by ≥2 log10 from 
baseline to Week 24.  
Secondary Efficacy Endpoints:  


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 Durability of HDV RNA response to 24 weeks post treatment 
 Combined response: HDV RNA negativation or ≥2 log 
decline and normal ALT at treatment week 24 
 Changes in ALT values at Week 24 and Week 48 compared 
to baseline. 
 Lack of fibrosis progression based on transient elastometry 
(Fibroscan) at Week 24 compared to baseline.  
 Changes (absence of increase) in fibrosis marker: serum 
alpha-2-macroglobulin at Week 24 and Week 48 compared to 
baseline.  
 Changes in HBsAg (decreased levels, disappearance of 
HBsAg, antibodies to HBsAg) at Week 24 and Week 48 
compared to baseline. 
 Change in HBV DNA levels at Week 24 and Week 48 
compared to baseline.   
Safety Endpoints  
 Adverse events, physical examination, vital signs, 12-lead 
ECG, hematology, coagulation panel, blood chemistry, 
urinalysis, blood bile acids levels.  
 Development of anti- Myrcludex B antibodies.  
Investigational Product 
Doses  
Study Drug 
Phase IIa study in HDV patients demonstrated efficacy of the 2 mg 
dose. The 10 mg dose showed the most prominent effect in a phase 
Ib/IIa study in patients with chronic hepatitis B.  
Concomitant Medication for Hepatitis B Infection  
Tenofovir, used for concomitant treatment for hepatitis B infection, 
is approved to treat chronic HBV infection. Tenofovir dose will be 
selected based on Summary of Product Characteristics.  
Inclusion Criteria: 
1. Age from 18 to 65 years inclusively at the time of signing 
Informed Consent Form.  
2. Positive serum HBsAg for at least 6 months before Screening.  
3. Positive serum anti-HDV antibody for at least 6 months before 
screening.  
4. Positive PCR results for serum HDV RNA at Screening.  
5. Patients with liver cirrhosis, irrespective of previous interferon 
treatment1.  
6. Patients without liver cirrhosis, who failed prior interferon 
treatment or for whom, in the opinion of the Investigator, such 
                                                 
1 Patients with liver cirrhosis should be included in case the interim analysis (Section 9.4. Interim and Final Data 
Analysis) will provide positive safety assessment. The sponsor will notify the centers on the results of the analysis 
and the permission to enroll cirrhotic patients. 


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treatment is currently contraindicated (including history of interferon 
intolerance)2.  
7. Alanine aminotransferase level >1 x ULN, but less than 
10 x ULN.  
8. Previous nucleotide/nucleoside analogue treatment within at least 
12 weeks prior to the planned start of study treatment or subject’s 
willingness to take tenofovir for at least 12 weeks prior to the 
planned start of study treatment.  
9. Negative urine pregnancy test for females of childbearing 
potential.  
10. Inclusion criteria for female subjects:  
 Postmenopausal for at least 2 years, or  
 Surgically sterile (total hysterectomy or bilateral 
oophorectomy, bilateral tubal ligation, staples, or another 
type of sterilization), or  
 Abstinence from heterosexual intercourse throughout the 
study, or  
 Willingness to use highly effective contraception  throughout 
the study and for 3 months after the last dose of the study 
medication.  
11. Male and female subjects must agree to use a highly effective 
contraception3 throughout the study and for 3 months after the last 
dose of the study medication. 
12. Male subjects must agree not to donate sperm throughout the 
study and for 3 months after the last dose of the study medication. 
Exclusion Criteria: 
1. Child-Pugh score of B-C or over 6 points.  
2. HCV or HIV coinfection. Subjects with anti-HCV antibodies can 
be enrolled, if screening HCV RNA test is negative.  
3. Creatinine clearance <60 mL/min.   
4. Total bilirubin ≥ 2mg/dL. Patients with higher total bilirubin 
values may be included after the consultation with the Study`s 
Medical Monitor, if such elevation can be clearly attributed to 
Gilbert’s syndrome associated with low-grade hyperbilirubinemia. 
5. Any previous or current malignant neoplasms, including hepatic 
carcinoma.  
                                                 
2 Patients with previous interferon treatment can be enrolled only at least 30 days after the last interferon dose.  
3 According to CTFG Recommendations related to contraception and pregnancy testing in clinical trials dated 15 
Sep 2014, the following birth control methods should be considered as highly effective: 1) combined (estrogen 
and progestogen containing) hormonal contraception associated with inhibition of ovulation 
(oral, intravaginal, transdermal); 2) progestogen-only hormonal contraception associated with 
inhibition of ovulation (oral, injectable, implantable); 3) intrauterine device (IUD); 4) 
intrauterine hormone-releasing system (IUS); 5) bilateral tubal occlusion; 6) vasectomised 
partner; 7) sexual abstinence. 


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6. Systemic connective tissue disorders.  
7. NYHA (New York Heart Association) class III-IV congestive 
heart failure.  
8. Patients with uncontrolled arterial hypertension (BP 
>150/100 mm Hg despite antihypertensive treatment) within 
3 months prior to start of clinical phase of the study.  
9. Previous or unstable concurrent diseases or conditions that in 
investigator`s opinion prevent subject’s enrolment into the study.  
10. Patients with mental disorders or social circumstances that 
preclude them from following protocol requirements.  
11. Current or previous decompensated liver disease, including 
coagulopathy, hyperbilirubinemia, hepatic encephalopathy, 
hypoalbuminaemia, ascites, and esophageal varices hemorrhage.  
12. Patients with history of pancreatitis or pancreatic insufficiency. 
13. WBC count <3000 cells/mm3.  
14. Neutrophil count <1500 cells/mm3. 
15. Platelet count <60,000 cells/mm3. 
16. Proof of use of prohibited psychotropic agents at Screening.  
17. Use of interferons within 30 days before Screening.  
18. History of solid organ transplantation.  
19. Current alcohol abuse or alcohol abuse within 6 months prior to 
enrolment in this study.  
20. History of disease requiring regular use of systemic 
glucocorticosteroids.   
21. Pregnant or breast-feeding females.   
22. Participation in another clinical study within 30 days prior to 
Screening.  
23. Prior treatment with Myrcludex B in previous studies.  
Statistical Analysis:  
Primary efficacy analysis will be based on the following efficacy 
endpoint:  
 Negative PCR results for HDV RNA or decrease by ≥2 log 
from baseline at Week 24.  
Treatment arms will be compared using the Wald test for Superiority 
by Margin of 5%;  95% Clopper-Pearson confidence interval will 
also be calculated for treatment response rates (for each treatment 
arm). Each experimental treatment arm (Myrcludex B) will be 
compared to the control arm receiving tenofovir alone. Each 
Myrcludex B treatment arm will be compared to the control arm 
separately. Hypotheses will be tested sequentially, using Bonferroni-
Holm method.  Null hypotheses will be defined for each prior test, 
and appropriate p-values will be calculated (based on data obtained 
in the study). After that, null hypotheses will be rejected in 


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descending order of respective p-values for critical values of type I 
error (α), calculated as α/(k – i + 1), where k is the number of 
planned comparisons and i is the sequential number of the 
comparison.  
Qualitative secondary endpoints (ALT normalization and 
disappearance of HBsAg/ seroconversion) will be analyzed using the 
Fisher’s exact test.  Quantitative secondary endpoints (serum fibrosis 
marker, HBsAg and HBV DNA) will be presented as absolute values 
and changes from baseline. To compare treatment arms on the basis 
of endpoints two-sided Wilcoxon rank sum test will be employed 
with adjustment at the significance level of 0.0167.  If the 
assumptions necessary for carrying out parametric approach are not 
violated, parametric analogues of the above methods will be used: 
ANOVA/ ANCOVA, the Student’s t-test for dependent  samples.  
The assumptions will be verified using graphical methods.   
Numerical safety data will be presented as summary tables of 
descriptive statistics for each treatment arms.    Descriptive statistics 
will be provided for each numerical safety endpoint. AEs will be 
tabulated per treatment group and System Organ Class (SOC) at 
Preferred Term (PT) level of MedDRA. SAEs will be reported in 
form of narratives. Vital sign and laboratory data as well as change 
from baseline will be summarized (where applicable) by visit of 
assessment and by treatment group. In addition, shifts in laboratory 
parameters will be presented by treatment group. 
 
 
 


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List of Abbreviations  
AE 
- Adverse event  
AFP  
- Alpha fetoprotein  
ALT 
- Alanine aminotransferase   
AP 
- Alkaline phosphatase 
AST 
- Aspartate aminotransferase   
AUC0-t 
- Area under curve from dosing to time t  
AUCtau 
- Area under curve over the dosing interval  
cccDNA 
- Covalently closed circular deoxyribonucleic acid 
CHB 
- Chronic hepatitis B 
CHD 
- Chronic hepatitis B with delta-agent  
CK 
- Creatine kinase  
Cmax 
- Maximal concentration  
Cmean 
- Mean concentration  
Cmin 
- Minimal concentration  
CRF 
- Case Report Form 
CRP 
- C-reactive protein  
CT 
- Computer tomography  
CTCAE 
- Common Terminology Criteria for Adverse Events   
CTFG 
-Clinical Trial Facilitation Group 
DLT 
- Dose-limiting toxicity 
DNA 
- Deoxyribonucleic acid  
ECG  
- Electrocardiogram  
FDA 
- U.S. Food and Drug Administration 
GCP 
- Good Clinical Practice  
GCP 
- Good Clinical Practice  
GGT 
- Gamma-glutaminetransferase 
GMP 
- Good Manufacturing Practice  
HBeAg 
- Hepatitis B virus e-antigen  
HBsAg 
- Hepatitis B virus s-antigen 
HBV 
- Hepatitis B virus  
HCC 
- Hepatocellular carcinoma 
HCV 
- Hepatitis C virus 
HDV 
- Hepatitis delta (D) virus  


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HED 
- Human equivalent dose  
HLA 
- Human leukocyte antigen 
HPLC 
- High-performance liquid chromatography 
HPLC-MS 
- High-performance liquid chromatography - mass spectrometry 
IC 
- Ion chromatography  
ICF 
- Informed Consent Form  
ICH 
- International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC  
- Independent ethics committee  
IL 
- Interleukin  
IMP  
- Investigational medicinal product  
IMPD 
- Investigational Medicinal Product Dossier 
INF-α 
- Interferon-alfa  
INR 
- International normalized ratio  
IP  
- Investigational product  
IRB 
- Institutional Review Board  
IU  
- International unit  
IWRS 
- Interactive Web-Response System  
LDH 
- Lactate-dehydrogenase   
MBX 
- Myrcludex B  
MCH 
- Mean corpuscular hemoglobin 
MCHC  
- Mean corpuscular hemoglobin concentration 
MCV 
- Mean corpuscular volume 
MedDRA 
- Medical Dictionary for Regulatory Activities 
MRI 
- Magnetic resonance imaging 
MRT 
- Mean residence time  
NCI 
- National Cancer Institute (USA)  
NOAEL 
- No Observed Adverse Effect Level 
NOEL 
- No Observed Effect Level 
NTCP 
- Na+- taurocholate cotransporter polypeptide 
NYHA 
- New York Heart Association  
PBMC 
- Peripheral mononuclear blood cells 
Ph. Eur. 
- European Pharmacopoeia 
PK 
- Pharmacokinetics  
RH 
- Relative humidity  


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RIA 
- Radioimmunoassay 
s.c. 
- Subcutaneous  
SAE 
- Serious adverse event  
SAP 
- Statistical Analysis Plan  
Scr 
- Screening period 
SOC 
- System Organ Class  
SOP 
- Standard Operating Procedure  
SUSAR 
- Suspected unexpected serious adverse reaction  
T1/2 
- Terminal half-life  
TEC 
- Therapeutic effect concentration  
Tmax 
- Time to reach maximum concentration  
TMF 
- Trial Master File  
TNFα 
- Tumor necrosis factor α 
TRAE -  
Therapy related adverse event 
ULN 
- Upper limit of normal  
WFI  
- Water for injection  
 
 
 


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1. Administrative Study Structure  
1.1. Protocol Identification  
Study Title:  
A Multicenter, Open-label, Randomized Clinical Study to Assess 
Efficacy and Safety of 3 Doses of Myrcludex B for 24 Weeks in 
Combination with Tenofovir Compared to Tenofovir Alone to 
Suppress HBV Replication in Patients with Chronic Hepatitis D 
Protocol Number: 
MYR 202 
Version: 
Country-specific version 3.0 (Germany) 
Date: 
25 December 2017 
 
 
 


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1.2. Sponsor’s and Authorized Representatives’ Contact Information  
Study Sponsor: 
Name of the contact person: Yana Deloveri. 
Position: CEO  
Organization: OOO Hepatera, Russia 
Sponsor’s Address: 12/19 Verkhnyaya Radischevskaya Ul, Bld. 1, 
Moscow, 109240 
Telephone/fax: +7 (495) 726-52-53. 
E-mail: deloveri@ammaxwell.ru 
Sponsor`s Legal 
Representatvive 
Name of the contact person: Dr. Alexander Alexandrov 
Position: Medical Director 
Organization: MYR GmbH 
Address: Weinbergsweg 66, 61348 Bad Homburg, Germany 
Telephone: +491777168259 
E-mail: alexandrov@myr-pharma.com 
Study Management 
and Monitoring: 
Name of the contact person: Anton Chugunov 
Position: Project Manager 
Organization: Smooth Clinical Trials 
Address: 153, business center „LIGOV“, floor 10, Ligovsky pr., Saint-
Petersburg, 192007, Russia 
Telephone: +7 812 913 04 23 
E-mail: chugunov@smoothdd.com 
 
 
 


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1.3. Signature Page 
MYR 202 
Sponsor:  
Name: Yana Anatolyevna Deloveri. 
Position: Director General  
Organization: OOO Hepatera, Russia 
Sponsor’s Address: 12/19 Verkhnyaya 
Radischevskaya Ul, Bld. 1, Moscow, 
109240 
 
 
 
……………………………. 
Date  
 
……………………………. 
Signature  
 
Sponsor’s legal representative:  
Name of the contact person: Dr. 
Alexander Alexandrov 
Position: Medical Director 
Organization: MYR GmbH 
Address: Weinbergsweg 66, 61348 Bad 
Homburg, Germany 
 
 
……………………………. 
Date 
 
……………………………. 
Signature  
 
Lead clinician 
Prof. Dr. Heiner Wedemeyer 
Dept. of Gastroenterology, Hepatology 
and Endocrinology 
Medizinische Hochschule Hannover 
Carl-Neuberg Str. 1 
30625 Hannover, Germany 
……………………………. 
Date 
 
……………………………. 
Signature 
 
 
 


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1.4. 
Sites contact list and Principal Investigators 
Clinical Site 1 
“Moscow Regional Research Clinical Institute n.a. M.F. 
Vladimirskiy”, 61/2, Shchepkina str., 129110, Moscow, Russia 
Principal Investigator 
Pavel Olegovich Bogomolov, MD, PhD 
Clinical Site 2 
State Budgetary Institution of Healthcare  “Stavropol Regional 
Clinical Hospital”, 1, ulitsa Semashko, 355000, Stavropol, Russia  
Principal Investigator 
Nataliya Ioganovna Geyvandova, MD, DMSc 
Clinical Site 4 
State Budgetary institution of the Republic of Sakha (Yakutia) 
"Yakutsk Clinical Hospital" 
677005, Republic of Sakha (Yakutia), Yakutsk, ul. Stadukhina, 
81, build. 5 
Principal Investigator 
Snezhana Spiridonovna Slepcova 
Clinical Site 5 
State Budgetary Healthcare Institution "Moscow Clinical 
Scientific and Practical Center of the Department of Public 
Health of Moscow" 
111123, Moscow, Highway Enthusiasts, 86 
Principal Investigator 
Igor Gennadievich Bakulin 
Clinical Site 6 
State Autonomous Healthcare Institution "Republican Clinical 
Infectious Diseases Hospital named after Prof. A.F. Agafonov 
"(SAHI RCID) 
420138, Republic of Tatarstan, Kazan, Pobedy Avenue, 83 
Principal Investigator 
Ilsiyar Mansurovna Khaertunova 
Clinical Site 12 
State Budgetary Educational Institution of Higher Professional 
Education “South Ural State Medical university” of the Ministry 
of Healthcare of the Russian Federation, 2 Cherkasskaya str., 
454052, Chelyabinsk, Russia 
Principal Investigator 
Olga Igorevna, Sagalova, MD, PhD, DMSc 
Clinical Site 13 
State Budget Health Institution of Moscow "Infectious Clinical 
Hospital No. 1 of the Moscow Healthcare Department" 
125367, Moscow, Volokolamskoye road, 63 
Principal Investigator 
Marina Rusanova from January 13, 2017 (Elena Andreevna 
Nurmukhametova, till 13.01.2017) 
Clinical Site 16 
LLC "Clinic of Modern Medicine" 
121293, Moscow, Ploschad Pobedi, 2, bldg. 1 
Principal Investigator 
Tatyana Vladimirovna Stepanova 
Clinical Site 18 
State Budgetary Educational Institution of Higher Professional 
Education "Novosibirsk State Medical University" of the 
Ministry of Health of the Russian Federation 
630091, Novosibirsk, Krasny prospect, 52  
Principal Investigator 
Marina Fedorovna Osipenko 


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Clinical Site 19 
Medical Company “Hepatolog” LLC, 36A, Serdobskaya str., 
430063, Samara, Russia 
Principal Investigator 
Vyacheslav Gennadievich Morozov, MD, PhD, DMSc 
Clinical Site 20 
Federal budgetary research institution Central Research Institute 
of Epidemiology  
111123, Russia, Moscow, ul. Novogireevskaya, house 3а  
Principal Investigator 
Vladimir Petrovich Chulanov 
Clinical Site 41 
Klinik für Gastroenterologie, Hepatologie und Endokrinologie, 
Medizinische Hochschule Hannover Carl-Neuberg-Str. 1, 30625 
Hannover  
Principal Investigator 
Prof. Dr. Heiner Wedemeier  
Clinical Site 42 
UniversitätsKlinikum Heidelberg – Medizinische Klinik, 
Abteilung Klinische Pharmakologie & Pharmakoepidemiologie  
Im Neuenheimer Feld 410 - 69120 Heidelberg 
Principal Investigator 
Prof. Dr. Walter Haefeli  
Clinical Site 43 
Ifi-Institut für interdisziplinäre Medizin an der Asklepios Klinik 
St. Georg, Haus L 
Lohmühlenstr. 5 20099 Hamburg 
Principal Investigator 
Prof. Dr. Jörg Petersen 
Clinical Site 44 
Universitätsklinikum Hamburg-Eppendorf Medizinische Klinik 
Studienambulanz Hepatologie - Haus O28 
Martinistr. 52  20246 Hamburg Germany 
Principal Investigator 
Dr. Julian Schulze-zur-Wiese 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.5. 
Investigator’s Signature  
I have read the protocol and appendices. I understand the content and intend to fully comply with all 
requirements and the applicable current local and international regulations and guidelines. No changes 
will be made without formal authorization by the Sponsor in the form of a protocol amendment. 
 
 
Investigator:  
Signature: _________________________________________________________________ 
Full Name: _________________________________________________________________ 
Institution: ____________________________________________________________________ 
Date: _____________________________________________________________ (DD/MMM/YYYY) 
 
 


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1.6 Central Laboratories Contact List 
1) Central laboratory №1 (Immunogenicity) 
Prolytiс GmbH 
Alt Fechenheim 34 
D-60386 Frankfurt am Main, Germany 
Contacts:  
Dr. Elizabeth Wilson, Email:  Elizabeth.Wilson@prolytic.de 
DM, Prof. Dorothee Krone, Email:  Dorothee.Krone@prolytic.de 
Tel:+49 (0) 69 4109 2534, Fax: +49 (0) 69 4269 4784 
 
2) Central laboratory №2 (Virology)  
Medizinische Hochschule Hannover 
Department of Gastroenterology, Hepatology and Endocrinology (Klinik für 
Gastroenterologie, Hepatologie und Endokrinologi) 
Carl-Neuberg_Straße 1 
D-30625 Hannover, Germany 
Contacts: 
Dr. Patric Lehmann, Email: Lehmann.Patrick@mh-hannover.de 
Dr. Birgit Bremer, Email: Bremer.Birgit@mh-hannover.de  
Tel:+49 (0) 51 1532 3304 
 
3) Central laboratory №3 (HDV and HBV genotyping, resistance, NTCP 
polymorphism, bile acids) 
Universitätsklinikum Heidelberg 
Department of Infectious Diseases, Molecular Virology University  (Zentrum für 
Infektiologie, Abteilung für Molekulare Virologie) 
Im Neuenheimer Feld 672 
D-69120 Heidelberg, Germany 
 Contacts: 
Dr. Katrin Schöneweis, Email: Katrin.Schoeneweis@med.uni-heidelberg.de 
MD, Prof. Stephan Urban, Email: Stephan.Urban@med.uni-heidelberg.de  
 
 
 
 
 


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4) Central laboratory №4 (PK) 
Universitätsklinikum Heidelberg 
Department of Infectious Diseases, Molecular Virology University (Zentrum für Innere 
Medizine, Abteilung Klinische Pharmakologie und Pharmakoepidemiologie, Analytisch-
Chemisches Labor) 
Im Neuenheimer Feld 410 
D-69120 Heidelberg, Germany 
Contacts: 
MSc, PhD., Juergen Burhenne, Email: Juergen.Burhenne@med.uni-heidelberg.de  
 
5) Central laboratory  №5 (biopsy study: immunohistochemical study, intrahepatic 
options) 
Universitätsklinikum Hamburg-Eppendorf 
Zentrum Innere Medizin (Zentrum Innere Medizin, I. Medizinische Klinik, AG 
Virushepatitis) 
Büro: Raum 332, 3.OG, Haus O58 
Martinistraße 52 
20246 Hamburg, Germany 
Contacts: 
DM, Prof. Maura Dandri, Email: m.dandri@uke.de 
Dr. Marc Lütgehetmann, Email: m.luetgehetmann@uke.uni-hamburg.de 
 
 
6) Central laboratory № 6 (separate bile acids) 
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology 
Auerbachstr. 112 
70376 Stuttgart, Germany  
Contacts: 
Dr. rer. nat. Mathias Haag,  Email: mathias.haag@ikp-stuttgart.de 
Dr. Matthias Schwab, Email: Matthias.Schwab@ikp-stuttgart.de 
Phone +49 (0)711 / 8101-5429        
 
 
 
 
 


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2. Study Rationale  
Hepatitis delta is liver inflammation caused by infection with hepatitis D virus, which requires 
presence of HBsAg for complete replication and transmission. Hepatitis D virus is a hepatotropic 
virus with a small RNA genome, HDV antigen. HDV is necessarily associated with HBV 
infection, as HDV ribonucleoprotein buds through the HBsAg secretory pathway. HDV genome 
is a single-stranded RNA of 1,680 bases; it has historical homology with viroids or plant virus 
satellite RNA [1].  The HDag consists of 2 isoforms, the small 24 kD protein which is required 
for the replication, and the larger 27 kD protein which is needed for virion formation [2].  Eight 
genotypes of HDV exist, whereas genotype 1 is the most common in the world and in Europe 
[3].  
In general, hepatitis delta is a highly pathogenic virus causing acute and chronic liver disease. 
Although benign course of the disease has been described [4], patients with hepatitis delta 
usually have progressive liver disease leading to compensated or decompensated cirrhosis. 
Evidence was reported in the literature, that unlike HBV, HDV can be associated with direct 
cytotoxicity which may hasten fibrosis process [5, 6]. However, the immune system plays the 
major role in the clearance of the infected hepatocytes; levels of HDV viremia are not directly 
associated with histological changes [7]. There is no histological feature distinctive of hepatitis 
delta from other types of viral hepatitis. Biopsy specimens of patients with chronic hepatitis delta 
exhibit portal and periportal inflammation, fragmentary necrosis, often accompanied by fibrosis 
and cirrhosis. Marked intraglobular infiltration by mononuclear cells and degenerative changes 
in hepatocytes [8] is seen.  Clinically, hepatitis delta may cause acute or fulminant hepatitis, 
chronic infection may lead to asymptomatic carrier state or evolve to rapidly progressive chronic 
liver disease. 
Chronic Hepatitis delta develops in 70–90% of patients with HDV superinfection. The liver 
disease associated with HDV runs a more progressive course than chronic hepatitis B and may 
lead to cirrhosis within 2 years in 10–15% of patients [9]. Hepatitis delta is considered the most 
severe form of viral hepatitis in humans [10], and is associated with progression of liver disease, 
development of cirrhosis and decompensation [11, 12].   
A tertiary clinic study with a longitudinal cohort of patients has shown a clear trend to worse 
survival in HBeAg negative patients with HDV, in comparison to HBV monoinfected [13]. In 
regions endemic for HDV infection, the liver disease is representing a major health care 
challenge. A study from Italy has shown existence of anti-HDV antibodies in as many as 40% of 
patients with liver cirrhosis in 1987. Although this number has declined to 11% in 2000 [14], the 
HDV-caused disease is still a significant burden. A longitudinal study has shown that 20% of 
hepatitis delta patients develop a liver-related first time event during the median follow up time 
of 4 years, vs only 8.5% of HBV monoinfected patients [15].  At baseline, 19.8% of the patients 
of this cohort had cirrhosis, compared to 7.3% of CHB patients. HDV was a cause of death for 
60% of patients in a 28-year study from Italy [16]. HDV co-infection is associated with faster 
progression to fibrosis and cirrhosis, earlier onset of hepatic complications and likelihood of 
liver transplantation [17-19].  Liver cirrhosis and cancer occur 10-15 years earlier in HBV/HDV 
co-infection and the 5-year mortality of co-infected individuals is twice that of HBV 
monoinfection [20].  Chronic HDV infection causes cirrhosis and HCC with annual rates of 4% 
and 2.8%, respectively [16].  
In average, 5-10% of HBsAg positive patients who admit to tertiary centres in Europe are tested 
positive for HDV. The calculation of total number of people affected by hepatitis delta in the EU 
has yielded the estimate of 145,000 persons. Accounting for EU population of 505,665,700 
(2013), the expected prevalence of HDV among EU citizens, under these assumptions, is 2.9 in 
10,000, where best-and worst case assumptions (the limits of the 95 per cent credibility interval) 


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are 1.6 and 4.7 in 10,000, respectively. The worst-case scenario is below the Orphan Drug 
designation threshold of 5 in 10,000 people affected by the condition. 
Very limited literature data could be identified to estimate HDV prevalence in the US. A recent 
study utilizing data of a tertiary center database revealed HDV prevalence of 8% among HBsAg 
carriers [21].  11% of injection drug users were tested positive for HDV in Baltimore; in those 
with chronic HBV infection, 50% were HDV positive [22]. In average, 5-10% of HBsAg 
positive patients who admit to tertiary centers are tested positive for HDV. The calculation of 
total number of people affected by hepatitis delta in the US has yielded the estimate of 63,800 
persons (worst-case scenario). This is below the Orphan Drug designation threshold of 200,000 
people affected by the condition. 
The therapeutic options for HDV co-infected patients are very limited. Only interferons show 
some degree of efficacy in a small proportion of patients with approximately 25% of virological 
and biochemical response. Antiviral agents active against HBV do not work against HDV [18].  
Several clinical trials were recently performed investigating the use of pegylated interferon alpha 
in hepatitis delta. The two largest trials in this indication, HIDIT-1 and HIDIT-2, did show only 
very modest long-term virological results. In the HIDIT-1 clinical trial, pegylated interferon was 
tested in combination with nucleotide analogue adefovir dipivoxil versus either drug alone in 91 
chronically HDV infected patients [23]. At test week 48, 23% of patients on combination 
therapy, 24% on pegylated interferon monotherapy, and no patients on adefovir reached HDV 
RNA negativation. The effect was sustained through follow up week 24. However, the follow up 
study revealed that from 16 individuals who have reached HDV RNA negativity at the end of 
treatment, 9 tested positive within the median follow up of 4.5 years (0.5-5.5 years) [24].  In the 
HIDIT-2 clinical trial, 120 patients received pegylated interferon alpha with or without tenofovir 
disoproxil fumarate for 96 weeks. The prolongation of the interferon treatment to 96 weeks and 
addition of nucleotide analogue tenofovir did not improve sustained virological response rates: 
30% of patients in the combination arm and 23% of patients in the monotherapy arm were HDV 
RNA negative 24 weeks after the end of treatment. Of note, 20 patients (16%) did not complete 
at least week 80 of treatment. A trial involving 49 patients treated with pegylated interferon 
alpha 2b has shown 33% of HDV RNA negativation at the end of treatment (48 weeks) and 25% 
at the end of follow up [25].  
In summary, there is an urgent unmet medical need for new medications to treat chronic HDV 
infection, as currently no treatment options exist for 75% of patients with HBV/HDV 
coinfection.  
2.1. Study Drug Name and Description  
2.1.1. General Properties   
Myrcludex B (MXB) is a myristoylated N-terminal and amidated C-terminal 47-amino acid 
lipopeptide. All amino acids are of L-forms.  
Molecular formula 
 
 
C248H355N65O72 (net) 
Molecular weight 
 
 
5398.9 g/M (mean weight, net) 
Salt 
 
 
 
 
Acetate 
Presentation 
 
 
 
White to off-white powder  
Solution 
 
 
 
Clear, colorless  
MXB is a 47 amino acids long, N-terminally myristoylated, HBV-L-protein derived lipopeptide. 
It blocks the entry of HBV into hepatocytes by binding to and inactivating an NTCP/SLC10A1, 
a bile acid liver transporter serving as essential HBV and HDV entry receptor. MXB was shown 


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to be effective against hepatitis B and delta virus in non-clinical in vitro and in vivo models. In a 
clinical trial, viral load reductions could be shown with best response in 10mg once daily cohort. 
For HDV and HBV, similar degree of efficacy was shown in vitro. In an immune deficient 
animal model, prevention of HDV infection and inhibition of HBV spread was demonstrated. In 
the clinical trial, a profound decline of HDV RNA viremia was shown at a daily dose of 2mg, 
including negativation in 2/7 patients. This suggests a pronounced dependence of HDV 
persistence on de novo infection of hepatocytes and thus a higher sensitivity against entry 
inhibition. This might be linked to pathophysiological properties of HDV/HBV co-infection: 
generally higher degree of immune reaction and inflammation, and possible pronounced 
cytopathic effects of HDV when compared to HBV. Moreover, HDV RNA represents a unique 
marker to measure response in the clinical trials; negativation of HDV RNA is a widely used 
endpoint for clinical trials in this indication. 
MXB will be supplied used to date in sterile vials with a nominal content of 2.0 mg and 5.0 mg 
of Myrcludex-B Acetate. The vial content has to be reconstituted in 1 mL sterile WFI prior to 
administration. The containers and closures are intended for single use. MXB is intended for 
parenteral administration. During the Phase 1 trial, single intravenous dosages of up to 20mg 
were applied to healthy volunteers. In the Phase 1b/2a, subcutaneous dosages of up to 10mg 
daily were applied to chronically HBV and HDV infected patients for the period of up to 24 
weeks with excellent safety profile. 
Further information is available in the Investigator Brochure.   
2.2. Summary of Pre-clinical and Clinical Data  
2.2.1. Pre-clinical Studies  
MXB blocks the entry of HBV into hepatocytes by binding to and inactivating an essential HBV 
entry receptor recently described as NTCP [26]. Myrcludex B acts when the virus has attached, 
and presumably is redirecting HBV entry path to a non-productive cellular channel.  
Antiviral effect was investigated [36] in the HBV and HDV inhibition tests in cell lines 
susceptible to HBV and HDV infection: HepaRG cell line, Tupaia belangeri and PHH primary 
hepatocytes [27, 28].  Secreted HBeAg and HBsAg were measured in cell culture supernatant 
using ELISA as infection markers. Infected cells were calculated using immunofluorescence 
technique with determination of the count of HBcAg-positive cells (HBV) and HDV-Ag-positive 
cells (HDV). IC50 was 14.5 pM to 9.5 nM, depending on the viral load and cell culture. No signs 
of in vitro toxicity measured by LDH release were reported at MBX concentrations of up to 
50 µM.  
The in vivo antiviral activity of acylated HBV derived peptides similar to MXB was tested in 
immunodeficient uPA/RAG-2 mice transplanted with susceptible hepatocytes from Tupaia 
belangeri and PHH. The mice were infected with HBV and the infection was competed by 
different concentrations of the active peptide or a control peptide. In this model, systemic 
application of the peptides allowed the complete prevention of the establishment of a HBV 
infection at 200 µg/kg, the lowest dose tested [29].  Myrcludex B is an optimization product of 
peptides evaluated in this study.  MXB was then tested in uPA/SCID mice transfected with 
human hepatocytes after infection with HBV.  Significant inhibition of HBV spread in the liver 
was observed in MBX-treated animals, compared to placebo-treated animals, as measured by 
serum HBV DNA and HbsAg levels and immunohistology data [30].  
Possible secondary pharmacology effects were explored in a single dose chimpanzee study. The 
chimpanzee is the only relevant animal model as it expresses the receptor for HBV and can 
reliably develop acute and chronic infection. The intravenous application of 300 µg/kg MXB did 
not produce any substance-related clinical or laboratory changes. 


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For the evaluation of the single dose toxicity, a study in CD® rats was performed (single high 
dose was applied in limit test). The study included evaluation of safety pharmacology parameters 
(Irwin screen). I.v.administration of 12.5 mg MXB/kg b.w. to rats did not reveal any signs of 
toxicity. No mortality did occur. 
The evaluation of some toxicology parameters (clinical signs, clinical chemistry/hematology 
evaluations) was included into a single dose chimpanzee secondary pharmacology and 
pharmacokinetic study. 
The repeat dose toxicity was evaluated after daily subcutaneous injection in rats (7 days, 4 
weeks, 6 months) and in dogs (3 months). The studies incorporated cytokine evaluation (4 week 
rat) and safety pharmacology evaluations (3 months dog study).  
In all studies completed so far, no signs of test item related mortality, systemic or local 
intolerance, body weight and body weight gain, food and drinking consumption, hematology and 
clinical biochemistry parameters were observed. Macroscopic necropsy evaluation or 
histological evaluation did not reveal any signs of test item related changes. 
  
2.2.2. Clinical Experience with Myrcludex B 
Three clinical studies have been conducted on Myrcludex-B and two ongoing under clinical trial 
applications: 
 Study MYR 101: 
A Phase 1 Study in Healthy Volunteers (Germany)-completed 
 Study MYR 201: 
A Phase 1b/2a clinical trial in HBV (Russia) - completed 
 Study MYR 102: 
A Phase 1 Drug Interaction Study in Healthy Volunteers 
(Germany) - completed 
 Study MYR 201 (substudy): A Phase  1b/2a study in hepatitis delta patients (Russia) – 
ongoing 
 Study MYR 202: A Phase 2 study of different doses of Myrcludex B on top of tenofovir 
in hepatitis delta (international) 
 
A Phase I single-dose study (MYR 101) was conducted in 36 healthy male volunteers. Selected 
dose groups were 0.3 µg, 3 µg, 10 µg, 100 µg, 800 µg, 3 mg, 5 mg, 10 mg, and 20 mg for 
intravenous application and subcutaneous administration was carried out with 800 µg, 5 mg, and 
10 mg. Each dose was administered to a cohort of 3 consecutive volunteers. For all cohorts and 
both administration routes administration of MXB was uneventful and well tolerated. After 
administration, there were no relevant changes in vital signs (blood pressure, heart rate, 
respiratory rate, and body temperature), 12-lead ECGs, and safety laboratory values. Overall, 85 
AEs were observed in 29 individuals, none of these was serious. Events were equally distributed 
between cohorts and no organ system was predominantly affected. Seventy-four events were 
mild in nature, nine moderate, and only two were severe (grade3) according to CTC-AE 4.0 
criteria (increased lipase; increased amylase). Anti-drug antibodies were measured until 6 
months after exposure and were negative for all individuals.  
MXB has been well tolerated in all volunteers, no SAE and no dose limiting toxicities occurred. 
The AEs were mostly mild in nature and self-limiting and no pattern suggesting a relationship 
with Myrcludex B or unexpected off-target effects were seen. There was no dose-dependency of 
AE frequency or severity. This matches the observations from animal studies, where Myrcludex 
B exhibited a highly specific and exclusive binding to hepatocyte. Therefore, MXB had a good 
safety profile even in the cohorts with high doses in this trial.  


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Myrcludex B showed strong dose dependent pharmacokinetics; the area-under-the-time-plasma-
concentration curve (AUC) increased disproportionally while the clearance and volume of 
distribution decreased with higher doses. The bioavailability of the drug after subcutaneous 
administration was estimated to be 88%. The release after subcutaneous administration was best 
described by a parallel slow and fast first-order process, where 59% of the bioavailable dose was 
absorbed fast and the remaining 41% of the dose was absorbed slowly with absorption half-lives 
of 1.3 h and 5.4 h, respectively. A simulation of the impact of various doses of Myrcludex B on 
the occupancy of the binding target revealed that at doses of 10 mg most of the binding target 
was occupied >80 % for at least twenty hours in a simulated steady-state after subcutaneous 
administration 
A Phase 1 drug interaction study (MYR 102) in healthy volunteers investigated the influence of 
receptor-saturating dose on PK of anti-HBV drug tenofovir. Twelve healthy volunteers received 
245 mg of oral tenofovir disoproxil for 5 days alone followed by 6 days of co-administration of 
10 mg subcutaneous myrcludex B. Plasma samples were collected and myrcludex B, tenofovir, 
and plasma bile acids were quantified. Repeatedly, a 30 µg midazolam microdose was 
administered to determine the impact of the antivirals on CYP3A activity. 
The combination of Myrcludex B and tenofovir was well tolerated. A total of 28 adverse events 
occurred in 10 out of 12 participants, 12 of which were considered to be at least possibly related 
to tenofovir or myrcludex B treatment (anemia (2), first-degree atrioventricular block (1), 
diarrhea (1), nausea (1), injection site hypersensitivity (2), increased ALT (5), increased amylase 
(1), increased AST (1), increased lipase (2), muscular weakness (1), and headache (1)). With the 
exception of one grade 3 increase in lipase levels, all treatment-related adverse events were mild. 
Lipase levels showed marked day to day fluctuations in this participant. Two volunteers 
experienced localized hypersensitivity reactions for about 30 min after each administration of 
myrcludex B (erythema, pruritus) without accompanying signs of systemic anaphylaxis. 
Myrcludex B did not have a significant effect on tenofovir pharmacokinetics including renal 
tenofovir clearance. Myrcludex pharmacokinetic parameters after first and repeated dosing were 
comparable to those observed in two other clinical studies with the substance. Therefore, a 
clinically relevant influence of tenofovir on myrcludex B concentrations seems unlikely. 
Estimated metabolic clearance of midazolam exhibited a downward trend with a gradual 
decrease during the course of the study. Geometric mean values were 1022 ml/min (95% CI: 
801.5, 1303) without co-medication, 869.1 ml/min (679.8, 1111) under tenofovir, and 724.8 
ml/min (592.5, 886.7; p-value 0.02 vs. baseline) under tenofovir and myrcludex B treatment. 
Differences were significant between baseline and co-administration of tenofovir and myrcludex 
B, but not between tenofovir monotherapy (baseline immediately before start of myrcludex B) 
and combination therapy. Therefore, our results did neither confirm nor rule out an influence of 
myrcludex B on CYP3A activity. The small and clinically irrelevant inhibition of CYP3A 
activity by tenofovir or its prodrug might account for the statistically inconclusive results. Co-
administration of regular tenofovir doses with myrcludex B was well tolerated and revealed no 
clinically relevant change in either drug`s pharmacokinetics or CYP3A activity, suggesting that 
these drugs can be safely combined without dose modification. 
 
Phase 1b/2a study in 48 chronic HBV infection is completed (MYR 201). HBeAg negative 
patients with increased ALT levels and viral load above 10,000 copies per mL were randomized 
into following cohorts: 
Cohort A:  
 
0.5 mg MXB daily sc / 12 weeks + 12 weeks follow up 
Cohort B: 
 
1 mg MXB daily sc / 12 weeks + 12 weeks follow up 


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Cohort C:  
 
2 mg MXB daily sc / 12 weeks + 12 weeks follow up 
Cohort D:  
 
0.5 mg Entecavir daily orally / 24 weeks 
Cohort E  
 
5 mg MXB daily sc / 12 weeks + 12 weeks follow up 
Cohort F  
 
10 mg MXB daily sc / 24 weeks + 12 weeks follow up 
 
Safety and tolerability, plasma pharmacokinetic parameters, immunogenicity and virological 
responses are assessed in this trial. Levels of HBsAg, HBV DNA and ALT are used to assess 
efficacy. 
A dose-dependent decrease in viral load was reported at week 12 of treatment. 6 of 8 patients 
(75%) of the 10mg cohort had a decline in serum HBV DNA of more than 1log10 in comparison 
to baseline. The patients of 10mg cohort continued the treatment for 24 weeks, maintaining HBV 
DNA levels achieved at week 12. At lower dose levels, no per cohort dose dependency was 
observed; per cohort, at most 25% of lower dose patients achieved >1 log10 HBV DNA 
reduction at week 12. Normal ALT was reported in 50%-75% of patients receiving Myrcludex B 
at week 12, irrespective of dose level. No effect on HBsAg was observed. 
A a total of 69 adverse events were reported during the study. Overall, in the Myrcludex B 
treatment groups the AEs were predominantly clustered in the same 4 SOCs: General disorders 
and administration site condition; Investigations; Skin and subcutaneous tissues disorders; Blood 
and lymphatic system disorders. In the Entecavir treatment group all the AEs were in the 3 
SOCs: General disorders and administration site condition; Infections and infestations; 
Respiratory, thoracic and mediastinal disorders. A total of 45 adverse events were considered as 
treatment-related (TRAE). In general, treatment-related AEs were of mild severity (a total of 41 
events). The events of moderate severity were erythema, gamma-glutamyltransferase increased, 
reticulocyte increased, injection site dermatitis. Neither treatment group had any reports of AEs 
judged to be severe. There were 2 AEs considered to be serious: drug withdrawal syndrome 
reported for 1 patient of the Myrcludex B 1 mg group (Arm B) and 1 patient of the Myrcludex B 
2 mg group (Arm C). There were no patients who prematurely discontinued participation in the 
study due to AE/SAE. There were no deaths in the study. Levels of bile acids are important 
secondary pharmacodynamics parameter, as a bile acid transporter NTPC is the target of MXB. 
A dose-dependent, asymptomatic increase of bile acids which are NTCP substrates (ie 
taurocholate and glycocholate) was detected; whereas lithocholic acid (non-substrate for NTCP) 
levels were not affected. Antibodies to MXB were detected in 58% of patients of MXB dose 
groups. No correlation was observed between the appearance of antibodies and 
pharmacodynamic parameters. Elevated levels of bile acids, which are a secondary 
pharmacodynamic parameter and are indicative for drug-target binding, were detected 
independent of antibody positivity. Virological and biochemical response was not different in 
patients who were antibody-positive versus antibody-negative. 
A Phase 2a study is currently ongoing in hepatitis delta patients. 24 patients with chronic 
hepatitis delta, determined by presence of anti-HDV antibody in serum and HBsAg positivity for 
more than 6 months were included in the study and randomized into the following 3 arms, 8 
patients each: 
Arm A:  
Myrcludex B 2mg once daily sc for 24 weeks, followed by pegylated interferon 
alpha, 180µg weekly sc for 48 weeks 
Arm B:  
Pegylated interferon alpha, 180µg weekly sc for 48 weeks; addition of Myrcludex 
B 2mg once daily sc for the first 24 weeks 
Arm C:  
Pegylated interferon alpha, 180µg weekly sc for 48 weeks 
  


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Currently, 24 week efficacy data is available. Six of the seven and 7/7 of patients with data 
available experienced >1log10 HDV RNA decline at week 24 during Myrcludex B monotherapy 
(A) or combination therapy (B) while this response was observed in 7/7 of group C patients. 
HDV RNA became negative in 2 and 5 patients of groups A and B, and in 2 patients of group C. 
ALT values declined at week 24 in 6/7 (A), 4/7 (B) and 2/7 (C) patients. One patient in A had 
negative HDV RNA and normal ALT at week 24. A tendency to ALT decline in comparison to 
baseline was observed in group A. Interestingly, median ALT levels demonstrated a tendency to 
decrease in Myrcludex monotherapy arm, from 66 U/L to 40 U/L (p=0.06). No such tendency 
was demonstrated in arms B and C. 
In summary, strong antiviral effect of MXB on HDV as monotherapy, as well as possible 
additive effect to pegylated interferon anti-HDV activity was demonstrated. MXB administration 
as monotherapy induced marked decrease in hepatitis activity measured by decline in ALT 
levels. MXB demonstrated very good safety and tolerability profile in this study with only 4 
TAEs and did not add to pegylated interferon toxicity.  
In conclusion, available data demonstrated favorable safety and efficacy profile of MXB and 
warrants further clinical application of the product. 
 
2.3. Information About Comparator / Background medication 
Tenofovir (Viread®) is a highly effective HBV polymerase inhibitor approved for the treatment 
of chronic hepatitis B.  Nucleoside/ nucleotide analogues are widely used by clinicians to treat 
background HBV infection in HDV patients. The dose of tenofovir used in the study will be 
according to the label for HBV infection.  
2.4. Rational for the study, dose selection and risk-benefit assessment 
The study is designed to evaluate the benefit of 3 MXB doses versus observation in patients 
suffering from hepatitis delta with very limited therapeutic options; the patients will be 
randomized 1:1:1:1 into 3 treatment arms and an observation arm. Patients with compensated 
cirrhosis at screening will be stratified to allow similar distribution into each treatment arm. If 
patients were not receiving treatment with nucleoside/nucelotide analogue, the 
comparator/background drug will be initiated after the eligibility confirmation, for 12 weeks 
prior to randomization visit; patients who previously received tenofovir will continue the dosing; 
patients on different nucleoside/nucleotide analogue will be switched to tenofovir. Observation is 
considered an adequate control group, as daily placebo injections for 24 weeks are regarded not 
feasible and ethically questionable. 
In the Phase 2a study, effects on HDV RNA including negativations were observed within 24 
weeks. Therefore, 24 weeks are considered adequate time frame for the evaluation of the primary 
endpoint. There will be a follow up of 24 weeks on comparator/background drug to study the 
durability of achieved responses.  
Patients with ALT >10 fold ULN, creatinine clearance < 60 mL/min, total bilirubin > 2 mg/dL, 
decompensated liver disease or liver carcinoma will not be allowed to enter the trial. Patients 
with presence of anti-HCV antibodies but with negative HCV RNA at screening will be 
permitted to participate. 
The dose of 2mg is theoretically sufficient to reach liver concentrations above in vitro IC90. In 
an ongoing Phase 2a study in patients with chronic hepatitis delta infection, 2mg of Myrcludex B 
dosed subcutaneously once daily for 24 weeks followed by or in addition to pegylated interferon 
alpha showed benefit with good tolerability.  


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In a Phase 2a study in HBV, the dose of 10mg once daily subcutaneous dosing for 24 weeks 
showed most pronounced effects on HBV DNA. The use of 10mg dose is further supported by 
pharmacokinetic modeling, showing that this dose should lead to 80% saturation of NTCP for at 
least 15 hours. 
The intermediate dose of 5mg will be investigated as well. Administration of 5mg dose can reach 
the target saturation for several hours. In in vitro experiments, cells susceptible to HBV/HDV 
infection were rendered unsusceptible by limited exposure to MXB (15-30 minutes), and 
maintained this status for 24 hours. It can be anticipated, that if the target saturation is important 
for increasing the antiviral effect, the use of 5mg dose may already be sufficient. Moreover, the 
increase in bile acid concentrations in 5mg and 10mg dose groups in the Phase 2a HBV study 
was similar, suggesting that both doses had similar effect on NTCP bile acid transporter 
function. 
It is not expected that the background medication anti-HBV polymerase inhibitor alone will 
influence HDV replication. The goals of the study are to investigate the effect of Myrcludex B 
on HDV RNA levels on the background of effective HBV replication suppression and to 
determine if there are synergistic effects of both medications on HBsAg levels decline. 
The primary endpoint is HDV RNA negativity or significant decline at treatment week 24 in 
comparison to tenofovir only arm.  Negative HDV RNA result is a standard parameter used in 
clinical studies and routine practice for monitoring of treatment success in HDV infection.  
Additional summaries of patients who had durable response during the treatment free follow-up 
will be summarized. Most important secondary endpoint will be ALT normalization showing the 
decline in hepatitis activity, which is important in this patient population.  
Analysis of qualitative secondary endpoints (ALT normalization and HBsAg 
Loss/Seroconversion) will be handled using the Fisher’s exact test.  Analysis of quantitative 
secondary endpoints (Serum fibrosis marker, HBsAg and HBV DNA) will be summarized over 
time (actual value and the change from baseline value).  Treatment group comparisons for these 
endpoints will be made using a two-sided Wilcoxon Rank-Sum test with an adjusted alpha of 
0.0167.  Each endpoint will also be summarized during treatment free follow-up.  No statistical 
testing is planned for this analysis. 
  
The sample size calculation is based on following considerations: the study is powered to detect 
34% increase in HDV RNA negativation or 2log10 decrease (37% activity in treatment arms) vs 
observation, assuming 3% spontaneous HDV RNA negativation in the observation arm. 30 
patients per arm were calculated to achieve two-sided alpha of 0.0167 with 80% power, 
accounting for multiple comparisons as 3 doses are investigated in the trial.  
Standard methods will be applied for safety monitoring, recording and treatment delay(s), dose 
modification and discontinuation. 
Considering all above information, the trial as described in the current protocol is justifiable. The 
scheduled treatment may be of benefit for included subjects, while the risks remain well-
predictable and acceptable. Moreover, the trial will provide crucial information in the course of 
clinical development of Myrcludex B.     
 


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2.6. Study Population  
The study will enroll male and female patients, 18 to 65 years of age (inclusively), with chronic 
HDV infection, positive HDV RNA results at Screening, in order to evaluate Myrcludex B 
efficacy in this population.   
Initial evidence of Myrcludex B efficacy in patients with chronic HDV infection was obtained in 
a phase Ib/IIa clinical trial. In this trial led to a decrease in HDV RNA and ALT values. Three 
out of 24 subjects enrolled into the phase Ib/IIa study had liver cirrhosis, and 9 had a history of 
previous interferon therapy.  Potential benefit of Myrcludex B was demonstrated in this 
population of patients, for whom therapeutic options are particularly limited. 
The current study will enroll patients with chronic HDV infection, who failed previous interferon 
therapy or for whom, in the opinion of the investigator, such therapy is contraindicated 
(including history of interferon intolerance), as well as cirrhotic patients. Inclusion of such 
patients is ethically appropriate and justified by data obtained in the previous study.  
Up to 200 patients will be screened. 120 patients will be participating in this trial (up to 30 
thereof in Germany).  
Only subjects who sign informed consent form and who meet all eligibility criteria will be 
enrolled into this study.  
3. Study Objectives and Endpoints  
Primary Objective  
To investigate the efficacy of MXB and to compare 3 doses of MXB versus observation on 
background therapy with tenofovir in hepatitis delta patients. 
Secondary Objectives  
To investigate further efficacy parameters as well as safety and tolerability, as well as to assess 
pharmacokinetics and immunogenicity, of three doses of MXB in hepatitis delta patients. 
Primary Efficacy Endpoint:  
 HDV RNA negativation or decrease by ≥2 log10 from baseline to Week 24 
Secondary Efficacy Endpoints:  
 Durability of HDV RNA response to 24 weeks post treatment 
 Combined response: HDV RNA negativation or ≥2 log decline and normal ALT at 
treatment week 24 
 Changes in ALT values at Week 24 and Week 48 compared to baseline. 
 Lack of fibrosis progression based on transient elastometry (Fibroscan) at Week 24 
compared to baseline.  
 Changes (absence of increase) in fibrosis marker: serum alpha-2-macroglobulin at 
Week 24 and Week 48 compared to baseline.  
 Changes in HBsAg (decreased levels, disappearance of HBsAg, antibodies to HBsAg) at 
Week 24 and Week 48 compared to baseline. 
 Change in HBV DNA levels at Week 24 and Week 48 compared to baseline.   


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Safety Endpoints  
 Adverse events, physical examination, vital signs, 12-lead ECG, hematology, coagulation 
panel, blood chemistry, urinalysis, blood bile acids levels.  
 Development of anti- Myrcludex B antibodies.   
4. Study Design  
4.1. Summary of Study Design  
Taking into consideration the screening failure rate, approximately 200 patients will be screened, 
and 120 patients will be randomized in the 1:1:1:1 ratio to one of the four treatment arms: 
Arm A (30 patients): Myrcludex B, 2 mg/day subcutaneously (s.c.) for 24 weeks + tenofovir 
with a further follow-up period of 24 weeks of continued tenofovir therapy.  
Arm B (30 patients): Myrcludex B, 5 mg/day subcutaneously (s.c.) for 24 weeks + tenofovir 
with a further follow-up period of 24 weeks of continued tenofovir therapy.  
Arm C (30 patients): Myrcludex B, 10 mg/day subcutaneously (s.c.) for 24 weeks + tenofovir 
with a further follow-up period of 24 weeks of continued tenofovir therapy.  
Arm D (30 patients): tenofovir treatment for 48 weeks.  
The main part of the study includes screening period of 28 days (Days -28/-1), pre-treatment 
period for patients, for whom a preliminary therapy with tenofovir of up to 84 days is indicated, 
baseline randomization visit (Day 1), and study period of 24 weeks. Follow-up period will be 
24 weeks for all treatment arms.  
 
 


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Figure 1а. Phase II Study Scheme  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Only subjects who require tenofovir pre-treatment (Pretreatment period - PreT).  
 
 
 
Screening 
Visit 01 
Screening assessments, 
inclusion/exclusion criteria  
Randomization visit        Arm A      МХВ 2 mg + tenofovir  
        Visit 1                       Arm B      МХВ 5 mg + tenofovir 
        (Day 1)                     Arm C      МХВ 10 mg + tenofovir                
Arm D                Tenofovir  
Study Period 
(treatment per randomization 
scheme) 
Visit 2 (Week 1 after Randomization Visit) 
Visit 3 (Week 2 after Randomization Visit) 
Visit 4 (Week 4 after Randomization Visit) 
Visit 5 (Week 8 after Randomization Visit) 
Visit 6 (Week 12 after Randomization Visit) 
Visit 7 (Week 16 after Randomization Visit) 
Visit 8 (Week 20 after Randomization Visit) 
Visit 9 (Week 24 after Randomization Visit) 
Follow-up Period 
(tenofovir only treatment for all 
subjects) 
Visit FU1 (Week 25 after Randomization Visit) 
Visit FU2 (Week 26 after Randomization Visit) 
Visit FU3 (Week 28 after Randomization Visit) 
Visit FU4 (Week 36 after Randomization Visit) 
Visit FU5 (Week 48 after Randomization Visit) 
End-of-Study  
Telephone Contact 03* 
(Day (-)28) 
Visit 04* 
(Day (-)14 – (-)1) 
Tenofovir Pre-Treatment 
Period * 
(Day (-)84 – (-)1) 
Visit 02* 
(Day  (-)84) 


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Table 1. Study Flowchart  
Procedures  
SCR 
PreT* 
 
RV 
Study Period  
Follow-up Period  
Early 
Termination  
Visits  
01 
02 
03 
04 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
FU1 
FU2 
FU3 
FU4 
FU5 
Final Visit  
Day (D)/ Week (W) 
D 
–28/-
112* -1 
D 
-84 
 
D 
- 28 
  
D 
-14 
- 1 
 
D1 
 
W1/D8 
± 2D 
W2/D15 
± 2D 
W4/D28 
± 2D 
W8 
± 
2D 
W12 
± 
2D 
W16 
± 
2D 
W20 
± 
2D 
W24 
± 2D 
FUW1/ 
W25 
± 2D 
FUW2/ 
W26 
± 2D 
FUW4/ 
W28 
± 5D 
FUW12/ 
W36 
± 5D 
FUW24/ 
W48 
± 2D 
D Х 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical 
History  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination (including 
weight) 
X 
Х 
 
Х* 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
Х 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs  
X 
Х 
 
Х* 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG  
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Urine Pregnancy Test 1 
X 
 
 
Х* 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Urine Drug Screening (test 
strips)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
Х 
Serology  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AFP Test  
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal Ultrasound  
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breath Alcohol Test  
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria  
X 
 
 
Х* 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transient Elastometry  
Х 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensing of Study Medication 
(for 28 days of treatment)  
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Dispensing of Tenofovir 
(nucleotide analogue therapy)   
 
Х* 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
Compliance Assessment  
 
 
Х* 
Х* 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Dispensing and Review of 
Subject Diaries  
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
PK main study  
(for all subjects) 
 
 
 
 
 
Х 
 
 
Х 
Х 
Х 
Х 
Х 
Х 
 
 
 
 
 
 
HBV/HDV Genotyping (frozen 
samples) 
 
(X) 
 
 
 
(X)**** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NTCP Polymorphism (frozen cell 
pellet) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, coagulation panel  
X 
Х** 
 
Х* 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Х 
Blood chemistry (complete 
panel) 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
Х 
Blood chemistry (abbreviated) 
 
Х** 
 
Х* 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
 


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Procedures  
SCR 
PreT* 
 
RV 
Study Period  
Follow-up Period  
Early 
Termination  
Visits  
01 
02 
03 
04 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
FU1 
FU2 
FU3 
FU4 
FU5 
Final Visit  
Day (D)/ Week (W) 
D 
–28/-
112* -1 
D 
-84 
 
D 
- 28 
  
D 
-14 
- 1 
 
D1 
 
W1/D8 
± 2D 
W2/D15 
± 2D 
W4/D28 
± 2D 
W8 
± 
2D 
W12 
± 
2D 
W16 
± 
2D 
W20 
± 
2D 
W24 
± 2D 
FUW1/ 
W25 
± 2D 
FUW2/ 
W26 
± 2D 
FUW4/ 
W28 
± 5D 
FUW12/ 
W36 
± 5D 
FUW24/ 
W48 
± 2D 
D Х 
 
Total Blood Bile Acids  
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Х 
Blood Bile Acids (frozen 
samples)  
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Х 
HDV RNA (ambient samples) 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HDV RNA (frozen samples) 
 
Х* 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Х 
HBV DNA 
 
Х* 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
Х 
HBsAg (frozen samples) 
 
Х* 
 
 
 
X 
 
 
Х 
Х 
X 
Х 
Х 
X 
 
 
Х 
X 
X 
Х 
HBeAg and anti-HBeAg 
antibodies  
X 
 
 
 
 
 
 
 
 
 
 
 
 
X*** 
 
 
 
 
X*** 
 
Immunogenicity (frozen samples) 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
Serum Fibrosis Marker (frozen 
samples)  
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Resistance Test (frozen 
samples) 
 
(X) 
 
 
 
(X)**** 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Adverse Events  
X 
Х* 
Х* 
Х* 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Х 
Concomitant Medications*****  
X 
Х* 
Х* 
Х* 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Х 
* Only subjects who require pre-treatment with tenofovir (Pretreatment period - PreT).  
** Done, if laboratory test at Screening was performed over 14 days ago.    
***Only for patients who are HBeAg-positive at Screening. 
****In patients who need pre-treatment with tenofovir, the sample should be taken at visit 02 and omitted at RV Visit  
***** Including the previous therapy of hepatitis with interferon medications regardless of treatment prescription 
(1) Women of childbearing potential only.  


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Overview of study visits.  
 Screening Period of 28 days (Visit 01);  
 Tenofovir Pre-Treatment Period for subjects requiring pre-treatment with tenofovir for up to 
12 weeks (84 days) (starting from the moment when screening results become available that 
allow to assess inclusion/exclusion criteria for this study); this period includes the following:  
- 
Visit 02 (attending the study site) – start of tenofovir treatment 84 days before 
planned randomization visit;  
- 
Visit 03 (telephone contact) – telephone call to the subject 28 days before planned 
randomization visit;  
- 
Visit 04 (attending the study site) – up to 14 days before planned randomization visit.  
 Randomization Visit (Visit 1 – Day 1);  
 Treatment Period of up to 24 weeks (Visits 2-9 at Weeks 1, 2, 4, 8, 12, 16, 20, and 24 after 
Randomization Visit);  
 Follow-up Period of 24 weeks (Visits FU1-FU5 at Weeks 25, 26, 28, 36, and 48 after 
Randomization Visit, respectively).  
Screening Period  
The following procedures will be done at Screening, Visit 01 (up to 112 days prior to the first dose 
of Myrcludex B in case of pre-treatment with tenofovir; up to 28 days before the first dose of the 
study drug for subjects, who do not require tenofovir pre-treatment): informed consent form signing,  
physical examination (including weight measurement), laboratory tests, serology tests (HIV, HCV, 
HBsAg and HBeAg antibodies, HBsAg, HBeAg), HCV RNA in patients with HCV antibodies, 
antibodies to HDV, HDV RNA,  abdominal ultrasound, urine pregnancy test, breath alcohol test, 
urine drug screening (test strips), evaluation of inclusion/ exclusion criteria. 
Transient elastometry (Fibroscan) to assess fibrosis will be perfomed during screening.  
If the subject requires pre-treatment period for nucleotide analogue treatment, he/she receives 
tenofovir for the entire pre-treatment period (84 days of dosing).  
Tenofovir Pre-Treatment Period  
Tenofovir Pre-treatment Period is included in order to allow to enroll patients, who did not receive 
prior treatment with nucleoside/nucleotide analogues. This will ensure a more homogeneous 
population of subjects participating in this clinical trial.  Total duration of this period will be 
12 weeks.  
Tenofovir Pre-treatment Period includes the following:  
- 
Visit 02 (attending the study site) – start of tenofovir treatment 84 days before 
planned randomization visit;  
- 
Visit 03 (telephone contact) – telephone call to the subject 28 days before planned 
randomization visit to collect compliance data, concomitant treatments and adverse 
events;  
- 
Visit 04 (attending the study site) –up to 14 days before planned randomization visit 
(physical examination, laboratory tests, counting of tenofovir tablets, compliance 


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assessment, repeated evaluation of inclusion/exclusion criteria, concomitant 
treatments and adverse events ).  
Randomization Visit  
All patients, who meet inclusion/ exclusion criteria and who received treatment with nucleoside/ 
nucleotide analogues for at least 12 weeks before the planned start of study treatment or underwent 
protocol-specified tenofovir pre-treatment, will be asked to attend Randomization Visit. The 
following tests and procedures are performed at this visit: physical examination, safety laboratory 
tests, virology parameters, serum fibrosis marker, immunogenicity.  All assessments at this visit will 
be regarded as baseline for safety monitoring (and should not be qualified as the inclusion/exclusion 
criteria). Upon completion of all protocol-defined procedures, patients are randomly assigned to one 
of the 4 treatment arms and receive study medication for the first 28 days of use. 
Treatment Period  
Treatment with the study medication in combination with tenofovir or tenofovir alone will last for 
24 weeks, followed by a 24-week follow-up period.  Treatment will be performed in the outpatient 
settings. 
Follow-up Period  
Follow-up period lasts for 24 weeks. During this period, patients will receive treatment with 
tenofovir.  
4.2. Pharmacokinetic Study 
For a more precise investigation of the possible study drug accumulation all the patients of each 
Myrcludex B treatment arm will be included in this sub-study. 
Blood samples for pharmacokinetic study are to be collected at Randomization Visit, at Week 4, 8, 
12, 16, 20, 24 (1 hour +/- 15 min after Myrcludex B administration).  
 
4.3. Randomization  
Subjects are randomized in the 1:1:1:1 ratio into arms A, B, C and D using a digital randomization 
scheme.  
In order to minimize bias, subjects will be stratified based on the presence of liver cirrhosis (yes/no). 
Stratification is aimed on enrolling comparable number of cirrhotic subjects into each of the 
treatment arms. In this open-label study, neither subjects, nor investigators will be blinded to 
treatment assignments.   
More details are given in the Randomization Plan.  
4.4. Study Periods and Procedures  
Any deviations from protocol-defined procedures must and reported to the Sponsor and CRO. Study 
procedures and visits are described below. Unscheduled visits may be performed, if deemed 
necessary by the Investigator, and must be documented in the CRF.  


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4.4.1. Screening Procedures  
Inclusion and exclusion criteria will be verified during Screening Period (up to 112 days prior to the 
first dose of Myrcludex B in case of pre-treatment with tenofovir; up to 28 days before the first dose 
of the study drug for subjects, who do not require tenofovir pre-treatment).  
The following procedures will be done in the outpatient settings at Screening Visit (Visit 01):  
 Subjects receive information about the study and provide written informed consent to 
participate in the study (ICF must be signed and dated by the subject and the responsible 
Investigator);  
 Medical history and demographics; 
 Recording of concomitant medications including the previous therapy of hepatitis with 
interferon medications regardless of treatment prescription ; 
 SAE recording; 
 Physical examination including weight; 
 Height; 
 Vital signs (blood pressure, heart rate, body temperature, respiratory rate); 
 12-lead ECG;  
 Hematology, coagulation panel; 
 Blood chemistry (complete panel); 
 Serology; 
 Urinalysis; 
 Abdominal ultrasound; 
 Transient elastometry (Fibroscan) ; 
 AFP test; 
 HDV RNA (ambient samples, central laboratory) ; 
 HBeAg and anti-HBeAg antibodies; 
 Alcohol breath test; 
 Urine drug screening (test strips); 
 Urine pregnancy test (for women of childbearing potential only) 
 Assessment of inclusion/exclusion criteria; 
Patients who meet all of the inclusion criteria and none of the exclusion criteria will be ask to return 
to the clinic within 4 weeks after Screening for Randomization Visit.  
Only subjects with positive HDV RNA test obtained from central laboratory may be enrolled into 
the study.   


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If pre-treatment with nucleotide analogue is indicated (subject has not received 
nucleotide/nucleoside analogues for at least 12 weeks prior to enrollment), patient will be asked to 
attend Visit 02 of the Tenofovir Pre-Treatment Period. 
 During Screening Period, subjects are monitored for adverse events. However, all unfavorable 
medical events (other than serious adverse events) that occurred during the screening period will be 
recorded as medical history of patients. 
4.4.2. Tenofovir Pre-Treatment Period Procedures and Assessments  
If a patient, who has not received nucleotide/nucleoside analogues for at least 12 weeks prior to 
enrollment, consents to taking part in the study and meets all of the inclusion criteria and none of the 
exclusion criteria, tenofovir pre-treatment period will be performed for up to 84 days prior to 
Randomization Visit.  
Eligibility of subgroup subjects for whom pre-treatment with tenofovir is indicated will be 
confirmed based on data obtained at Visit 04 (no more than 14 days prior to the first dose of the 
study medication).  
Tenofovir pre-treatment period includes the following:  
Visit 02 (at the study site) – outpatient settings. The following procedures are performed at this visit:  
 Recording of concomitant medications; 
 SAE recording; 
 Physical examination including weight; 
 Vital signs (blood pressure, heart rate, body temperature, respiratory rate); 
 Hematology, coagulation panel (if more than 14 days elapsed since blood collection at 
Screening); 
 Blood chemistry (abbreviated panel; if more than 14 days elapsed since blood collection at 
Screening); 
 HBV/HDV genotyping (frozen samples); 
 Resistance testing (frozen samples); 
 HDV RNA (frozen samples); 
 HBV DNA and HBsAg (frozen samples);  
 Dispensing of tenofovir. 
Visit 03 (by telephone) – is a telephone contact with the patient 28 days before planned 
randomization date. The following procedures are performed at this visit: 
 Recording of concomitant medications; 
 SAE recording; 
 Assessment of compliance, as reported by the subject. 
Visit 04 (at the study site), in the outpatient settings, 14 days before planned randomization date. 
The following procedures are performed at this visit: 
 SAE recording; 


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 Recording of concomitant treatment; 
 Physical examination including weight; 
 Vital signs (blood pressure, heart rate, body temperature, respiratory rate); 
 Hematology, coagulation panel; 
 Blood chemistry (abbreviated panel); 
 Urine pregnancy test (for women of childbearing potential only) 
 Calculation of medication (tenofovir) taken; 
 Assessment of compliance; 
 Assessment of inclusion/exclusion criteria. 
Subjects must return used and unused tenofovir bottles to the study site for assessment of 
compliance (after that unused bottles will be returned to the patient for continuation of therapy). 
Investigator enters compliance data into the CRF.  
Investigator must reassess subject’s eligibility based on inclusion/exclusion criteria, and if the 
subject meets all inclusion criteria and none of the exclusion criteria, Visit 1 will be scheduled for 
randomization procedure.  
During pre-treatment period, subjects are monitored for adverse events (will be recorded as 
indicators to be included in patient’s medical history, except for serious adverse events).  
4.4.3. Randomization Visit 
All eligible subjects will be asked to attend Randomization Visit (Visit 1, Day 1).  At 
Randomization Visit, upon completion of all scheduled procedures, subjects are randomized to one 
of the four treatment arms.   
Treatment and visits will be done in the outpatient settings.  
Subcutaneous injections of the study medication and oral intake of tenofovir must be done every 
24 ± 1 hour after the first dose. However patient can adjust the introduction of the second and 
subsequent doses of the study drug under a convenient schedule which should be reflected in the 
patient's diary. Administration of subsequent doses of the drug should be carried out every 24 ± 1 
hours from the time set by the schedule. 
 
The following procedures and baseline assessments will be performed at Randomization Visit:  
 AE recording; 
 Confirmation of meeting inclusion/ exclusion criteria based on results obtained during 
Screening;  
 Randomization; 
 Dispensing subject diary; 
 Dispensing of study medication for 28 days of treatment; 
 Dispensing of tenofovir for 28 days of treatment; 
 Recording of concomitant treatment; 


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 Physical examination including weight; 
 Vital signs; 
 Hematology and coagulation panel; 
 Blood chemistry (complete panel); 
 Total blood bile acids ; 
 Blood bile acids (frozen samples); 
 Urinalysis; 
 HDV RNA (frozen samples); 
 HBV DNA and HBsAg (frozen samples);  
 HBV/HDV genotyping (frozen samples): only if no sample was taken at visit 02; 
 Resistance testing (frozen samples); only if no sample was taken at visit 02 
 Urine pregnancy test (for women of childbearing potential only) 
 Alcohol breath test; 
 Immunogenicity (frozen samples); 
 Serum fibrosis marker (frozen samples); 
 NTCP polymorphism (frozen cell pellet); 
 Blood sample for pharmacokinetic study (1 hour +/- 15 min after Myrcludex B 
administration, frozen sample). 
Subject receives study medication, tenofovir, and all other study materials for Days 1 through 28 of 
the study.  
All assessments done at this visit will be regarded as baseline for safety monitoring and should not 
be considered as inclusion/ exclusion criteria.  
4.4.4. Treatment Period Procedures and Assessments  
Patients start treatment at the Randomization Visit.  Subcutaneous injections of the study medication 
and oral intake of tenofovir must be done every 24 ± 1 hour after the first dose. However patient can 
adjust the introduction of the second and subsequent doses of the study drug under a convenient schedule 
which should be reflected in the patient's diary. Administration of subsequent doses of the drug should be 
carried out every 24 ± 1 hours from the time set by the schedule. Subject visits must take place in 
compliance with the schedule described in this section and detailed in the Study Flowchart.  
Randomization Visit, visits in weeks 1, 2, 4, 8, 12, 16, 20, and 24, follow-up visits at weeks 1, 2, 4, 
12, and 24.  
Week 1/ Day 8 ± 2 days/ Visit 2: the following procedures will be performed in the outpatient 
settings:  
 AE recording; 
 Measurement of vital signs; 
 Hematology, coagulation panel; 


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 Blood chemistry (abbreviated panel); 
 Total blood bile acids; 
 Blood bile acids (frozen samples); 
 HDV RNA (frozen samples); 
 Recording of concomitant treatment; 
 Evaluation of the correctness of patient diaries filling (copies of the completed pages should 
be stored in the primary documentation); 
 Assessment of compliance. 
Investigator reviews records in the subject diary and enters compliance data into the CRF. Subject 
diary is part of source documents. 
Week 2/ Day 15 ± 2 days/ Visit 3: the following procedures will be:  
 AE recording; 
 Measurement of vital signs; 
 Hematology, coagulation panel; 
 Blood chemistry (abbreviated panel); 
 Total blood bile acids; 
 Blood bile acids (frozen samples); 
 HDV RNA (frozen samples); 
 Recording of concomitant treatment; 
 Evaluation of the correctness of patient diaries filling (copies of the completed pages should 
be stored in the primary documentation); 
 Assessment of compliance. 
Investigator reviews records in the subject diary and enters compliance data into the CRF. Subject 
diary is part of source documents. 
Week 4/ Day 28 ± 2 days/ Visit 4: the following procedures will be performed in the outpatient 
settings:  
 AE recording; 
 Measurement of vital signs; 
 Hematology, coagulation panel; 
 Blood chemistry (abbreviated panel); 
 Urinalysis; 
 Urine pregnancy test (for women of childbearing potential only) 
 Total blood bile acids; 
 Blood bile acids (frozen samples); 


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 HDV RNA (frozen samples); 
 HBsAg (frozen samples), 
 Blood sample for pharmacokinetic study (1 hour +/- 15 min after Myrcludex B 
administration), frozen sample. 
 Recording of concomitant treatment; 
 Evaluation of the correctness of patient diaries filling (copies of the completed pages should 
be stored in the primary documentation); 
 Assessment of compliance; 
 Dispensing of study medication for 28 days of treatment; 
 Dispensing of tenofovir. 
Subjects must return used and unused study drug vials, as well as used and unused tenofovir bottles 
to the study site. Investigator reviews records in the subject diary and enters compliance data into 
the CRF. Subject diary is part of source documents. 
Week 8 ± 2 days/ Visit 5: the following procedures will be performed in the outpatient settings:  
 AE recording; 
 Measurement of vital signs; 
 Hematology, coagulation panel; 
 Blood chemistry (abbreviated panel); 
 Total blood bile acids; 
 Blood bile acids (frozen samples); 
 Urine pregnancy test (for women of childbearing potential only) 
 HDV RNA (frozen samples); 
 HBsAg (frozen samples), 
 Blood samples for pharmacokinetic study (1 hour +/- 15 min after Myrcludex B 
administration, frozen sample). 
 Recording of concomitant treatment; 
 Evaluation of the correctness of patient diaries filling (copies of the completed pages should 
be stored in the primary documentation); 
 Assessment of compliance; 
 Dispensing of study medication for 28 days of treatment; 
 Dispensing of tenofovir. 
Subjects must return used and unused study drug vials, as well as used and unused tenofovir bottles 
to the study site. Investigator reviews records in the subject diary and enters compliance data into 
the CRF. Subject diary is part of source documents. 


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Week 12 ± 2 days/ Visit 6: the following procedures will be performed in the outpatient settings:  
 AE recording; 
 Physical examination including weight; 
 Measurement of vital signs; 
 12-lead ECG;  
 Hematology, coagulation panel; 
 Blood chemistry (complete panel); 
 Urinalysis; 
 Urine pregnancy test (for women of childbearing potential only) 
 Total blood bile acids; 
 Blood bile acids (frozen samples); 
 HDV RNA (frozen samples); 
 HBV DNA (frozen samples); 
 HBsAg (frozen samples), 
 Blood samples for pharmacokinetic study (1 hour +/- 15 min after Myrcludex B 
administration, frozen sample). 
 Immunogenicity (frozen samples); 
 Recording of concomitant treatment; 
 Evaluation of the correctness of patient diaries filling (copies of the completed pages should 
be stored in the primary documentation); 
 Assessment of compliance; 
 Dispensing of study medication for 28 days of treatment; 
 Dispensing of tenofovir. 
Subjects must return used and unused study drug vials, as well as used and unused tenofovir bottles 
to the study site. Investigator reviews records in the subject diary and enters compliance data into 
the CRF. Subject diary is part of source documents. 
Week 16 ± 2 days/ Visit 7: the following procedures will be performed in the outpatient settings:  
 AE recording; 
 Measurement of vital signs; 
 Hematology, coagulation panel; 
 Blood chemistry (abbreviated panel); 
 Total blood bile acids; 
 Blood bile acids (frozen samples); 


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 Urine pregnancy test (for women of childbearing potential only) 
 HDV RNA (frozen samples); 
 HBsAg (frozen samples), 
 Blood samples for pharmacokinetic study (1 hour +/- 15 min after Myrcludex B 
administration, frozen sample). 
 Recording of concomitant treatment; 
 Evaluation of the correctness of patient diaries filling (copies of the completed pages should 
be stored in the primary documentation); 
 Assessment of compliance; 
 Dispensing of study medication for 28 days of treatment; 
 Dispensing of tenofovir. 
Subjects must return used and unused study drug vials, as well as used and unused tenofovir bottles 
to the study site. Investigator reviews records in the subject diary and enters compliance data into 
the CRF. Subject diary is part of source documents. 
Week 20 ± 2 days/ Visit 8: the following procedures will be performed in the outpatient settings:  
 AE recording; 
 Measurement of vital signs; 
 Hematology, coagulation panel; 
 Blood chemistry (abbreviated panel); 
 Urine pregnancy test (for women of childbearing potential only) 
 Total blood bile acids; 
 Blood bile acids (frozen samples); 
 HDV RNA (frozen samples); 
 HBsAg (frozen samples), 
 Blood samples for pharmacokinetic study (1 hour +/- 15 min after Myrcludex B 
administration, frozen sample). 
 Recording of concomitant treatment; 
 Evaluation of the correctness of patient diaries filling (copies of the completed pages should 
be stored in the primary documentation); 
 Assessment of compliance; 
 Dispensing of study medication for 28 days of treatment; 
 Dispensing of tenofovir. 
Subjects must return used and unused study drug vials, as well as used and unused tenofovir bottles 
to the study site. Investigator reviews records in the subject diary and enters compliance data into 
the CRF. Subject diary is part of source documents. 


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Week 24 ± 2 days/ Visit 9: the following procedures will be performed in the outpatient settings:  
 AE recording; 
 Physical examination including weight; 
 Measurement of vital signs; 
 12-lead ECG;  
 Hematology, coagulation panel 
 Coagulation panel; 
 Blood chemistry (complete panel); 
 Urinalysis; 
 Urine pregnancy test (for women of childbearing potential only) 
 Total blood bile acids; 
 Blood bile acids (frozen samples); 
 HDV RNA (frozen samples); 
 HBV DNA (frozen samples); 
 HBsAg (frozen samples); 
 Blood samples for pharmacokinetic study (1 hour +/- 15 min after Myrcludex B 
administration, frozen sample). 
 HBeAg and anti-HBeAg antibodies (frozen samples) – only for subjects with positive 
HBeAg test at Screening; 
 Transient elastometry (Fibroscan); 
 Serum fibrosis marker (frozen samples); 
 Resistance test (frozen samples); 
 Immunogenicity (frozen samples); 
 Recording of concomitant treatment; 
 Subject diary review; 
 Assessment of compliance; 
 Dispensing of tenofovir for 56 days. 
Subjects must return used and unused study drug vials, as well as used and unused tenofovir bottles 
to the study site. Investigator reviews records in the subject diary and enters compliance data into 
the CRF. Subject diary is part of source documents.  
4.4.5. Post-treatment Assessments  
Upon completion of treatment period, subjects enter the follow-up period that lasts for 24 weeks. 
During the follow-up period, all subjects continue taking tenofovir.   


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FU Week 1 – Study Week 25 ± 2 days/ FU Visit 1: the following procedures will be performed in 
the outpatient settings: 
 AE recording; 
 Measurement of vital signs; 
 Hematology, coagulation panel; 
 Blood chemistry (abbreviated panel); 
 Total blood bile acids; 
 Blood bile acids (frozen samples); 
 HDV RNA (frozen samples); 
 Recording of concomitant treatment. 
FU Week 2 – Study Week 26 ± 2 days/ FU Visit 2: the following procedures will be performed in 
the outpatient settings: 
 AE recording; 
 Measurement of vital signs; 
 Hematology, coagulation panel; 
 Blood chemistry (abbreviated panel); 
 Total blood bile acids; 
 Blood bile acids (frozen samples); 
 HDV RNA (frozen samples); 
 Recording of concomitant treatment. 
FU Week 4 – Study Week 28 ± 5 days/ FU Visit 3: the following procedures will be performed in 
the outpatient settings: 
 AE recording; 
 Measurement of vital signs; 
 Hematology, coagulation panel 
 Coagulation panel; 
 Blood chemistry (abbreviated panel); 
 HDV RNA (frozen samples); 
 HBsAg (frozen samples); 
 Recording of concomitant treatment; 
 Dispensing of tenofovir for 56 days. 
All subjects must return used tenofovir bottles to the study site.  


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FU Week 12 – Study Week 36 ± 5 days/ FU Visit 4: the following procedures will be performed in 
the outpatient settings: 
 AE recording; 
 Measurement of vital signs; 
 Hematology, coagulation panel; 
 Coagulation panel; 
 Blood chemistry (abbreviated panel); 
 Urinalysis; 
 HDV RNA (frozen samples); 
 HBV DNA (frozen samples); 
 HBsAg (frozen samples); 
 Immunogenicity (frozen samples); 
 Recording of concomitant treatment; 
 Dispensing of tenofovir for 56 days. 
All subjects must return used tenofovir bottles to the study site.  
FU Week 24– Study Week 48 ± 2 days/ FU Visit 5 (End-of-Study Visit): the following procedures 
will be performed in the outpatient settings: 
 AE recording; 
 Physical examination including weight;  
 12-lead ECG;  
 Measurement of vital signs; 
 Hematology, 
 Coagulation panel; 
 Blood chemistry (complete panel); 
 Total blood bile acids; 
 Blood bile acids (frozen samples); 
 Urinalysis; 
 HDV RNA (frozen samples); 
 HBV DNA (frozen samples); 
 HBsAg (frozen samples); 
 HBeAg and anti-HBeAg antibodies - only for subjects with positive HBeAg test at 
Screening; 
 Immunogenicity (frozen samples); 


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 Serum fibrosis marker (frozen samples); 
 Recording of concomitant treatment. 
All subjects must return used and unused tenofovir samples to the study site.  
4.5. Premature Discontinuation, Study Drug Interruption, Dose Adjustments 
If a study participant discontinues MXB injections, for example, due to an adverse event, every 
effort must be made to motivate the the subject to continue participating in the study and undergoing 
all study procedures and follow-up, including tenofovir treatment.  If this is not possible or 
inapplicable for the study participant, he/she will prematurely discontinue the study participation.   
Before withdrawing subjects assigned to 5 mg and 10 mg MXB doses, Investigator should consider 
reducing the study drug dose: doses are reduced from 10 mg to 5 mg and from 5 mg to 2 mg per 
day.  During dose adjustments AE monitoring must continue.  If Investigator believes, that the 
treatment may be continued at the 2 mg dose level, the subject should continue with this dose and 
undergo all study procedures and follow-up.  
If Investigator believes, that the subject requires temporary interruption in the MXB or tenofovir 
treatment, he/she should discuss it with the Sponsor’s Medical Monitor.  
If a study participant from any of the MXB treatment arms discontinues tenofovir, but continues 
with the MXB treatment, he/she should continue participation in the study. If a subject discontinues 
tenofovir treatment during follow-up period, every effort should be made to motivate the subject to 
continue with participation in the study.  
Subjects discontinuing from the study will complete End-of-Treatment Visit, that includes the below 
assessments, within 14 days after the last dose of the study medication:  
At the End-of Treatment Visit, the following procedures will be performed in the outpatient settings: 
 AE recording; 
 Physical examination including weight; 
 Measurement of vital signs; 
 Hematology; 
 Coagulation panel; 
 Blood chemistry (complete panel); 
 Total blood bile acids; 
 Blood bile acids (frozen samples); 
 HDV RNA (frozen samples); 
 HBV DNA (frozen samples); 
 HBsAg (frozen samples); 
 Urinalysis; 
 Recording of concomitant treatment. 


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4.6. Management of Hepatitis Exacerbations  
Hepatitis flair is defined as ALT increase as ALT  2  baseline or 10  ULN. 
Hepatitis exacerbations during MXB treatment 
In case a hepatitis flair occurred during the treatment period, and no singes of hepatic function 
worsening are detected (bilirubin increase ≥ 2mg/dL, INR ≥1.7), the treatment should be continued 
under close monitoring of hepatic function. Unscheduled visits to monitor patient`s status and 
laboratory parameters should be discussed with sponsor`s medical monitor.  
In case hepatic function worsening occurred, MXB treatment should be stopped and background 
therapy continued. At investigator`s discretion, switch to other commercially available anti-HBV 
therapy may be appropriate. 
 
Hepatitis exacerbation after cessation of MXB treatment 
MXB has been shown to significantly decrease HDV replication in previous studies. As with any 
effective antiviral treatment, the therapy stop may lead to viral rebound and hepatitis exacerbation.  
In case of hepatitis exacerbation accompanied with HDV RNA replication increase is detected 
during the follow-up phase of the trial, at investigator`s discretion a therapy with interferon alpha 
can be initiated. 
 
  
4.7. Description of Study Procedures  
This section provides description of assessments. More details are given in the Laboratory Manual.  
Demographics and Medical History  
The following demographic details are to be collected during Screening:  
 Date of birth;  
 Sex;  
 Race.  
Information about underlying disease, other concurrent or previous conditions (deemed relevant by 
Investigator) and information about the previous interferon treatment of hepatitis regardless of the 
treatment  prescription  must also be entered into CRF. Information on any concomitant treatment / 
therapy should be collected from the time of screening. 
Vital Signs and physical examination 
Respiration rate, blood pressure, heart rate and body temperature will be measured regularly during 
the study. Time points for measuring vital signs are indicated in the study schedule.  Vital signs are 
entered into CRF.   
A complete physical examination and body weight determination will be done in this study at time 
points indicated in the Study Flowchart. The results must be entered into CRF.  


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Height  
Height will be measured at time points indicated in the Study Flowchart and will be entered into 
CRF.  
Urine Pregnancy Test  
Urine pregnancy test is required for women of childbearing age. Pregnancy testing will be done 
locally, using test strips. The result will be documented in the CRF. 
Drug Screening (urine test using test strips) 
Urine test strips will be used to detect traces of methadone, benzodiazines, cocaine, amphetamines, 
cannabinoids, opiates, barbiturates, tricyclic antidepressant. The result will be documented in the 
CRF. 
Alcohol Breath Test  
Alcohol levels in exhaled oxygen will be measured using electronic breathalyzer. The result will be 
documented in the CRF. 
Abdominal Ultrasound 
Abdominal ultrasound is done at Screening. Special attention must be paid to liver structure. All 
abnormalities must be reported in the Medical History section of the CRF.  
Serum Alpha-Fetoprotein 
Serum alpha-fetoprotein will be measured for all subjects at Screening. The alpha-fetoprotein test is 
intended to rule out hepatocellular carcinoma. The result will be documented in the CRF. 
Transient Elastometry 
Transient elastometry (Fibroscan) is done at screening and at the End-of-Treatment Visit period to 
assess liver fibrosis staging. The result will be documented in the CRF. 
Blood Tests for Safety Assessments 
Safety blood tests will be performed by local center laboratories at time points indicated in the Study 
Schedule. Laboratory results will be entered into CRFs. Investigator must review laboratory results 
in the CRF and comment on values outside of the reference range or values that significantly differ 
from the previous results.  
Clinical laboratory tests to be done during the study are listed below:  
Hematology and Coagulation Panel  
 WBC differential (percentage): neutrophils, eosinophils, basophils, monocytes, lymphocytes;  
 WBC differential (absolute counts): neutrophils, eosinophils, basophils, monocytes, 
lymphocytes;  
 RBC count;  
 WBC count;  
 Hematocrit;  
 Hemoglobin;  
 Platelets;  


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 Reticulocytes;  
 Prothrombin time;  
 Activated partial thromboplastin time.  
Blood Chemistry  
Complete blood chemistry panel:  
 Sodium;  
 Potassium;  
 Chloride;  
 C-reactive protein;  
 Total protein;  
 Albumin;  
 Total bilirubin;  
 Direct (unconjugated) bilirubin;  
 Total cholesterol;  
 Creatinine;  
 Blood urea;  
 Glucose;  
 Gamma glutaminetransferase;  
 Alanine aminotransferase;  
 Alkaline phosphatase;  
 Aspartate aminotransferase;  
 Lipase;  
 P-amylase;  
 Phosphate.  
Abbreviated blood chemistry panel:  
 Albumin;  
 Total bilirubin;  
 Creatinine;  
 Gamma glutaminetransferase;  
 Alanine aminotransferase;  
 Aspartate aminotransferase;  
 Phosphate; 


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 Lipase.  
 P-amylase; 
Blood Bile Acids  
Specific bile acid levels will be analyzed by central laboratory in Germany. Samples will be 
collected in compliance with instructions provided by the central laboratory and stored at -20°С  
before courier shipment to the central laboratory. 
Serology Screening  
 HIV antibodies;  
 HCV antibodies;  
 HDV antibodies;  
 Non-quantitative HBsAg test for eligibility assessment;  
 Non-quantitative HBeAg test;  
 HBeAg antibodies.  
The above laboratory tests will be done at local laboratory of the study site, unless specified 
otherwise.  In case of positive HCV antibodies test, HCV RNA test must be done. If the result for 
HCV RNA test is negative, the patient can be enrolled into the study.  
Safety Urinalysis  
Urinalysis will be done as indicated in the Study Flowchart. Results are entered into CRF.  
The following parameters will be measured:  
 pH; 
 Specific gravity; 
 Protein; 
 Glucose; 
 Bilirubin; 
 Urobilinogen; 
 Ketones; 
 Erythrocytes; 
 Leukocytes; 
 Nitrites. 
Urinalysis will be done at the local laboratory of study site.  
Protocol-specified laboratory tests performed at local laboratories will be done in compliance with 
local standard operating procedures.  
Laboratory tests performed at central laboratory will be done using the following methods:   


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Virology Tests  
The following virology parameters will be evaluated in the study: HDV RNA, HBsAg and HBV 
DNA.  Samples of venous blood will be collected at specified time points.  
 HDV RNA by quantitative PCR;  
 HBsAg levels by quantitative immunoassay;  
 HBV DNA by quantitative PCR;  
 HBV genotyping – once as a part of the study during the 02 Pre-T visit for patients whom 
the pre-treatment period with tenofovir has been indicated, or during the randomization               
visit – if no pre-treatment period is indicated, using sequencing technique;  
 HDV genotyping – once as a part of the study during the 02 Pre-T visit for patients whom 
the pre-treatment period with tenofovir has been indicated, or during the randomization              
visit – if no pre-treatment period is indicated, using sequencing technique;  
 Resistance testing – at the start of the study and at end of treatment, using sequencing 
technique. The first blood sample should be collected for analysis during the 02 Pre-T visit 
for patients whom the pre-treatment period with tenofovir has been indicated, or during the 
randomization visit – if no pre-treatment period is indicated. 
These tests will be done by central virology laboratory.  
Blood samples will be collected in sterile, air-locked single-use plastic K2-EDTA Vacutainer® vials.  
All plasma samples will be stored at -20°С until shipment to the central laboratory. Vials are 
shipped to the central laboratory in validated freezer containers at -20°С or -80°С.  
Plasma samples for HDV RNA collected at Screening are stored and shipped to the central 
laboratory in ambient conditions. 
Determination of antibodies to HBsAg will be performed at the end of the study in a central virology 
laboratory using appropriate back-up samples (for HBsAg determination) in patients with negative 
result of quantitative HBsAg determination at Week 24 and Week 48 of active treatment. The 
samples are not to be taken separately for this analysis. 
 
NTCP Polymorphism  
NTCP polymorphism is assessed once during the study (at baseline), at the central laboratory, using 
sequencing technique.  
Serum Fibrosis Marker  
EIA test for serum fibrosis marker, alpha-2-macroglobulin, will be done at the start of the study, at 
the end of treatment and at the end of follow-up period, at site local laboratory. The result will be 
documented in the CRF. 
Immunogenicity  
Anti-MXB antibodies will be determined only in subjects receiving Myrcludex B by ELISA 
technique.  


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Plasma PK Parameters  
Blood samples will be collected in sterile, air-locked single-use plastic Li-Heparin Vacutainer® 
vials. The volume of the blood samples for this test must be at least 4 mL.  
Plasma levels of Myrcludex B will be measured using a validated HPLC-MS/MS technique. 
Quantitative analysis of concentration will be done by the Central Laboratory. 
Blood amount taken during the study  
The total amount of blood taken for the study will be approximately 648 ml. In account with the             
12-week course of pre-treatment with tenofovir the blood volume increases on 30 ml.  
If there is a need to conduct re-analyzes or safety monitoring of investigational therapy, additional 
visits can be scheduled. After the unscheduled visit, the next visit is to be carried out in accordance 
with previously approved plan and protocol. 
 
To determine Myrcludex B effects or physiological effect of increased level of bile acids on the 
metabolism or inflammation, blood samples collected in the study can be analyzed for parameters 
that characterize carbohydrate and lipid metabolism and also play a role in the development of 
vascular diseases. 
 
Subject Diary  
During Treatment Period subjects receive diaries to record the following information:  
 Adverse events, specifically injection site reaction;  
 Date and time of each dose of the study medication and the nucleotide analogue medication.  
Copies of completed diary pages will be stored in the source documentation.  
4.8. Study Completion, Interruption and Termination, Individual Study Site 
Termination and Subject Withdrawal  
4.8.1. Study Completion  
A subject is considered to complete the study, when he/she completes all study procedures listed in 
Section 4.4 of the protocol.  
Completion of study participation is defined as the date of the last visit or the last scheduled 
procedure per Section 4.4 of the study protocol.  Completion of the whole study is defined as the last 
visit of the last enrolled subject.  
The Sponsor has the right to suspend or terminate the study at any time, due to reasons, that include, 
but are not limited to safety issues, ethical considerations and significant violations of pre-defined 
rules and requirements. If the study is suspended or terminated for safety concerns, the Sponsor will 
in a timely manner inform the contract research organizations (CROs), investigators, IEC and the 
competent as well as local regulatory authorities of suspension/termination and reasons for this 
decision.  
4.8.2. Study Suspension or Early Termination   
Investigator and Sponsor reserve the right to terminate the study at any moment.  If necessary, 
procedures will be agreed upon after consultation of both parties. If the study is terminated early or 
suspended, the Sponsor has to immediately notify investigators/ institutions and authorized bodies of 


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termination or suspension stating the reasons for termination or suspension. Local ethics committee, 
the competent and local authorities have to be notified by the Sponsor or investigator/ institution, as 
well (as per regulatory requirements) specifying reasons for termination or suspension of the study.  
At the study termination, the Sponsor and the investigator will ensure compliance with regulations 
for the best protection of patients’ interests.   
The most probable reasons for suspension or early termination of the study may be serious and 
unexpected adverse reactions in the majority of patients during the first study days, noncompliance 
with study rules, and impossibility to conduct the study according to the protocol.   
The possible reasons for the study termination by the Sponsor may include the increased risk for 
patients’ life and health, significant deviations during the study, etc.  In case the study is terminated 
by the Sponsor, the company has to notify the CROs, investigators, as well as the local ethics 
committees, competent and local authorities.  The Sponsor has the right to stop the study at any 
moment.   
Investigator has the right to stop the participation of her/his center if in their opinion increased risk 
for patients’ life and/or health is not acceptable.  In this case the investigator has to notify the CRO/ 
Sponsor and the local ethics committee.   
If the study is terminated early or suspended for any reason, the investigator should immediately 
notify enrolled patients and ensure they are adequately treated and followed up.   
4.8.3. Premature Discontinuation of Study Site by the Sponsor  
A study site may be prematurely closed, or its activities suspended in case the study staff 
significantly deviates from requirements of GCP, protocol and/or regulatory authorities, contract 
obligations, and cannot ensure adequate study conduct.   
4.8.4. Early Termination of Patient’s Participation   
For patients, who were included in the study and finished participation not according to the protocol, 
i.e. were excluded from the study, the Final Visit section of the CRF will be completed with 
obligatory reporting of the reason for the patient’s withdrawal.  The following may be among the 
reasons:   
 Investigator decides that the patient has to be excluded for safety reason. 
 Inclusion by mistake.   
 Serious protocol deviation, protocol violation.   
 Serious adverse event, including death (report date).   
 Adverse event.   
 Patient undergoes/ needs additional treatment which may affect study results.   
 Positive pregnancy test (for female patients).   
 Patient did not come for a visit or is lost to follow up.   
 Subject’s consent withdrawal or non-compliance.   
4.9. List of Data Entered Directly into CRF  
Source data is defined as all information in original records and certified copies of original records 
of clinical findings, observations, or other activities in a clinical trial necessary for the 


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reconstruction and evaluation of the trial. Source data is contained is source documents (originals or 
certified copies).  
All source data including AE information will first be recorded in source documents (medical charts, 
case histories), and then transferred to CRF. CRF will not contain any data not reflected in the 
source documents, except when original printouts are available or data can be entered directly into 
the system, as stated in the Monitoring Manual.   
Completed CRFs will be checked against source data by Study Monitor. All deviations and errors 
must be corrected by Investigator and documented in Monitor’s Report.  
5. Selection and Withdrawal of Study Participants  
This study will enroll subjects with chronic HDV infection and detectable HDV RNA replication 
level.  
5.1. Inclusion Criteria  
Subjects must meet all of the below inclusion criteria in order to be eligible for participation in this 
study.   
1. Age from 18 to 65 years inclusively at the time of signing Informed Consent Form.  
2. Positive serum HBsAg for at least 6 months before Screening.  
3. Positive serum anti-HDV antibody for at least 6 months before Screening.  
4. Positive PCR results for serum HDV RNA at Screening. 
5. Patients with liver cirrhosis, irrespective of previous interferon treatment.4  
6. Patients without liver cirrhosis, who failed prior interferon treatment or for whom, in the opinion 
of the Investigator, such treatment is currently contraindicated (including history of interferon 
intolerance)5.  
7. Alanine aminotransferase level >1 x ULN, but less than 10 x ULN.  
8. Previous nucleotide/nucleoside analogue treatment within at least 12 weeks prior to the planned 
start of study treatment or subject’s willingness to take tenofovir for at least 12 weeks prior to the 
planned start of study treatment.  
9. Negative urine pregnancy test for females of childbearing potential.  
10. Inclusion criteria for female subjects:  
 Postmenopausal for at least 2 years, or  
 Surgically sterile (total hysterectomy or bilateral oophorectomy, bilateral tubal ligation, 
staples, or another type of sterilization), or  
 Abstinence from heterosexual intercourse throughout the study, or  
 Willingness to use highly effective contraception throughout the study and for 3 months after 
the last dose of the study medication.  
                                                 
4 Patients with liver cirrhosis should be included in case the interim analysis (Section 9.4. Interim and Final Data 
Analysis) will provide positive safety assessment. The sponsor will notify the centers on the results of the analysis and 
the permission to enroll cirrhotic patients. 
5 Patients with previous interferon treatment can be enrolled only at least 30 days after the last interferon dose.  


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11. Male and female subjects must agree to use a highly effective contraception6 throughout the 
study and for 3 months after the last dose of the study medication. 
12. Male subjects must agree not to donate sperm throughout the study and for 3 months after the 
last dose of the study medication. 
5.2. Exclusion Criteria  
Patients meeting any of the below exclusion criteria cannot take part in this study.   
1. Child-Pugh score of B-C or over 6 points.  
2. HCV or HIV coinfection. Subjects with anti-HCV antibodies can be enrolled, if screening HCV 
RNA test is negative.  
3. Creatinine clearance <60 mL/min.   
4. Total bilirubin ≥ 2mg/dL. Patients with higher total bilirubin values may be included after the 
consultation with the Study`s Medical Monitor, if such elevation can be clearly attributed to 
Gilbert’s syndrome associated with low-grade hyperbilirubinemia. 
5. Any previous or current malignant neoplasms, including hepatic carcinoma.  
6. Systemic connective tissue disorders.  
7. NYHA (New York Heart Association) class III-IV congestive heart failure.  
8. Patients with uncontrolled arterial hypertension (BP >150/100 mm Hg despite antihypertensive 
treatment) within 3 months prior to start of clinical phase of the study.  
9. Previous or unstable concurrent diseases or conditions that in investigator’s opinion prevent 
subject’s enrolment into the study.  
10. Patients with mental disorders or social circumstances that preclude them from following 
protocol requirements.  
11. Current or previous decompensated liver disease, including coagulopathy, hyperbilirubinemia, 
hepatic encephalopathy, hypoalbuminaemia, ascites, and esophageal varices hemorrhage.  
12. Patients with history of pancreatitis or pancreatic insufficiency. 
13. WBC count <3000 cells/mm3.  
14. Neutrophil count <1500 cells/mm3. 
15. Platelet count <60,000 cells/mm3. 
16. Proof of use of prohibited psychotropic agents at Screening.  
17. Use of interferons within 30 days before Screening.  
                                                 
6 According to CTFG Recommendations related to contraception and pregnancy testing in clinical trials dated 15 Sep 
2014, the following  birth control methodsshould be considered as highly effective: 1) combined (estrogen and 
progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, 
intravaginal, transdermal); 2) progestogen-only hormonal contraception associated with 
inhibition of ovulation (oral, injectable, implantable); 3) intrauterine device (IUD); 4) 
intrauterine hormone-releasing system (IUS); 5) bilateral tubal occlusion; 6) vasectomised 
partner; 7) sexual abstinence. 


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18. History of solid organ transplantation.  
19. Current alcohol abuse or alcohol abuse within 6 months prior to enrolment in this study.  
20. History of disease requiring regular use of systemic glucocorticosteroids.   
21. Pregnant or breast-feeding females.   
22. Participation in another clinical study within 30 days prior to Screening.  
23. Prior treatment with Myrcludex B in previous studies. 
5.3. Subject Withdrawal Criteria    
5.3.1. Withdrawal Criteria  
Study subjects can withdraw from the study at any moment and without having to explain their 
decision.  However, Investigator will make every reasonable effort to document exact reasons for 
subject’s decision to withdraw and enter them into CRF.  
Subjects may be withdrawn from the study in the following circumstances:  
1. Investigator believes that it is not in the subject’s best interests to continue participation in the 
study.   
2. Investigator decides to withdraw the study subject due to a serious protocol deviation/violation.  
3. Concurrent disease or progression of the underlying disease that, in the opinion of Investigator, 
can significantly affect evaluation of subject’s clinical status.   
4. In case of suspected pancreatitis, the treatment with the study medication should be stopped and 
further diagnostic procedures undertaken. Patients should be informed about the symptoms of 
pancreatitis and contact the investigator immediately in case of occurrence of such symptoms. 
5. Use of prohibited medication is required.  
6. Unacceptable toxicities, as defined in Toxicity Management Section of the Protocol, or a reaction 
that, in the Investigator’s opinion, precludes further study procedures or requires discontinuation of 
the subject from the study.  
7. Subject’s decision to discontinue from the study for any reason.  
8. Unsatisfactory compliance, defined as missing study drug doses for 3 consecutive days or 
4 missed doses over 28 days.  
9. Pregnancy during the study.  
10. Sponsor, regulatory authority or IRB/IEC decide to terminate the study.  
11. Subject is lost to follow-up.   
The following protocol violations may require withdrawing subject from the study. In such cases, 
decision regarding subject’s continuation with the study will be made by the Sponsor alone or after 
discussion with the Investigator.  
 Failure to inform the Sponsor about AE in a timely manner (if Investigator becomes aware of 
the AE, and this is documented).  
 Concurrent disease or condition that interferes with protocol-required procedures, which, in 
the Investigator’s opinion, can bias interpretation of the subject’s condition.  


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 Need to use other medications, other than the study drug, that do not significantly affect 
study results.  
 Other protocol violations that are not considered significant by Investigator or Sponsor.  
Subject may be immediately withdrawn from the study at any stage of the study.  
In case of a serious disease or intolerance of the study medication, Investigator is responsible for 
deciding, whether the subject must be withdrawn from the study.  Subjects withdrawn from the 
study due to a serious concurrent disease or for safety reasons will receive appropriate standard 
medical care and will be followed until resolution or stabilization of their condition. In such cases, 
Investigator must notify the Sponsor in advance and provide sufficient medical rationale for his/her 
decision.  
Patients will also be considered withdrawn, if they are lost to follow-up, i.e. when a patient 
withdraws from the study without notifying the Investigator.  
As excessive dropout rate may render study results not interpretable, unnecessary withdrawals 
should be avoided.  
5.3.2. Withdrawn Subject Data  
Investigator is responsible for documenting the reason(s) for subject’s withdrawal from the study 
after randomization and entering all relevant information into CRF.  Investigator must complete the 
Final Visit page in the CRF, indicating detailed information about the reason for the subject’s 
withdrawal from the study.  If the subject was withdrawn due to an AE, the primary term or a 
laboratory test must be reported in the CRF, and Investigator must make every effort to accurately 
report all AE characteristics.  
Investigator will report information about withdrawn subjects to the Sponsor and site monitor within 
24 hours, including the reason for subject withdrawal:  
 Investigator’s mistake;  
 Adverse events;  
 Serious adverse events;  
 Pregnancy;  
 Protocol violations; 
 Subject’s decision to withdraw;  
 Subject’s failure to attend visits or lost to follow-up;  
 Other reasons (specify).   
5.3.3. Replacement of Subjects  
If a subject was randomized in the study, but did not start treatment with the study medication, 
he/she will be replaced. Subjects discontinued during the pre-treatment period will be considered 
screening failures and will be replaced. Subjects who received at least one dose of the study drug 
will not be replaced.  


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5.3.4. Follow-Up of Withdrawn Subjects  
In case of a SAE, subject must be followed until SAE resolution or reaching stable conditions by 
collecting information about symptoms and history by telephone, and during unscheduled visits, 
required to ensure subject’s safety.  
If, in the opinion of treating physician, a non-serious adverse event requires follow-up, information 
about symptoms and the course of the event can be collected by telephone and at visits to the study 
site.  
If Investigator considers an SAE to be probably related to the study medication, subject will be 
followed and treated appropriately until SAE resolution, irrespective of the time that elapsed from 
SAE occurrence.  
If a subject withdraws from the study on his/her own request, every effort will be taken to follow-up 
the (S)AEs until their resolution and/or reaching stable conditions. 
6. Treatment of Patients   
6.1. Myrcludex B   
6.1.1. Formulation   
Myrcludex B is produced as lyophilized powder for solution for injection.  Myrcludex B is supplied 
in sterile vials, the contents of which must be diluted in 1 mL of sterile water for injection.   
Composition:   
Active Ingredient: Myrcludex B acetate, 2.0 mg/vial, 5.0 mg/vial.   
Excipients: water for injection, sodium carbonate, sodium hydrocarbonate, mannitol, hydrochloric 
acid, and sodium hydroxide are used for solution of the drug substance before aseptic filling and 
lyophilization. Pharmaceutically pure substances are used.   
Physical Formulation: white or grayish-white powder.   
Solution Appearance: clear and colorless.   
6.1.2. Container Closure System   
Myrcludex B study drug will be used in the form of lyophilized powder for solution for injection 
2.0 mg/vial and 5.0 mg/vial.   
Primary Packaging   
Container: 2 R vial for injection, colorless glass, Ph. Eur. Hydrolytic class I.   
Closure Element: lyophilization rubber stopper for 2R vials, Ph. Eur. type I (diameter 13 mm).   
Secondary Packaging   
Closure Element: 13 mm flip clap seal, aluminum with a plastic disk.   
Container closure system is for single use only. Vials and lyophilization rubber stoppers are sterile, 
all materials are tested before use.   
6.1.3. Drug Storage and Handling  
At study site, the drug should be stored at -20±5°C, protected from light.   
At home, the drug is can be stored at +5°C (in refrigerator).   


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Deviation of the cold chain conditions is allowed (storage at room temperature up to 3 days).   
After reconstitution of vial contents with water for injection the drug remains stable for 120 minute 
at room temperature.   
6.2. Dosing and Administration of Myrcludex B   
Study site staff will instruct patients on subcutaneous administration of the drug.  Training materials 
will be provided to the patients separately.   
Arm A: Myrcludex B 2 mg/day SC   
During the treatment period at each visit patients randomized into Arm A will receive study drug 
kits to be used over 28 days, including:   
30 vials of Myrcludex B 2.0 mg 
30 vials of sterile water for injection (2 mL minimum)   
30 single-use syringes   
Patients will be instructed to reconstitute the entire content of the Myrcludex B 2.0 mg vial contents 
with 1 mL of water for injection, and to carry out a self-administration once per day. The drug 
should be diluted immediately before injection.  Reconstituted solution is stable for 2 hours.   
Arm B: Myrcludex B 5 mg/day SC   
During the treatment period at each visit patients randomized into Arm B will receive study drug 
kits to be used over 28 days, including:   
30 vials of Myrcludex B 5.0 mg 
30 vials of sterile water for injection (2 mL minimum)   
30 single-use syringes   
Patients will be instructed to reconstitute the entire content of the Myrcludex B 5.0 mg/vial with 1 
mL of water for injection and to carry out a self-administration once per day.  The drug should be 
diluted immediately before injection. Reconstituted solution is stable for 2 hours.   
Arm C: Myrcludex B 10 mg/day SC   
During the treatment period at each visit patients randomized into Arm C will receive study drug 
kits to be used over 28 days, including:   
60 vials of Myrcludex B 5.0 mg 
30 vials of sterile water for injection (5 mL minimum)   
60 single-use syringes   
Patients will be instructed to reconstitute the entire content of the two Myrcludex B 5.0 mg/vials 
with 1 mL of water for injection each, and to carry out a self-administration once per day.  Interval 
between both injections should be 1-30 minutes. 
The drug should be diluted immediately before injection.  Reconstituted solution is stable for 2 
hours.   
Dose Adjustment   
Dose adjustment in Arm A is not allowed.   


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In arms B and C, dose may be adjusted in case of toxicity. Further details are provided inn 
Section 4.5, Premature Discontinuation, Study Drug Interruption, Dose Adjustments.   
Missed Dose 
In case of a missed dose the following procedure is to be followed:   
If a patient remembered of the missed dose before 4 hours have lapsed from the daily administration 
time frame, the dose should be administered. The next day, the planned dose should be administered 
at the initially set up time.  If more than 4 hours have passed from the planned time point, the dose 
should not be administered and should be considered missed, and the next day the planned dose 
should be administered at the initially set up time.   
The missed dose should be reported in a patient’s diary and CRF.  Patient should notify the 
investigator of the missed dose by phone.   
6.3. Previous and Concomitant Medications   
Patients who previously received treatment for HBV with another nucleoside/ nucleotide analogue 
will be switched to tenofovir in the beginning of the study (randomization visit).   
Tenofovir (VIREAD®) will be provided by Gilead Sciences (Ireland) in market package for 
Germany in the form of film-coated tablets of 245 mg tenofovir disoproxil, N30 vials in a cardboard 
box.  Primary and secondary drug packaging will be labeled according to requirements of the 
German legislation.   
VIREAD® (tenofovir disoproxil 245 mg, equivalent to tenofovir disoproxil fumarate 300 mg), film-
coated tablets.   
Trademark: VIREAD®   
Registration Numbers:   
EU/1/01/200/001 
EU/1/01/200/002   
INN: tenofovir disoproxil (fumarate)   
Chemical Name: 9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]metoxy]phosphenyl]metoxy]propyl] 
adenine fumarate   
Manufacturer: Patheon Inc., Canada, 
Gilead Sciences (Ireland), 
Marketing Authorization Holder: Gilead Sciences, Ireland   
Formulation   
Film-coated tablets, 245 mg (tenofovir disoproxil)   
Contents   
Each film-coated tablet contains:   
Active Ingredient: tenofovir disoproxil 245 mg equivalent to tenofovir disoproxil fumarate 300 mg; 
Excipients:   


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Tablet Core: pregelatinized starch, croscarmellose sodium, lactose monohydrate, microcrystalline 
cellulose, magnesium stearate;   
Film Coat: glycerol triacetate (Е1518), indigo carmine aluminum lake (Е132), hypromellose 
(Е464), lactose monohydrate, titanium dioxide (Е171).   
Description   
Film-coated almond-shaped light blue tablets, 16.8 mm × 10.3 mm, “GILEAD” and “4331” 
engraved on one side and “300” – on another.   
Formulation   
Film-coated 245 mg tenofovir disoproxil tablets.  30 tablets in a HDPE vial with dessicator (silica 
gel) sealed by a child resistant cap.   
Storage Conditions   
In a dry place protected from light, at temperature not exceeding 30°C.   
Keep away from children.   
Shelf Life   
5 years. 
Do not use after expiration date printed on the package.   
6.4. Prohibited Products   
 Systemic glucocorticosteroids.   
 Prohibited psychotropic agents, drugs, and psychoactive substances.   
 Use of immunomodulatory agents and antiviral drugs, apart from tenofovir, should be 
discussed with the medical monitor.   
6.5. Methods to Control Patients’ Compliance with Study Procedures   
At screening or randomization, patients undergo laboratory and instrumental examinations to 
confirm they meet or do not meet inclusion/ exclusion criteria.  Female patients will additionaly 
undergo pregnancy test.   
During the study, each visit also implies concomitant therapy reporting, evaluation of treatment 
compliance and AEs.  These procedures also confirm patients’ compliance with study procedures.   
7. Efficacy Assessments  
7.1. Efficacy Endpoints  
Primary Endpoint  
 HDV RNA negativation or decrease by ≥2 log10 from baseline to Week 24. 
As Myrcludex B has no direct effects on HDV replication levels, but prevents HBV entry into 
hepatocytes by blocking HBV and HDV receptor NTCP/SLC10A1, thus suppressing viral spread in 
the liver, HDV RNA decrease by ≥2 log10 can most probably indicating a 100-fold decrease in the 
number of infected cells. This information is needed to establish duration of treatment with 
Myrcludex B, required for HDV RNA negativation / complete viral elimination in an individual 
patient, depending on the viral load decrease progress.  


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Secondary Endpoints  
Secondary Efficacy Endpoints:  
 Durability of HDV RNA response to 24 weeks post treatment 
 Combined response: HDV RNA negativation or ≥2 log10 decline and normal ALT at 
treatment week 24 
 Changes in ALT values at Week 24 and Week 48 compared to baseline. 
 Lack of fibrosis progression based on transient elastometry (Fibroscan) at Week 24 
compared to baseline.  
 Changes (absence of increase) in fibrosis marker: serum alpha-2-macroglobulin at Week 24 
and Week 48 compared to baseline.  
 Changes in HBsAg (decreased levels, disappearance of HBsAg, antibodies to HBsAg) at 
Week 24 and Week 48 compared to baseline. 
 Change in HBV DNA levels at Week 24 and Week 48 compared to baseline.   
7.2. Efficacy Assessment Methods and Time Points  
Protocol defines baseline data for Myrcludex B efficacy assessments as values obtained at 
Randomization Visit (Visit 1).  
Efficacy assessments will be done as follows:  
 HDV RNA negativation or decrease by ≥2 log10 from baseline (Visit 1) to Week 24 
(Visit 9) will be analyzed by HDV RNA PCR.  
 Durability of HDV RNA response to 24 weeks post treatment (FU Visit 5; Study Week 48) 
compared to end of treatment (Visit 9: Study Week 24) will be analyzed by HDV RNA PCR.  
 Combined response: HDV RNA negativation or ≥2 log10 decline and normal ALT at 
treatment week 24 (Visit 9) compared to baseline (Visit 1) will be analyzed based on PCR 
data and blood chemistry results. 
 Changes in ALT values at Week 24 (Visit 9) and Week 48 (FU Visit 5) compared to baseline 
(Visit 1) will be analyzed based on blood chemistry results.  
 Lack of fibrosis progression at Week 24 (Visit 9) compared to baseline (Visit 01) will be 
assessed based on transient elastometry (Fibroscan) results.  
 Changes (absence of increase) in fibrosis marker: serum alpha-2-macroglobulin at Week 24 
(Visit 9) and Week 48 (FU Visit 5) compared to baseline (Visit 1). 
 Changes in HBsAg (decreased levels, disappearance of HBsAg, antibodies to HBsAg) at 
Week 24 (Visit 9) and Week 48 (FU Visit 5) compared to baseline (Visit 1) will be assessed 
based on quantitative immunoassay results.   
 Decreased HBV DNA levels at Week 24 (Visit 9) and Week 48 (FU Visit 5) compared to 
baseline (Visit 1) will be assessed based on quantitative HBV DNA PCR results. 


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8. Safety Assessment   
8.1. Safety Endpoints   
 Adverse events, physical examination, vital signs, 12-lead ECG, hematology, coagulation 
panel, blood chemistry, urinalysis, blood bile acids levels.  
 Development of anti- Myrcludex B antibodies.   
8.2. Adverse Events   
Study subjects will be thoroughly monitored for serious adverse events (SAEs) by interviewing, 
physical examinations and laboratory tests from the moment of signing the informed consent form.  
The AEs reported after the first dose of the study drug will be collected and included in the 
statistical analysis.  Monitoring will be conducted as per the schedule of procedures.  AEs will be 
classified and reported in CRFs.  Classification will be based on the following parameters: 
seriousness, severity, relation to the study drug, outcome, measures related to the study drug and 
other countermeasures undertaken.  Classification will be done by the responsible investigator 
according to the definitions presented below.   
The planned study implies reporting of all abnormalities in patients’ health (based on results of 
physical examination, laboratory and instrumental examinations) compared to screening data, data 
collected at other visits of the planned study and approved reference values.   
Having received necessary information the investigating physician will classify a patient’s condition 
as “normal”, “clinically insignificantly abnormal”, or “clinically significantly abnormal”.  In case 
detected abnormalities have been considered by investigator as clinically significant, have not been 
previously reported, or exacerbation of a patient’s condition takes place compared to screening data 
or data received before the first dose of study drug administration, the detected abnormalities will be 
classified as adverse events (AEs) and evaluated as per CTCAE, version 4.0.   
In case the detected abnormalities have been reported at screening or before the first dose of study 
drug administration and no negative trend is evident, the detected abnormalities will be classified as 
clinically insignificant.   
All documented abnormalities irrespective of their classification as AEs or clinically insignificant 
abnormalities will be analyzed for clinical study reports.   
The protocol includes reporting of all AEs detected in patients after the first dose of study drug 
administration  and throughout their participation in the study. An adverse event is defined as “any 
untoward medical occurrence in a patient administered a study drug which may or may not have a 
causal relationship with the study drug” according to the  ICH Guideline for good clinical practice, 
E6(R1) .   
An AE may be any unfavorable (including abnormal laboratory finding) symptom, complaint, or 
disease which is temporally associated with the use of a study drug, whether or not considered 
related to the study drug.   
All changes in laboratory, instrumental and physical parameters compared to normal and/or baseline 
will be reported by the investigating physician followed by the investigating physician’s medical 
judgment of the detected abnormalities.  In case the detected change meets the definition of an AE, 
the investigating physician should report the AE, otherwise, the detected change will be considered 
a clinically insignificant abnormality.   


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8.2.1. Definitions   
The following definitions have been adopted in the protocol (italics mean citations from ICH E2A 
Guidelines “Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting”).   
Adverse Event:   
“any untoward medical occurrence in a patient administered a study drug which may or may not 
have a causal relationship with the study drug”.   
AEs include:   
 new symptoms/ medical conditions, 
 new diagnosis,   
 changes in laboratory parameters,   
 concomitant diseases and accidents,   
 worsening of medical condition/ disease present before the start of the clinical study, 
 disease recurrence,   
 increased rate and severity of disease exacerbation episodes.   
Already present diseases and symptoms will be considered as adverse events only if their severity or 
rate worsens, or they change in nature.  The responsible investigator will document such changes as 
adverse events.   
Surgical procedures are not AEs as such, but measures undertaken to treat diseases requiring 
surgical intervention.  Condition requiring surgical intervention may be considered an AE.  Planned 
hospitalization, surgery or conditions resulting in these measures are not AEs, if the condition 
resulting in necessary hospitalization/ surgery was evident before the enrollment of the subject.   
All AEs (including SAEs) will be reported in CRFs.   
AEs will be categorized as “serious” and “non-serious” (see below).   
Serious Adverse Event:   
“A serious adverse event (SAE) is any untoward medical occurrence that at any dose of the drug: 
 results in death; 
 is life-threatening; 
 requires in-patient hospitalization or prolongation of existing hospitalization;   
 results in persistent or significant disability /incapacity;   
 is a congenital anomaly/ birth defect.” 
In addition, adverse events or reactions considered by the responsible investigator as important 
medical or scientific events may also be classified as “serious”.   
SAEs appearing after the study completion i.e. after the Follow-up Visit 05 are NOT to be reported, 
excluding cases when, in the investigator’s opinion, the event could be the result of the study drug 
administration or any protocol procedure.   
Death is an outcome of an AE, not an event as such.  If no other information is included in a report 
of the lethal outcome due to “disease progression”, it is implied that death is the result of 
progression of the disease treated by the study drug.   


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All deaths of study subjects should be reported over 30 days from the last dose of the study drug or 
up to 30 days from the last study evaluation which is earlier irrespective of relationship of the death 
with the study drug.   
“At any dose” does not mean that the subject received the study drug at the moment an adverse 
event developed.  The drug could be administered within the treatment course, treatment could be 
suspended before a SAE developed, but it could affect emergence of an AE.   
“Life-threatening” means that the subject was at immediate risk of death at the time of the event.  
This does not include AEs that had they occurred in a more severe form, might have caused death.   
Complications during hospitalization are considered AEs.  If a complication results in prolongation 
of existing hospitalization, it is considered a SAE.   
“In-patient hospitalization” is defined as admission to a hospital for medical reasons for any time 
period.  It does not necessarily mean hospitalization over 24 hours.  This category does not include 
consultations and care in an emergency room.   
Investigator should try to diagnose an adverse event based on signs, symptoms and/or other clinical 
data.  In such cases a diagnosis should be reported as an AE or SAE, not individual signs/ 
symptoms.   
Expectedness:   
“An adverse reaction, nature and severity of which is not consistent with the current information on 
the drug (i.e. Investigator’s Brochure).” 
Furthermore, reports which add significant information on specificity or severity of a known adverse 
reaction constitute “unexpected” events. 
   
8.2.2. Suspected Unexpected Serious Adverse Reaction (SUSAR)   
Both suspected (i.e. (possibly) related to the study drug) and “unexpected” serious adverse events 
are considered suspected unexpected serious adverse reactions (SUSARs).   
If an investigator, who first reported an SAE, considered the SAE at least as “unlikely” related to the 
study drug and this SAE is “unexpected”, then this SAE must be considered as a SUSAR.   
All SUSARs meet the requirements for expedited reporting.  Reports will be submitted to 
responsible ethics committees and competent regulatory authorities i.e. BfArM according to the 
applicable regulations.   
8.2.3. Follow-Up Period and Documentation   
In this study, adverse events will be recorded from the first dose of the study medication (Study 
Day 1 Visit) through the last visit of the follow-up period. All adverse medical events present before 
the first administration of the study medication will be reported as part of subject’s medical history. 
At each study visit the responsible investigator will question the subjects about adverse events.  If 
necessary, AEs and SAEs will be documented in eCRFs and and/or reported in writing on a pre-
specified SAE-form.   
All subjects with AEs, both related and unrelated to the study drug, will be followed by the 
responsible investigator in order to report the outcome.  Clinical course of AEs will be followed 
until complete resolving or stabilization.   


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8.2.4. Characteristics of Adverse Events  
All AEs will be classified according to the following characteristics:   
Intensity/ Severity   
Severity of AEs during the study is assessed according to NCI-CTC, version 4.0, see 
http://ctep.cancer.gov.   
 Mild: presence of signs and symptoms, but easily tolerated and not affecting everyday 
activities. Symptoms do not require therapy or medical evaluation, signs and symptoms are 
transient.   
 Moderate: AEs result in inconvenience or discomfort of the subject and may affect 
everyday activities, but are usually reversed by simple therapeutic measures.  Moderate AEs 
may affect body functioning to a certain extent.   
 Severe: AEs forcing the subject to stop everyday activities and usually requiring systemic 
drug therapy or other treatment.  Usually they result in disability.   
For serious adverse events, there are also possible degrees: Life-threatening and Death. 
AEs and adverse drug reactions seriousness, and not intensity (severity), will be used as a criterion 
of regulatory authorities notification.   
Causal Relationship with the Study Drug   
Investigator is responsible for assessment of relationship between AEs and the study drug.  
Investigator must establish if there is a reasonable probability that the study drug caused or 
contributed to emergence of an AE.  Assessment of the causal relationship based on clinical 
evaluation often relies on the following criteria:   
 Temporal relationship between an AE and the study drug administration.   
 Probable biological mechanism of an AE emergence due to the study drug.   
 Another possible nature of an AE.   
 Previous reports of similar AEs related to the study drug or drugs of a similar class.   
 Recurrence of an AE after reinitiation of therapy or resolving after treatment withdrawal, if 
applicable.   
The following terms are used to assess relationship of an event with the study drug:   
 Related – suspected probability that an AE may be related to the study drug.   
 Unrelated – no suspected probability that an AE may be related to the study drug.   
In case an event is considered an “unrelated” to the study drug, another etiology, diagnosis or 
rationale of an AE development should be reported.   
Outcome   
AE outcomes will be classified as follows:   
 Resolved/recovered: all signs and symptoms of an AE disappear without sequelae by the 
moment of the last interview.   
 Resolving/ recovering: intensity of signs and symptoms is decreasing, up to the last 
interview their clinical nature was changing typically for resolving.   


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 Not resolved/ not recovered: signs and symptoms of an AE almost did not change from the 
moment of the last interview.   
 Resolved/ recovered with sequelae: actual signs and symptoms of an AE disappeared, but 
had sequelae related to the AE.   
 Death: AE resulted in death.  If the patient reported several AEs only the AE that resulted in 
death is qualified as such.   
 Unknown: outcome is unknown or unlikely, and information cannot be supplemented or 
confirmed.   
Actions Taken Regarding the Study Drug   
The actions taken regarding the study drug should fall into one of the following categories:   
 Dose not changed: the study drug dose remains unchanged.   
 Dose decreased: the study drug dose is decreased.   
 Drug temporary discontinued: interruption of the study drug therapy.   
 Drug withdrawn: permanent termination of the study drug therapy.   
 Not applicable: the issue is irrelevant (due to the subject’s death or single administration of 
the drug, precluding possibility to change the dose). 
   
Countermeasures:   
The term “countermeasures” means special actions taken for treatment or relief in case of AEs in 
order to prevent sequelae.  The following categories have been approved:   
 None: no actions taken.   
 Drug treatment: a newly prescribed drug, or modification of the study drug dose.   
 Other: other countermeasures, e.g. surgery.   
8.2.5. Investigator’s Notifications of Serious Adverse Events   
Investigator will submit notifications of all SAEs within 24 hours he/she learnt of the SAE by 
sending an SAE form to the PV-department of the KKS Heidelberg.  
The reporting will be carried out by faxing of the SAE form to the number: +49 (0)6221-56-33725.  
The initial report must be as complete as possible and contain information on the current disease and 
event, as well as assessment of the causal relationship between an AE and the study drug.   
Detailed information on reporting of SAEs and a SAE form completion will be provided in the 
Safety Manual. 
8.2.6. Second Assessment   
All SAE will be subject to a second assessment by the second assessor designated by the Sponsor or 
his deputy. The second assessor will fill out a ‘Second Assessment Form’ for each SAE and send it 
back per fax to the responsible person at the KKS Heidelberg within 48 hours.  
The ‘Second Assessment Form’ will contain the following information:  
 assessment of relationship between SAE and the study drug,  
 assessment of expectedness of SAE to the study drug (derived from IB),  


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 statement if the benefit/ risk assessment of the trial did change as a result of the current 
SAE.   
In case of SUSARs or other safety issues, the expedited reporting will be carried out by a 
responsible Safety Officer or Safety Data Manager at KKS Heidelberg. 
   
8.2.7. Expedited Reporting   
SUSARs will be reported to the ethics committee and the competent regulatory authority within 
timeframes defined by regulatory documents, i.e. they are subject to the expedited reporting.   
Participating investigators should report all SAEs to the responsible member of the safety 
department as soon as possible, but not later than 24 hours after the relevant information was 
received. (see above). 
Expedited reporting is conducted by a responsible staff at the KKS (see above).     
8.2.8. Pregnancy   
In case of pregnancy of a female subject, the study drug treatment should be stopped immediately.   
Pregnancy is not considered an AE, apart from cases when it is reasonably supposed that the study 
drug resulted in decreased efficacy of contraceptives.  Congenital anomalies and developmental 
disturbances in subjects’ children are considered SAEs.  Medical abortions and other serious 
pregnancy complications (including spontaneous abortion) are classified as SAEs.  Induced abortion 
without complications is not considered as an additional AE.   
All pregnancy cases (including pregnancies in female partners of male study subjects) that occur 
during the clinical study must be appropriately documented.  Upon confirmation of a pregnancy, 
Investigator must send a notification to the Sponsor and to the KKS Heidelberg. Sponsor and KKS 
Heidelberg will also be notified of the course of pregnancy and its outcome. Pregnancies in female 
subjects and partners of male subjects are to be documented starting from Day 1 of the study drug 
dosing and until the completion of the trial.  
Pregnancy outcome (spontaneous abortion, elective termination, birth of a healthy child or a child 
with congenital anomalies or malformations) must be documented, even if the subject did not 
complete the participation in the clinical trial. 
8.2.9. Reporting Requirements after the Study   
All deaths within the study period and at least within 30 days after the last administration of the 
study drug must be reported irrespective of their reasons or relation to the study drug.   
8.3. Clinical Laboratory Abnormalities and Other Abnormalities Considered AEs or SAEs   
Laboratory abnormalities are usually not recorded as adverse events or serious adverse events unless 
they are associated with clinical signs and/or symptoms.  However, laboratory abnormalities (e.g. 
clinical chemistry, hematology, urinalysis, etc.) independent from the underlying medical condition, 
in case of medical significance, such as requirement for medical or surgical intervention, or lead to 
study drug interruption or discontinuation should be recorded as AEs. In addition, laboratory or 
other abnormal assessments (e.g. electrocardiogram, X-rays, vital signs) that are associated with 
clinical signs and/or symptoms must be recorded as an AE or SAE if they meet the respective 
definitions described in the section. If the laboratory abnormality is part of a syndrome or diseased, 
the respective diagnosis must be recorded. 


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Severity of AEs will be assessed as per common toxicity criteria (CTCAE, Common Terminology 
Criteria for Adverse Events and Reactions of the National Cancer Institute, version 4.0, see 
http://ctep.cancer.gov).  Special attention should be paid to injection site reactions and dermatitis as 
they may appear during treatment with Myrcludex B.   
For adverse events associated with laboratory abnormalities, the event should be graded based on 
the clinical severity in the context of the underlying conditions, which may or may not be in 
agreement with the grading of the laboratory abnormality. 
For possible renal toxicities, associated with the administration of the background medication 
Viread® (tenofovir), adverse events should be recorded in case creatinine clearance is <50 mg/dL – 
0.48 mmol/L (two independent calculations), or serum phosphate is >0.5 mg/dL on two separate 
occasions. Tenofovir should be stopped and the renal function should be assessed weekly. Further 
management of the patient should be discussed with the study medical monitor. 
The increase of bile acid levels against the background of the use of Myrcludex B is directly related 
to the mechanism of the drug effect – blocking NTCP receptor on the liver cells, which functions as 
a reverse transport of bile acids from the bloodstream to the liver. Therefore, an isolated increase in 
bile acid level in the absence of clinical significance should not be classified as an AE. If the 
investigator considers the increase to be clinically significant or it will be associated with the 
occurrence of clinical symptoms, this increase should be recorded as an AE. 
In case detected changes in laboratory or instrumental examinations have been reported at screening 
or before the first dose of study administration and no negative trend is evident, the detected 
abnormalities will be classified as clinically insignificant.   
All detected changes will be analyzed for the clinical study reports irrespective of their classification 
as AEs or clinical significance.   
8.4. Toxicity Management   
 Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within three calendar days of receipt of results and before study drug discontinuation, 
unless such a delay is not consistent with good medical practice.  
 Clinical events and clinically significant laboratory abnormalities will be graded according to 
CTC AE version 4.0. 
 When restarting study drug following resolution of the adverse event, the study drug should 
be restarted at full dose or modified dose which is dependent upon discussion with the 
Medical Monitor. 
 Any recurrence of the study drug related grade 3 or 4 clinical or clinically significant 
laboratory adverse event following dose interruption mandates permanent discontinuation of 
study drug. 
 Any questions regarding toxicity management should be directed to the Medical Monitor. 
 


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Grades 1 and 2 Laboratory Abnormality or Clinical Event 
 Continue study drug at the discretion of the investigator. 
Grade 3 Laboratory Abnormality or Clinical Event 
 For grade 3 clinically significant laboratory abnormality or clinical event, study drug may be 
continued if the event is considered to be unrelated to study drug. 
 For a grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to study drug, study drug should be withheld 
until the toxicity returns to  grade 2. 
 If a toxicity recurs to  grade 3 following re-challenge with study drug and is considered 
related to study drug, then study drug should be permanently discontinued and subjects 
managed according to local practice.  Recurrence of events considered unrelated to study 
drug may not require permanent discontinuation. 
Grade 4 Laboratory Abnormality or Clinical Event 
 For grade 4 clinical event or clinically significant grade 4 laboratory abnormality confirmed 
by repeat testing that is considered related to study drug, study drug should be permanently 
discontinued and subjects managed according to local practice.  The subject should be 
followed as clinically indicated until the event resolves to baseline, or is otherwise explained, 
whichever occurs first.  Clinically significant grade 4 laboratory abnormality that is not 
confirmed by repeat testing should be managed per algorithm for the new toxicity grade.   
Study drug may be continued without dose interruption for non-clinically significant grade 4 
laboratory abnormality or clinical event considered unrelated to study drug. 
8.5. Risks for Females of Childbearing Potential and Risk during Pregnancy   
The risks of treatment with MXB during pregnancy have not been evaluated. Animal studies do not 
indicate direct or indirect harmful effects of MXB with respect to pregnancy.  Please refer to the 
latest version of the Investigator’s Brochure for additional information.  
Highly effective contraception should always be used by women of child bearing potential who are 
less than 2 years post-menopausal while participating in the study and for 30 days following the last 
dose of study medication.  
Male subjects in the study who are sexually active must use highly effective contraception methods 
for the same period of time with their female partners of childbearing potential or agree to abstain 
from heterosexual intercourse. 
According to CTFG Recommendations related to contraception and pregnancy testing in clinical 
trials dated 15 Sep 2014, the following birth control methods should be considered as highly 
effective: 


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1. combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
 oral; 
 intravaginal; 
 transdermal; 
progestogen-only hormonal contraception associated with inhibition of 
ovulation: 
 oral; 
 injectable; 
 implantable; 
3. intrauterine device (IUD); 
4. intrauterine hormone-releasing system ( IUS); 
5. bilateral tubal occlusion; 
6. vasectomised partner; 
7. sexual abstinence. 
 
A female subject must be instructed to discontinue all study drugs and inform the investigator 
immediately if she becomes pregnant during the study. Likewise, a male subject must inform the 
Investigator immediately if his partner becomes pregnant during the study. 
 The Investigator should report all pregnancies to the Sponsor within 24 hours of becoming aware of 
the pregnancy.  The Investigator should counsel the subject regarding the possible effects of prior 
study drug exposure on the fetus and the need to inform the study site of the outcome of the 
pregnancy.  
Any pregnancy complication or elective termination of a pregnancy for medical reasons will be 
recorded as an AE and is always to be handled as an SAE.   
A spontaneous abortion is always considered to be a SAE and will be reported as described in the 
adverse and Serious Adverse Events section.  Furthermore, any SAE occurring as an adverse 
pregnancy outcome post-study must be reported to the Sponsor. 
Additionally all pregnancies that occur during the study should be reported using the Pregnancy 
Report CRF page.  Monitoring of the subject should continue until the conclusion of the pregnancy.  
The outcome should be reported to the sponsor using the Pregnancy Outcome (and Abnormal 
Pregnancy Outcome, if applicable) CRF page(s).  If the end of the pregnancy occurs after the study 
has been complete, the outcome should be reported directly to the sponsor.  Pregnancies that occur 
after the subject has discontinued study drugs do not require monitoring. 
 
 


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9. Statistical Analysis  
9.1. Analytical Methods  
9.1.1. General Information  
Statistical analysis of the study data will be performed under supervision of responsible 
biostatistician in compliance with applicable laws and regulations.  
Prior to statistical analysis, data obtained at all sites will be combined into one data set.  
If preliminary assumptions made at study planning are erroneous, analytical methods will be 
adjusted for a more appropriate analysis. If changes to the statistical analysis plan are significant and 
affect study results or their interpretation, a protocol amendment will be issued in a timely manner.   
Statistical analysis is planned to be performed using IBM SPSS Statistics (IBM Corporation, 
Armonk, New York, USA), SAS (Statistical Analysis Software, SAS Institute Inc. Cary, NC, USA) 
or another commercially available software with a validated algorithm for statistical methods and 
appropriate documentation.  
9.1.2. Demographics and Baseline Characteristics  
Demographic data and baseline characteristics will be analyzed for the complete analysis set and by 
treatment arms using descriptive statistics. For interval variables, arithmetic mean (with a 95% 
confidence interval for mean), standard deviation, median, 25th and 75th percentiles will be 
calculated. For nominal variables, frequency rates and confidence intervals for rates (95% Clopper-
Pearson confidence intervals) will be presented.  
9.1.3. Efficacy Analysis  
Primary efficacy analysis will be based on the following efficacy endpoint:  
 HDV RNA negativation or decrease by ≥2 log10 from baseline to Week 24.  
This endpoint will be analyzed in modified Intent-to-Treat Set (mITT), which includes all 
randomized subjects who started study treatment (Myrcludex B or Tenofovir) in study period after 
randomization.  Additionally these data will be analyzed in the Per Protocol (PP) set that includes 
subjects with available Week 24 efficacy results (see below for PP set definition).  
Treatment arms will be compared using the Wald test for Superiority by Margin of 5%; 95% 
Clopper-Pearson confidence interval will also be calculated for treatment response rates (for each 
treatment arm). Each experimental treatment arm (Myrcludex B) will be compared to the control 
arm receiving tenofovir alone. Each Myrcludex B treatment arm will be compared to the control arm 
separately (Arm A vs Arm D, Arm B vs Arm D, Arm C vs Arm D). Hypotheses will be tested 
sequentially, using Bonferroni-Holm method. Null hypotheses will be defined for each prior test, 
and appropriate p-values will be calculated (based on data obtained in the study). After that, null 
hypotheses will be rejected in descending order of respective p-values for critical values of type I 
error (α), calculated as α/(k – i + 1), where k is the number of planned comparisons and i is the 
sequential number of the comparison [31]. 
Qualitative secondary endpoints (ALT normalization and disappearance of HBsAg/ seroconversion) 
will be analyzed using the Fisher’s exact test.  Quantitative secondary endpoints (serum fibrosis 
marker, HBsAg and HBV DNA) will be presented as absolute values and changes from baseline. To 
compare treatment arms on the basis of endpoints, two-sided Wilcoxon rank sum test will be 
employed with adjustment at the significance level of 0.0167.  If the assumptions necessary for 


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carrying out parametric approach are not violated , parametric analogues of the above methods will 
be used: ANOVA/ ANCOVA, the Student’s t-test for dependent samples.  The assumptions will be 
verified using graphical methods. 
9.1.4. Safety Analysis 
Myrcludex B safety will be analyzed based on the following endpoints:  
Primary Safety Endpoint:  
 Incidence of treatment-related adverse events from Visit 1 to End-of-Study Visit.  
Secondary Safety Endpoint: 
 Nature and severity of treatment-related adverse events from Visit 1 to End-of-Study Visit.  
 Incidence, nature and severity of all other adverse events, and assessment of physical 
examination results, vital signs, 12-lead ECG, hematology, coagulation panel, blood 
chemistry, urinalysis, blood bile acids, development of anti- Myrcludex B antibodies from 
Visit 1 to End-of-Study Visit.  
These endpoints will be analyzed in Safety Set (see Section 9.7).  
Treatment-related adverse event is defined as any AE that occurred after the start of study drug 
treatment or pre-existing condition that worsened after the start of study drug treatment and that has 
any degree of relationship to the study drug, with the exception of “unrelated”.  Information on AE 
will be presented overall and by severity as numbers (and proportions) of subjects.   
Adverse events, including serious adverse events, will be classified using the latest version Medical 
Dictionary for Regulatory Activities (MedDRA) available at the time of database lock.  Further 
analysis  will include all AEs, SAEs,  AEs requiring treatment discontinuation, and discontinuations 
due to AEs.  
Incidence and severity of all AEs and treatment-related adverse events will be provided for all SOCs 
in accordance with MedDRA terminology.  SAE will also be presented in the form of descriptions 
(narratives). 
Safety analysis data will be presented as summary tables of descriptive statistics for each treatment 
arms.  Descriptive statistics will be provided for each safety endpoint. Vital sign and laboratory data 
as well as change from baseline will be summarized (where applicable) by visit of assessment and 
by treatment group. In addition, shifts in laboratory parameters will be presented by treatment group. 
Safety data listings will also be included in the final analysis.  
9.2. Planned Number of Subjects  
This study is a comparative parallel-group clinical study with three treatment arms receiving study 
medication (2 mg, 5 mg and 10 mg) and one control arm (all three comparisons will be done 
independently) to test the hypothesis of superiority of the study medication over reference product.  
The primary variable for this study is treatment response rate, defined as HDV RNA decrease by 
2 log10 from baseline or absence of HDV RNA (after 24 weeks of treatment).  This is a frequency 
parameter.  
As warranted by study aim and objectives, the null hypothesis (H0) will be defined the following 
way:  


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H0: ε ≤ δ 
and the alternative hypothesis (Ha) will be:  
Ha: ε > δ 
where ε is the anticipated difference between treatment response rates in the experimental arm and 
the control arm, and δ is the threshold for clinically significant values (superiority threshold).  
Considering study design, as well as type and nature of the primary endpoint (comparative study in 
parallel arms), sample size for each treatment arm can be calculated as follows:  
 
where 
 and 
 are the respective z-function values for planned type I and II error values; p1 and 
p2 are the treatment response rates in the experimental and control arms, respectively;  is the 
expected difference between treatment arms in the primary variable; k is the coefficient for uneven 
number of subjects per treatment arm (in this study k =1); n1 and n2 are the planned number of 
subjects for the experimental and control arms, respectively.  
Thus, the sample size was calculated based on the following assumptions:  
1. Critical level of significance for null hypothesis testing α = 0.0167 (Bonferroni adjustment).  
2. Study power – at least 0.8 (80%), probability of type II error (β) will not exceed 0.2.  
3. Superiority limit (clinical significance of the difference) δ will be assumed as 5%.  
4. Expected difference in the primary variable between treatment arms will be at least 34.0%. 
Previous phase Ib/IIa clinical study in patients with chronic hepatitis D demonstrated efficacy in 
monotherapy arm in 57% of subjects after 24 weeks of treatment with a lower limit of confidence 
interval of approximately 37%.  
5. Expected treatment response rate in the control arm is no more than 3% (in the absence of 
treatment and with nucleoside/nucleotide analogue therapy approved for hepatitis B in subjects with 
chronic hepatitis D, no response was observed; for example, study HIDIT-1 in 90 patients with 
chronic hepatitis D showed no effect on HDV RNA with monotherapy with adefovirm, a nucleotide 
analogue). It is believed, that spontaneous decrease in HDV RNA by 2 log10 can occur in no more 
than 3%.  
Sample size has been calculated the following way:  
 
𝑛1 = 𝑛2 = (2.13 + 0.84)2 ∗(0.37 ∗(1 −0.37) + 0.03 ∗(1 −0.03))
(0.34 −0.05)2
= 8.8209 ∗0.2622
0.0841
≈28  
 
Thus, to test the hypothesis of superiority of the study medication (separately for each dose level) 
over control arm, at least 28 subjects from each treatment arm need to be included into efficacy 
analysis.  Assuming a dropout rate of no more than 5% of subjects in each treatment arm, at least 
30 subjects need to be enrolled into each treatment arm.  
z
z


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When last subject completes 24 weeks of treatment, viral load (PCR results for HDV RNA) will be 
analyzed for all subjects in all treatment arms (primary endpoint is negative PCR results for HDV 
RNA or decrease by ≥2 log from baseline at Week 24).  
 
9.3. Significance Level  
One-sided significance level will be employed to test the primary variable (superiority by margin 
testing). Efficacy hypotheses will be tested sequentially, using Bonferroni-Holm method.  This 
procedure allows to control the general probability of one or more type I errors (FWER - 
Familywise error rate).  In the planned comparisons, type I error rate will not exceed 0.05, and 
significance levels for each sequential comparison will be calculated individually using the 
Bonferroni-Holm method (see above). 
9.4. Interim and Final Data Analysis  
When 10 patients of each arm will complete 28 days of treatment (starting from randomization 
visit), an Interim Safety Analysis will be performed. Based on the results of the analysis, the 
decision will be met by the sponsor, if cirrhotic patients can be included into the study. 
When the last patient completes 24-week treatment period, an Interim Report will be compiled on 
efficacy and safety of the study treatment.  
When the last patient completes follow-up period Final Study Report will be prepared.  
9.5. Handling of Missing and Non-Evaluable Data  
At interim analysis (when the last patient completes 24-week treatment period), missing data 
imputation for the primary efficacy endpoint will be based on Missing = Failure approach.  
Detailed procedure of missing data imputation will be provided in the Statistical Analysis Plan. 
      
9.6. Reporting of Any Deviations from Initial Statistical Plan 
Detailed description of statistical analysis will be provided in Statistical Analysis Plan. Statistical 
Analysis Plan will be finalized before database closure and deviations from the final version of the 
Statistical Analysis Plan will be described (with rationale) in the Final Study Report.  
9.7. Selection of Subjects for Statistical Analysis  
The following analytical sets will be included into data analysis:  
Safety Set: all subjects who received at least one dose of the study medication (Myrcludex B or 
Tenofovir) in the study period.  
Modified Intent-to-Treat Set (mITT): all randomized subjects who started study treatment 
(Myrcludex B or Tenofovir) in the study period after randomization .  
Per Protocol Set (PP): subjects from mITT set who completed24-week treatment period without 
major protocol deviations and with efficacy results for 24 weeks time point.  


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10. Direct Access to Source Data/ Documents  
10.1. Access and Review of Source Data and Records  
All information contained in source documents and certified copies and concerns clinical data, 
observations and other study-related activities, that is required for reconstruction and evaluation of 
the study is regarded as source data.  
Direct access to source data and documents must be provided to the study monitor and authorized 
representatives (CRO), Sponsor’s/CRO’s auditor, regulatory inspectors, members of ethics 
committees and representatives of insurance companies.  
10.2. Additional Information  
Upon request, Investigator provides additional study-related data or copies of relevant 
pseudonymized source documents to the Sponsor.  This may be relevant in such cases, when CRF 
records are illegible or contain errors. In special circumstances, or upon request form competent 
governmental authorities, access to complete study records may be required, provided that 
confidentiality requirements are met.   
11. Quality Control and Assurance   
11.1. Periodic Monitoring   
Monitoring will be done by a clinical monitor according to SOPs of the clinical research 
organisation. At the beginning of the trial the responsible monitor will perform an Initiation visit at 
the trial site (prior to the inclusion of the first study participant). During regular On-site visits the 
monitor will review the entries into the CRFs on the basis of applicable source documents. The 
investigators must allow the monitor to verify all essential documents and must provide support to 
the monitor at any time.  Frequency of monitoring will be defined in the Monitoring Manual. By 
frequent communications (letters, telephone, fax), the site monitor will ensure that the trial is 
conducted according to the protocol and regulatory requirements. 
11.2. Audit and Inspection   
Competent and local authorities and an auditor authorized by the Sponsor may request access to all 
source documents, CRF, and other trial documentation. Direct access to these documents must be 
guaranteed by the investigators who must provide support at all times for these activities. 
In case inspections will be announced to the Principal Investigator, the Sponsor and site monitor 
should be informed in time. 
12. Ethical and Legal Issues   
12.1. Good Clinical Practice   
The procedures set out in this trial protocol, pertaining to the conduct, evaluation, and 
documentation of this trial, are designed to ensure that all persons involved in the trial abide by 
Good Clinical Practice (GCP) and the ethical principles described in the applicable version of the 
Declaration of Helsinki. The trial will be carried out in keeping with local legal and regulatory 
requirements. 


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12.2. Patient information leaflet and informed consent form  
Before entering the study, the subject should provide the informed consent to the nature of the study, 
its methods and possible risks which must preliminary be explained to the subject. The subject must 
give the written informed consent. The signed informed consent form will be filed in the ISF. One 
copy of the patient leaflet and the written informed consent will be given to the subject. Subjects 
incapable of giving informed consent or minors are not allowed to participate in the study. 
All documents provided to the subject must be written in understandable language. The data on 
person providing the information to the subject should also be indicated. 
The participants will be informed as soon as possible if any new information may influence his/her 
decision to participate in the trial. The communication of this information will  be documented.  
   
12.3. Confidentiality 
The data obtained in the course of the trial will be treated pursuant to the applicable national and EU 
regulations.  
During the clinical trial, participants will be identified solely by means of their date of birth and an 
individual identification code (participant number). Trial findings will be stored in accordance with 
local data protection law and be handled with strict confidence. For protection of these data, 
organizational procedures are implemented to prevent distribution of data to unauthorized persons. 
The appropriate regulations of local data legislation will be fulfilled in their entirety. 
The participant consents in writing to release the investigator from his/her professional discretion in 
so far as to allow inspection of original data for monitoring purposes by health authorities and 
authorized persons (inspectors, monitors, auditors). Authorized persons (clinical monitors, auditors, 
inspectors) may inspect the participant-related data collected during the trial ensuring the data 
protection law. 
The investigator will maintain a patient identification list (patient numbers with the corresponding 
patient names) to keep records identifiable. This list will be filed in the ISF. 
Patients who did not consent to distribution of their pseudonymized data will not be included into 
the trial. 
   
12.4. Responsibilities of Principal Investigator  
A Principal Investigator will be appointed at each study center. He/she should ensure that all persons 
assisting in the trial are adequately informed about the protocol, any amendments to the protocol, the 
trial treatments, and their trial-related duties and functions. He should maintain a list of investigators 
at his study center and other appropriately qualified persons to whom he has delegated significant 
trial-related duties. 
 


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12.5. Approval of Trial Protocol and Amendments 
Before the start of the trial, the trial protocol, patient information leaflet and informed consent form, 
and any other appropriate documents will be submitted to the local independent ethics committees 
(IEC) as well as to the competent higher federal authority. A written favourable vote of the IEC and 
an (implicit) approval by the competent higher federal authority are a prerequisite for initiation of 
this clinical trial. The statement of IEC should contain the title of the trial, the trial code, the trial 
site, and a list of reviewed documents. It must mention the date on which the decision was made and 
must be officially signed by a committee member. This documentation must also include a list of 
members of the IEC participating in the applicable IEC meeting and a GCP compliance statement. 
Before the first participant is enrolled in the trial, all ethical and legal requirements must be met. All 
planned substantial changes will be submitted to IEC and the competent higher federal authority in 
written as protocol amendments. They have to be approved by the IEC and the competent higher 
federal authority.  
The Lead Clinician and the CRO will keep a record of all communication with the IEC and the 
regulatory authorities. 
12.6. Notification of Regulatory Authorities   
Local regulatory authorities responsible for each investigator have to receive information before, 
during and in the end of the study according to the current legislation. 
 
12.7. Continuous Information to Independent Ethics Committee 
According to the applicable national laws, EU regulations and the GCP, the IEC and the competent 
higher federal authority will be informed of all suspected serious unexpected adverse reactions 
(SUSARs) occurring during the trial. Both institutions will be informed in case the risk/benefit 
assessment did change or any others new and significant hazards to participants’ safety or welfare 
did occur.  
The IEC and the regulatory authorities must be informed about the end of the trial. They will be 
provided with a summary of trial results within one year after the end of clinical phase. 
 
13. Data Management   
13.1. Data collection 
All data obtained during the study will be documented in the electronic CRF. The investigator is 
responsible for ensuring that all sections of the CRF are completed correctly and that the entries can 
be verified against source data whenever applicable.  
The correctness of entries in CRF will be confirmed by dated electronic signature of the responsible 
investigator and reviewed by the responsible monitor.  
 


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13.2. Data handling 
CRF are provided for each subject in electronic format. 
All protocol-required information collected during the study must be entered in English into the 
electronic CRF by the investigator or a designated representative. The data has to be recorded on 
source documents immediately, except for data that are available on original printouts or that were 
defined as direct entries in the monitoring manual. An explanation should be given for all missing 
data. If the investigator authorizes other persons to make entries into the CRFs, the names, positions, 
signatures, and initials of these persons must be recorded. The Investigator must verify that all data 
entries in the CRF are accurate and correct. Therefore completed CRF must be reviewed and signed 
by the Investigator. 
All missing data or inconsistencies will be reported back to the center as queries and clarified by the 
responsible Investigator. If no further corrections are to be made in the database it will be declared 
closed and used for statistical analysis. 
 
13.3. Storage and archiving of data 
In accordance with ICH/GCP requirements the Investigator/the trial site will keep the electronic 
copy of the site-specific entries in the CRF and source data which confirm data obtained from 
patients as well as all documents indicated in section 8 “Essential documents for the conduct of a 
clinical trial” ICH/GCP, and all clinical trial documents as specified in by corresponding regulatory 
requirements. The Sponsor is responsible for archiving of TMF including all important trial 
documents. Furthermore, the Principal Investigator will archive all trial-specific data (the electronic 
copy of the site-specific entries in the CRF, source data and Investigator Site File (ISF) including 
participant identification list and relevant correspondence) according to the section 4.9 of the ICH 
Consolidated Guideline on GCP (E6) and to the local law and regulations. 
 
14. Insurance   
According to applicable national laws and EU regulations, an insurance policy has to be subscribed 
covering in its terms and provisions the legal liability for injuries caused to participating persons and 
arising out of this research performed strictly in accordance with the scientific protocol as well as 
with applicable law and professional standards.  
The insurance was taken out at: 
 
Great Lake Reinsurance (UK) PLC, 30 Fenchburch Street London EC3M 3AJ 
Insurance number: DE400-02-16  
Maximum limit 500,000€ per participating person 
 
Any impairment of health which might occur in consequence of trial participation must be notified 
to the insurance company. The participant is responsible for notification. The insured person will 
agree with all appropriate measures serving for clarification of the cause and the extent of damage as 
well as the reduction of damage. 


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During the conduct of the trial, the participant must not undergo other clinical treatment, except for 
cases of emergency, without prior consultation with the responsible Investigator. The participant is 
bound to inform the Investigator immediately about any adverse events and additional drugs taken. 
The terms and conditions of the insurance will be handed out to the participant on request. 
The insurance company has to be informed about all amendments that could affect participants’ 
safety. 
 
15. Publication and Other Use of Study Results   
The Sponsor encourage the presentation and/or publication of the results of their studies, using only 
clean, checked and validated data in order to ensure the accuracy of the results.  
At least forty-five (45) days in advance of proposed submission, the Investigator should forward a 
copy of the manuscript or abstract for review by Hepatera/MYR, and, if necessary, delay publication 
or communication for a limited time in order to protect the confidentiality or proprietary nature of 
any information contained therein. 
  
16. Confidentiality   
Information in this document is proprietary to the Sponsor and may be disclosed to the third parties 
only with the written consent from the Sponsor.  The right to review this information will be granted 
only to the investigator(s) and members of the study site(s) staff, members of the independent ethics 
committee(s) and healthcare officials entitled to control the study conduct.  Information sufficient to 
make a decision regarding consent to participate in the study will be provided to the patients whom 
the investigator plans to enroll.   
17. Protocol Amendments and/or Revisions  
Any changes to the study protocol must be agreed upon between Investigator and Sponsor prior to 
the implementation.  Any deviations in the study process that occur after approval of the protocol 
must be documented in a form of addendums or amendments to the protocol and/or updated versions 
of the protocol.  Depending on the nature of amendment, it needs to be submitted to the Ethics 
Committee and regulatory authorities as a notification or for approval.  Ethics Committee approval 
will be required for any change that affects subjects’ safety, study scale/design, involves increase in 
dose or duration of study drug treatment, increase in the number of subjects treated with the study 
medication, addition of a new test/procedure or elimination of a safety test. Any changes can only be 
implemented after they are approved by the Sponsor, all Investigators, and, if applicable, ethics 
committee and regulatory authorities, except for cases when such changes are required to avoid 
direct threat to life or health of subject participating in the clinical trial, or when the changes to the 
protocol involve administrative or logistics issues only.  
 
 
 
 


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14. Gaeta, G. B., Stroffolini, T., Chiaramonte, M., Ascione, T., Stornaiuolo, G., Lobello, S., … 
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Prot_SAP_ICF_000.pdf: 
Hepatera LLC 
Page 1 of 90 
Protocol No. MYR 202, Version 7.0 
Translation into English, dd. September 28, 2017 
Date: September 28, 2017 
 
 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
No. MYR 202 
 
 
 
«Multicenter, Open-Labeled, Randomized Clinical Study to Assess Efficacy and Safety of 3 Doses of 
Myrcludex B for the Treatment of Patients with Chronic Hepatitis B with delta agent for 24 weeks in 
Combination with Tenofovir to Suppress Hepatitis B Virus Replication Vs. the Administration of 
Tenofovir to Suppress Hepatitis B Virus Replication” 
 
Version: 7.0 
 
Date: September 28, 2017 
 
Test product: Myrcludex B, lyophilisate for solution for injection. 
 
Sponsor: Hepatera LLC, Russia 
 
Sponsor’s Address: 109240, Moscow, Verkhnyaya Radishchevskaya Street, 12/19, bldg. 1 
 
Clinical phase: II-III. 
Moscow, 2017 
 
 
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Protocol No. MYR 202, Version 7.0 
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Date: September 28, 2017 
 
 
 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ....................................................................................................................................... 5 
LIST OF ABBREVIATIONS ............................................................................................................................... 12 
1. 
BACKGROUND INFORMATION ............................................................................................................. 14 
1.1. 
Protocol Identification ..................................................................................................................... 14 
1.2. 
Contact Information about Sponsor................................................................................................. 15 
1.3. 
Page of the Protocol Approval by Sponsor ..................................................................................... 16 
1.4. 
Contact Information about Clinical Centers and Investigators ........................................................ 17 
1.5. 
Investigator Agreement ................................................................................................................... 19 
1.6. 
Contact Information about the Central Clinical Laboratory and Other Study Services .................. 20 
2. 
JUSTIFICATION OF STUDY .................................................................................................................... 22 
2.1. 
Name and Description of the Study Drug ....................................................................................... 23 
2.1.1. 
Background information ................................................................................................ 23 
2.2. 
Summary of Preclinical and Clinical Studies .................................................................................. 24 
2.2.1. 
Preclinical studies .......................................................................................................... 24 
2.2.2. 
Clinical use of MXB ...................................................................................................... 25 
2.3. 
Information on the Drug for Treatment of the Co-Infection with Hepatitus B virus ....................... 27 
2.4. 
Administration, Dosage and Duration of the Administration of the Investigational Medical Product27 
2.5. 
Study Compliance with Regulatory Requirements ......................................................................... 29 
2.5.1. 
List of Applicable Standards and Regulatory Requirements ......................................... 29 
2.5.2. 
Clinical Center’s Responsibilities ................................................................................. 30 
2.6. 
Description of the Study Population................................................................................................ 30 
2.7. 
Literary Sources and Data ............................................................................................................... 31 
3. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................................... 32 
4. 
STUDY DESIGN ......................................................................................................................................... 33 
4.1. 
Study Design Description ................................................................................................................ 33 
4.2. 
Pharmacokinetic Study .................................................................................................................... 39 
4.2.1. 
Pharmacokinetic Substudy (PK-substudy) .................................................................... 39 
4.2.2. 
Pharmacokinetic main study (PK-main study) .............................................................. 41 
4.3. 
Randomization ................................................................................................................................ 41 
4.4. 
Study Stages and Procedures ........................................................................................................... 41 
4.4.1. 
Screening Procedures .................................................................................................... 42 
4.4.2. 
Procedures and evaluations during the period of pre-treatment period with 
tenofovir ........................................................................................................................ 42 
4.4.3. 
Randomization Visit ...................................................................................................... 44 
4.4.4. 
Procedures and Evaluations during the Treatment Period ............................................. 45 
4.4.5. 
Evaluation after the end of the treatment ....................................................................... 49 
4.5. 
Premature Drop-out from the Study, Dose Interruption, Dose Correction ...................................... 50 
4.6. 
Treatment of the Activation of an Inflammatory Process ............................................................... 51 
4.7. 
Detailed Description of the Study Procedures ................................................................................. 51 
4.8. 
Study Completion, Suspension or Termination and Withdrawal of a Center or a Patient .............. 56 
4.8.1. 
Study completion as per protocol .................................................................................. 56 
4.8.2. 
Study Suspension or Termination.................................................................................. 56 
4.8.3. 
Premature termination of a center’s participation in the study ...................................... 57 
4.8.4. 
Premature termination of a patient’s participation in the study ..................................... 57 
4.9. 
List of Data Registered Directly in the CRF ................................................................................... 57 
5. 
PATIENT SELECTION AND DROP-OUT ................................................................................................ 58 
5.1. 
Inclusion Criteria ............................................................................................................................. 58 
5.2. 
Exclusion Criteria ............................................................................................................................ 58 
5.3. 
Criteria for Premature Withdrawal of Patients from the Study ....................................................... 59 


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5.3.1. 
Withdrawal criteria ........................................................................................................ 59 
5.3.2. 
Data on the patients dropped out ................................................................................... 60 
5.3.3. 
Subject substitution ....................................................................................................... 60 
5.3.4. 
Follow-up of patients dropped out................................................................................. 60 
6. 
PATIENT TREATMENT ............................................................................................................................ 61 
6.1. 
Myrcludex B .................................................................................................................................... 61 
6.1.1. 
Dosage form .................................................................................................................. 61 
6.1.2. 
Container Closure System ............................................................................................. 61 
6.1.3. 
Drug Handling and Storage ........................................................................................... 61 
6.2. 
Dose and Administration of Myrcludex B ...................................................................................... 61 
6.3. 
Previous and Concomitant Medication ........................................................................................... 62 
6.4. 
Excluded medication ....................................................................................................................... 64 
6.5. 
Methods of Monitoring Patient Compliance ................................................................................... 64 
7. 
EFFICACY EVALUATION........................................................................................................................ 65 
7.1. 
Efficacy Criteria .............................................................................................................................. 65 
7.2. 
Efficacy Parameter Evaluation Methods and Terms ....................................................................... 65 
8. 
SAFETY EVALUATION ............................................................................................................................ 67 
8.1. 
Safety parameter evaluation criteria ................................................................................................ 67 
8.2. 
Adverse Events ................................................................................................................................ 67 
8.2.1. 
Definitions ..................................................................................................................... 67 
8.2.2. 
Suspected unexpected serious adverse reaction (SUSAR (SUSAR) ............................. 69 
8.2.3. 
Follow-up period and recordkeeping ............................................................................. 69 
8.2.4. 
Adverse event characteristics ........................................................................................ 69 
8.2.5. 
Investigator’s reports about serious adverse events ....................................................... 70 
8.2.6. 
Emergency notification ................................................................................................. 70 
8.2.7. 
Pregnancy ...................................................................................................................... 71 
8.2.8. 
After-treatment reporting requirements ......................................................................... 71 
8.3. 
Laboratory Abnormalities and Other Deviations Classified as Adverse Events and Serious Adverse 
Events .............................................................................................................................................. 71 
8.4. 
Managing Toxic Reactions .............................................................................................................. 72 
8.4.1. 
Grade 1 to 2 laboratory abnormalities ........................................................................... 72 
8.4.2. 
Laboratory abnormality or Grade 3 clinical event ......................................................... 72 
8.4.3. 
Laboratory abnormality or Grade 4 clinical event ......................................................... 72 
8.5. 
Risks for Women of Childbearing Age and Risks during Pregnancy ............................................. 73 
9. 
STATISTICS ............................................................................................................................................... 74 
9.1. 
Documentation of Statistical Methods ............................................................................................ 74 
9.1.1. 
General principles .......................................................................................................... 74 
9.1.2. 
Demographic and baseline characteristics ..................................................................... 74 
9.1.3. 
Efficacy analysis methods ............................................................................................. 74 
9.1.4. 
Safety analysis methods ................................................................................................ 74 
9.2. 
Scheduled Number of Subjects ....................................................................................................... 75 
9.3. 
Applicable Significance Level ........................................................................................................ 76 
9.4. 
Study Termination Criteria .............................................................................................................. 76 
9.5. 
Procedures for Accounting Missing Data not to be Analyzed......................................................... 77 
9.6. 
Procedures for Reporting Any Deviations from the Original Statistical Plan ................................. 77 
9.7. 
Selection of participant for the statistical analysis .......................................................................... 77 
10. DIRECT ACCESS TO SOURSE DATA/DOCUMENTS ........................................................................... 78 
10.1. 
Access and Verification of Source Data and Records ..................................................................... 78 
10.2. 
Access to Additional Information ................................................................................................... 78 
11. QUALITY CONTROL AND QUALITY ASSURANCE ........................................................................... 78 


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11.1. 
Periodic Monitoring ........................................................................................................................ 78 
11.2. 
Audit and Inspection ....................................................................................................................... 79 
12. LEGAL AND ETHICAL ISSUES IN STUDY MANAGEMENT .............................................................. 81 
12.1. 
General requirements ...................................................................................................................... 81 
12.2. 
Ethical Conduct of the Study........................................................................................................... 81 
12.3. 
Council on Ethics and Local Ethics Committee .............................................................................. 81 
12.4. 
Regulatory Approval ....................................................................................................................... 81 
12.5. 
Periodic Informing of the Independent Ethics Committee .............................................................. 81 
12.6. 
Notification to Regulatory Authorities ............................................................................................ 82 
12.7. 
Information for the Patient and Informed Consent Form ................................................................ 82 
13. DATA MANAGEMENT AND RECORDKEEPING ................................................................................. 83 
13.1. 
Clinical Study Documents ............................................................................................................... 83 
13.2. 
Presentation (Delivery) of Study Documents and Materials ........................................................... 83 
13.3. 
Primary Documentation .................................................................................................................. 83 
13.4. 
Data Collection: Case Report Forms (CRFs) .................................................................................. 84 
13.5. 
Data Processing and Introduction of Amendments to eCRFs ......................................................... 84 
13.6. 
Confidentiality of Patient Data ........................................................................................................ 84 
13.7. 
Investigator File (Study Documentation Log) ................................................................................. 85 
13.8. 
Data Archiving ................................................................................................................................ 85 
14. FINANCING AND INSURANCE .............................................................................................................. 85 
15. PUBLICATION AND STUDY RESULT USAGE ..................................................................................... 87 
16. FINAL REPORT .......................................................................................................................................... 87 
17. CONFIDENTIALITY .................................................................................................................................. 88 
18. PROTOCOL AMENDMENTS AND/OR PROTOCOL REVIEW ............................................................. 88 
19. REFERENCES ............................................................................................................................................. 89 
 
LIST OF FIGURES 
Figure 1а. Graphical scheme of the Phase II clinical study. ........................................................................ 34 
Figure 2b. Graphical scheme of the Phase III clinical study. ....................................................................... 35 
 
 
LIST OF TABLES 
Table 1. Study diagram for Phases II and III. .............................................................................................. 36 
Table 2 Classification of Skin Adverse Events, Associated with the Study drug Injections ....................... 72 
 


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PROTOCOL SYNOPSIS 
Protocol No.: MYR 202 
Study drug: Myrcludex B 
Study title: 
Multicenter, Open-Labeled, Randomized Clinical Study of the Efficacy and Safety of 3 Doses of 
Myrcludex B for the Treatment of Patients with Chronic Hepatitis B with delta agent for 24 weeks in 
Combination with tenofovir to Suppress Hepatitis B Virus Replication Vs. the Administration of tenofovir 
to Suppress Hepatitis B Virus Replication 
Clinical 
phase: 
II-III phase. 
Key 
information
: 
The HDV is a small RNA virus that needs auxiliary functions from the HBV for its assembly and 
multiplication, and that uses the HBV envelope to release the virus and infect new cells. 
Approximately 5-15% of cases of chronic HBV infection show the infection with HDV. Several studies 
have shown that chronic HDV infection leads to a more severe form of liver disease than chronic HBV 
monoinfection, accompanied by faster progression of fibrosis, an increased risk of hepatocellular 
carcinoma, and early decompensation in addition to fibroid induration. The recent study in Italy, in which 
patients with hepatitis D had been observed for 28 years, showed that 25% of patients with fibroid 
induration had HCC and that liver failure led to death in three-fifths of patients (Romeo et al, 2009). Fibroid 
induration and hepatic cancer develop 10-15 years earlier when there is a co-infection with HBV/HDV, and 
the 5-year mortality of co-infected patients is twice higher than that of the HBV-infected patients 
(Recommendations for the prevention, diagnosis and treatment of HBV infection in Germany, Cornberg et 
al. 2007). The current possibilities for treating patients with hepatitis D are extremely limited, since 
interferon-alpha allows to achieve complete suppression of HDV activity in a small part of patients only: 
wherein, the treatment is accompanied by significant side effects and is characterized by high cost. PEG-
INF-a has also been used in small studies for the treatment of hepatitis D, leading to a sustained virology 
response in about 20% of patients. In addition, the nucleoside and nucleotide analogues used to treat HBV 
are ineffective in HDV treatment. There remains a critical unmet medical need for new drugs for the 
treatment of chronic HDV infection, since essentially there are no treatment options for 75% of patients 
with the co-infection with HBV/HDV. 
Description 
of 
the 
patient 
population: 
The study will include patients with chronic HDV infection with positive HDV RNA at the screening stage 
to confirm the effectiveness of the treatment with Myrcludex B in this category of patients. 
Primary data on the efficacy of Myrcludex B in the treatment of patients with chronic viral hepatitis B with 
delta agent were obtained in the Phase Ib / IIa clinical study. 
In the Phase Ib/IIа study, treatment with Myrcludex B resulted in the increase of HDV RNA and ALT 
levels in patients with HDV infection. Out of 24 subjects in the Phase Ib/IIа, 10 patients had cirrhosis or 
had already undergone the IF therapy. In this patient population with the most limited therapeutic options, 
the possibility of a positive response to the treatment with Myrcludex B was demonstrated. 
Thus, the present study will include patients suffering from chronic hepatitis B with delta agent in whom 
the prior IF therapy has been ineffective or, in the opinion of the investigating physician, is currently 
contraindicated (including cases of interferon intolerance in the past medical history), as well as patients 
with hepatic cirrhosis. 
Inclusion of such a patient population is justified both ethically and by the previous study results. 
Number of 
patients: 
Phase II 
Screening will be performed on 200 patients, 120 of them will be randomized to one of 4 treatment Arms in 
the ratio of 1:1:1:1.  
Phase III 
The number of patients required to be enrolled in phase III will be calculated on the basis of data of the 
Interim report on the Clinical Study Results performed as a part of phase II. In Phase III, patients will be 
randomized to one of 2 treatment Arms in the ratio of 1:1. 
Study 
design: 
 
Justification of the Design  
The following features of the study drug (Myrcludex B): 
− it is administrated to treat chronic hepatitis B with delta agent - the most severe form of viral hepatitis; 
− it has an orphan status in the European Union and the United States; 
− there is currently no effective standard treatment for chronic hepatitis B with delta agent; 
− it has the ability to simulate a dose / response reaction based on the viral kinetics 
determine the availability of the possibility of using a two-phase adaptive design for the planned clinical 
study, with its assignment to phase II / III. 


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The possibility of using an adaptive design in clinical studies conducted on small patient populations, such 
as the population of patients with chronic hepatitis B with delta agent, is also described in the European 
Medicines Agency (EMA) [GUIDELINE ON CLINICAL STUDIES IN SMALL POPULATIONS. 
London, 27 July 2006. Doc. Ref. CHMP/EWP/83561/2005]. 
The methodology for the planned Phase II / III study is based on EMA guidelines [REFLECTION PAPER 
ON METHODOLOGICAL ISSUES IN CONFIRMATORY CLINICAL STUDIES PLANNED WITH AN 
ADAPTIVE DESIGN. London, 18 October 2007. Doc. Ref. CHMP/EWP/2459/02]. 
This  is a multicenter, open-labeled, randomized clinical study.  
Phase II 
Taking into account the dropout of patients at the stage of Screening, approximately 200 patients will 
undergo Screening procedures, and 120 of them will be randomized into 4 treatment Arms in the ratio of 
1:1:1:1: 
Arm A (30 patients): Myrcludex B 2 mg/day/subcutaneously (s/c) for 24 weeks + tenofovir, with the 
further follow-up period of 24-weeks of continued tenofovir therapy. 
Arm B (30 patients): Myrcludex B 5 mg/day/subcutaneously (s/c) for 24 weeks + tenofovir, with the 
further follow-up period of 24-weeks of continued tenofovir therapy. 
Arm C (30 patients): Myrcludex B 10 mg/day/subcutaneously (s/c) for 24 weeks + tenofovir, with the 
further follow-up period of 24-weeks of continued tenofovir therapy. 
Arm D (30 patients): tenofovir treatment for 48 weeks. 
The main part of the study includes Screening period of 28 days (day -28/-1), a pre-treatment period for 
patients, for whoma pre-treatment periodwith tenofovir, of 84 days is indicated, baseline randomization 
visit (Day 1) and a 24-week study period., Follow-up period will be 24 weeks for all treatment arms. 
Screening 
During the screening period (up to 28 days before the first drug administration and also the period of 
preliminary therapy (if applicable)), the following examinations will be performed: informed consent form 
signing, physical examination, laboratory tests, serological tests (HIV, HCV antibodies), HCV RNA in 
patients with anti-HCV antibodies, antibodies to HDV, HDV RNA, evaluation of inclusion/exclusion 
criteria, ultrasound, urine pregnancy test, alcohol-breath test, urine drug screen (test strips). 
During the screening, patients will undergo a liver biopsy study, with the determination of the level of 
hepatic necroinflammation and fibrosis. An immunohistochemical analysis of HDV RNA-positive cells will 
be performed 
A part of the biopsy material will be frozen to determine intrahepatic parameters. No use of maintenance 
drugs (for example, to stimulate the growth of platelets) is allowed. 
A liver biopsy study may be replaced, by the decision of the Investigator, with transient elastometry 
(fibroscan). 
Tenofovir Pre-treatment Period 
All patients who meet inclusion/exclusion criteria and who have not been treated with nucleoside / 
nucleotide analogues for at least 12 weeks before the planned start of study treatment will receive the 
protocol-specified nucleotide analogue, tenofovir, for 12 weeks prior to  randomization. 
Randomization visit 
All patients who meet inclusion/exclusion criteria and who have been treated with nucleoside / nucleotide 
analogues for at least 12 weeks before the planned start of study treatment or pre-treated with tenofovir as 
per the protocol will be invited to a randomization visit: the following examinations will be conducted: 
physical examination, weight measurements, safety laboratory tests, virology parameters, serum marker for 
fibrosis, immunogenicity, HBV and HDV genotyping and resistance analysis (in patients who have not 
underwent prior treatment with tenofovir). All evaluations performed during this visit should be qualified as 
the main parameters for safety monitoring and should not be qualified as the inclusion/exclusion criteria. 
During the randomization visit, after completion of all procedures specified in the protocol, patients will be 
randomized to one of 4 treatment Arms and will receive the study drug for the first 28 days of use. 
Treatment period 
A treatment with the study drug on combination with tenofovir, or with tenofovir alone, will last for 24 
weeks, followed by a 24-week follow-up period. Treatment will be conducted in an outpatient setting 
(except hospitalization for pharmacokinetic study and liver biopsy). 
The follow-up period 
Follow-up period will last for 24 weeks. During this period, patients from all groups will receive treatment 
with tenofovir.  


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Evaluations 
A detailed schedule of evaluations performed is presented in the study design. 
Pharmacokinetic study of Myrcludex B and study of systemic (general) metabolic CYP3A activity: 
1. 
Supportive pharmacokinetic study (PK-substudy) 
1.1. 
Substudy of Myrcludex B pharmacokinetics 
10 patients from Arms A, B and C (total 30) will participate in the pharmacokinetic substudy. On day 1-2 
and on day 14-15 of the drug administration, the patients will be hospitalized to the appropriate study site 
for blood sampling for PK study. 
Blood sampling time for the PK analysis: before the administration of Myrcludex B and MDZ, and in 
00:05; 00:15; 00:30; 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 10:00, 14:00, 24:00 (hh:min) after the 
administration of Myrcludex B. 
1.2. 
Substudy of the systemic (general) metabolic CYP3A activity 
It is also planned to study the P450 (CYP3A) cytochrome activity in 10 patients from Arms A, B and C 
(total 30), as a part the pharmacokinetic substudy (PK-substudy).  
Performance of this substudy is due to the fact that CYP3A is involved in the metabolism of about 50% of 
currently registered drugs and is the most common isoenzyme from the cytochrome family with localization 
in liver and intestines. 
To study the metabolic CYP3A activity in patients enrolled in the study, it is planned to use data on the 
pharmacokinetics of the benzodiazepine derivative, Midazolam (MDZ). 
In clinical practice, MDZ is used in patients with sleep disturbance, for premedication and sedation, and as 
an initial narcosis. In the planned substudy, patients will be injected with MDZ intravenously (iv) in a 
microdose (10 μg) that is unable to have any therapeutic effect due to the fact that the MDZ microdose is 
significantly less than the no observed adverse effect level (NOAEL) in humans. [Hohmann N. et al. 
Midazolam microdose to determine systemic and pre-systemic metabolic CYP3A activity in humans // Br J 
Clin Pharmacol /2014/79:2/278–285]. 
The possibility of using MDZ as an agent for studying the systemic metabolic CYP3A activity is regulated 
by the EMA guidelines [EMA. Guideline on the investigation of drug interactions. 2012, Available at 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf
] и FDA [CDER. Guidance for industry drug interaction studies – study design, data analysis, implications 
for 
dosing, 
and 
labeling 
recommendations. 
2012, 
Available 
at 
// 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory 
Information/Guidances/ucm292362.pdf]. 
The introduction of MDZ and its PK study is planned during the following time intervals: 
 
day (-13) – day (-12) [Visit 04] apart from the injection and PK-study of Myrcludex B; 
 
day 1 – day 2 [Visit 1] together with the injection and PK-study of Myrcludex B; 
 
day 14 – day 15 [Visit 3] together with the injection and PK-study of Myrcludex B. 
On day (-13-12), the PK of Midazolam is studied before starting the treatment with Myrcludex B at the 
following time points: before the injection of MDZ and in 00:05; 00:15; 00:30; 1:00, 1:30, 2:00, 2:30, 3:00, 
4:00, 6:00, 10:00, 14:00, 24:00 (hh:min) after the injection of MDZ. 
To study the PK of MDZ on day 1 and day 14, Midazolam is administered prior to the administration of the 
study drug Myrcludex B, and blood sampling (except for the zero line) is performed after the administration 
of Myrcludex B. The blood sampling for MDZ analysis: before the administration of MDZ and Myrcludex 
B and in 00:05; 00:15; 00:30; 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 10:00, 14:00, 24:00 (hh:min) after the 
administration of Myrcludex B. 
2. 
Pharmacokinetic main study (PK-main study). For a more accurate study of the possible 
cumulation of the study drug in all patients treated with Myrcludex B, blood sampling points for the 
pharmacokinetic study are assigned: Week 4, 8, 12, 16, 20, 24 (1 hour +/- 15 minutes after the drug 
administration). Patients not enrolled in the pharmacokinetic substudy are assigned with a blood sampling 
point at the randomization visit (1 hour +/- 15 minutes after the drug administration). 
Duration of the Study 
 Up to 64 weeks, including screening 
 
Phase III 
The number of patients required to be enrolled in phase III will be calculated on the basis of data of the 
Interim report performed as a part of phase II. Patients will be randomized to one of 2 treatment groups in 
the ratio of 1:1. 


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Group I: Myrcludex B in the optimal dosage /subcutaneously (s/c) for 24 weeks + tenofovir, with the 24-
week follow-up on treatment with tenofovir. 
Group II: treatment with tenofovir for 48 weeks. 
The main part of the study includes Screening period of 28 days (Day -28/-1),  pre treatment period for 
patients, for whom a pre-treatment periodwith tenofovir is indicated to, lasting up to 84 days, baseline 
randomization visit (Day 1) and a 24-week study period. the follow-up period will be 24 weeks for all 
treatment arms. 
Screening 
During the screening period (up to 28 days before the first drug administration), the following examinations 
will be performed: physical examination, laboratory tests, serological tests (HIV, HCV antibodies), HCV 
RNA in patients with anti-HCV antibodies, antibodies to HDV, HDV RNA, evaluation of 
inclusion/exclusion criteria. 
During the screening, patients will undergo a liver biopsy study, with the determination of the level of 
hepatic necroinflammation and fibrosis. An immunohistochemical analysis of HDV RNA-positive cells will 
be performed. 
A part of the biopsy material will be frozen to determine intrahepatic parameters. No use of maintenance 
drugs (for example, to stimulate the growth of platelets) is allowed. 
A liver biopsy study may be replaced, by the decision of the Investigator, with transient elastometry 
(fibroscan). 
Tenofovir Pre-treatment Period 
All patients who meet the inclusion / exclusion criteria and who have not been treated with nucleoside / 
nucleotide analogues for at least 12 weeks before the planned start of study treatment will receive the 
protocol-specified nucleotide analogue, tenofovir, for 12 weeks prior to the randomization. 
Randomization visit 
All patients who meet inclusion / exclusion criteria and who have been treated with nucleoside / nucleotide 
analogues for at least 12 weeks before the planned start of study treatment or pre-treated with tenofovir as 
per the protocol will be invited to a randomization visit: the following examinations will be conducted: 
physical examination, weight measurements, safety laboratory tests, virology parameters, serum marker for 
fibrosis, immunogenicity, HBV and HDV genotyping and resistance analysis (in patients who have not 
underwent prior treatment with tenofovir). All evaluations performed during this visit should be qualified as 
the main parameters for safety monitoring and should not be qualified as the inclusion/ exclusion criteria. 
During the randomization visit, after completion of all procedures specified in the protocol, patients will be 
randomized to one of the 2 treatment  and will receive the study drug for the first 28 days of use. 
Treatment period 
A treatment with the study drug on combination with tenofovir, or with tenofovir alone, will last for 24 
weeks, followed by a 24-week follow-up period. Treatment will be conducted in an outpatient setting. 
The follow-up period 
Follow-up period will last for 24 weeks. During this period, patients from all groups will receive treatment 
with tenofovir.  
Evaluations 
A detailed schedule of evaluations performed is presented in the study design. 
Duration of the Study 
Up to 64 weeks, including screening 
 
Interim and final data analysis as a part of Phase II  
When the last patient completes a 24-week treatment period as a part of Phase II clinical study, patients 
from all treatment arms will be analyzed for viral load based on PCR results for HDV RNA (negative PCR 
results for HDV RNA or decrease by ≥2 log from baseline at Week 24 will be considered as the primary 
endpoint). The results of this study will be used to draw up the Interim report on the results of the Phase II 
clinical study, herewith, all patients will continue to be treated with tenofovir. During the Interim analysis, 
the recruitment of new patients into the clinical study will be suspended. 
Based on the data from the Phase II Interim Report, the optimal (based on efficacy and safety analysis) 
dosage for the second part of the clinical study (corresponding to phase III) will be selected, and the 
required additional number of patients to be enrolled in Phase III will be calculated. When calculating the 
sample size, the correction for a plurality of comparisons (Pocock correction) will be taken into account 
with due regard to two statistical analyzes (at treatment week 24 of phase II and treatment week 24 of phase 


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III). The results of the Phase II Interim analysis will be submitted to the Ministry of Health of the Russian 
Federation. If a statistically significant conclusion is obtained based on the results of phase II on the 
statistical superiority of study drug in chosen dosage over the control group with respect to the primary 
endpoint at the bilateral significance level of 5%, then the recruitment of patients into Phase III of the study 
will not be performed, and the statistical analysis will be performed as a part of the Interim Report on Phase 
II and the Final Report on the Clinical Study Results. 
When the last patient completes the follow-up period of the first part of the clinical study, the data on the 
treatment studied will be analyzed in all patients completing 48-week treatment period in phase II, the Final 
Report on the Results of the Phase II Clinical Study will be prepared and submitted to the regulatory 
authorities.  
 
Interim and final data analysis as a part of Phase III 
When the last patient completes a 24-week treatment period as a part of Phase III clinical study, patients 
from all treatment arms will be analyzed for viral load based on PCR results for HDV RNA. These results 
will be used for preparing the Interim report on the results of the Phase III clinical study, herewith, all 
patients will continue to be treated with tenofovir. Negative PCR results for HDV RNA or decrease by ≥2 
log from baseline to Week 24 will be considered as the primary endpoint. The results of the Interim Report 
on the Results of the Phase III Clinical Study will be submitted to the regulatory authorities with the aim of 
the study drug marketing authorization. 
When the last patient completes the follow-up period of the second part of the clinical study, the results of 
the treatment studied will be analyzed in all patients who have completed the 48-week treatment period, the 
Final Report on the Clinical Study Results will be prepared and submitted to the regulatory authorities. 
Endpoints: 
Criteria for efficacy parameter evaluation for phases II and III 
Primary endpoint: 
● 
The negative PCR result for HDV RNA or a decrease by ≥2 log from baseline to week 24. 
Secondary endpoints: 
● 
The duration of the effect (no increase) on HDV RNA at Week 24 after treatment (study week 48) 
compared to the results obtained at the end of the treatment period (study week 24). 
● 
The presence of a combined response: the negative PCR result for HDV RNA, or a decrease by ≥2 
log and normalization of ALT at Week 24 compared to the results obtained before the treatment with the 
study drug. 
● 
Changes in ALT values at Week 24 and Week 48 compared to results obtained before the 
treatment with the study drug. 
● 
Improvement of the histological findings (reduction of necroinflammation, absence of fibrosis 
progression, etc.) according to the liver biopsy results or the lack of  fibrosis progression based on transient 
elastometry (fibroscan) at Week 24 compared to the results obtained before the  treatment with the study 
drug. 
● 
Canges (no increase) in marker for fibrosis – alpha-2 macroglobulin in the serum at Week 24 and 
Week 48 compared to the results obtained before the  treatment with the study drug. 
● 
Changes in  HBsAg (decrease levels, disappearance of HBsAg, HBsAg antibodies) at Week 24 and 
Week 48 compared to the results obtained before the  treatment with the study drug. 
● 
Changes in HBV DNA levels at Week 24 and Week 48 compared to the results obtained before the  
treatment with the study drug. 
Criteria for safety parameter evaluation for phases II and III 
● 
Data on adverse events, physical examination, weight measurement, vital signs examination, 12-
lead ECG, hematology, coagulation panel, blood chemistry, urinalysis, serum bile acid test. 
● 
Antibody response to Myrcludex B. 
Dosage 
strength: 
Study drug 
Phase II 
A 2 mg dose was effective in the Phase IIa studies in patients with HDV. A 10 mg dose showed the most 
pronounced effect in the Phase Ib/IIа clinical studies in patients with chronic hepatitis B. 
Phase III 
The dosage strength will be selected based on the Phase II results. 
 
The drug for the treatment of the concurrent infection with the hepatitis B virus  
The drug for the treatment of the concurrent infection with hepatitis B virus – tenofovir, is approved for the 


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treatment of chronic HBV infection. The dose of tenofovir will be selected according to the prescribing 
information. 
Inclusion 
criteria 
(similar 
both for 
Phases II 
and III): 
1. 
Age from 18 through 65 years at the time of granting of a written informed consent for the 
participation in the study. 
2. 
Presence of HBsAg in serum within at least 6 months before the screening period. 
3. 
Anti-HDV antibodies in serum within at least 6 months. 
4. 
Positive PCR on HDV RNA in serum during screening. 
5. 
Patients with hepatic cirrhosis, regardless of prior treatment with interferons. 
6. 
Patients without hepatic cirrhosis in whom prior IF treatment was ineffective or, in the opinion of 
the investigator, is currently contraindicated (including cases of interferon intolerance in the past medical 
history)1. 
7. 
Alanine aminotransferase index is >1 UNL, but less than 10 UNL.  
8. 
Prior treatment with nucleotide / nucleoside analogues for at least 12 weeks prior to the expected 
initiation date of the treatment period with the study drug or patient’s consent to take tenofovir for at least 
12 weeks before the planned start of study treatment. 
9. 
Negative urine pregnancy test in female subjects of childbearing age: 
10. 
Inclusion criteria for women. 
 
Menopause within at least 2 years, or 
 
Surgical sterilization (complete hysterectomy or bilateral oophorectomy, or ligation of both 
fallopian tubes, staples, or other method of sterilization), or 
 
No heterosexual contactsduring the study period, or 
 
Consent to use a highly effective contraceptive method (a double barrier method or a combination 
of a barrier method with a hormonal or intrauterine contraceptive) during the study period and within 3 
months after the last dose of the study drug 
11. 
Men must agree to use a highly effective contraceptive method (double barrier methods or a 
combination of a barrier method and a hormonal or intrauterine contraceptive used by a female partner) and 
not be a sperm donor during the study period and within three months after the last dose of the study drug. 
Exclusion 
criteria 
(similar 
both 
for 
Phases 
II 
and III): 
 
1. 
The Child Pugh score should be B-C or above 6 points; 
2. 
The co-infection with hepatitis C virus (HCV) or HIV. Patients with the presence of anti-HCV 
antibodies in the presence of negative HCV RNA at the stage of screening are considered acceptable to 
participate in the study; 
3. 
Creatinine clearance is <60 ml/min; 
4. 
Total bilirubin is> 34.2 μmol / L. Patients with an increased total bilirubin level may be included in 
the study after consulting with the Medical Research Monitor if it is clearly established that such an 
increase is an evidence of Gilbert’s syndrome. 
5. 
Malignant tumors in any organ system, including hepatocellular carcinoma, in the past or current 
history.  
6. 
Systemic connective-tissue diseases. 
7. 
Chronic heart failure of functional classes III-IV according to NYHA (New York Heart 
Association) classification. 
8. 
Patients with uncontrolled arterial hypertension (BP> 150/100 mm Hg affected by the 
administration of antihypertensive drugs) during previous 3 months before the initiation of the clinical 
phase. 
9. 
Patients with past or unstable concomitant diseases, or clinical conditions that prevent the inclusion 
of this patient in the study. 
10. 
Patients with mental disorders or social circumstances that interfere with the requirements of the 
protocol. 
11. 
Decompensated liver disease in the current or previous history, including coagulopathy, 
hyperbilirubinemia, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding esophageal varices; 
12. 
WBC count is <3000 cells/mm3; 
                                                 
 
1 Enrollment of patients who have previously undergone IF treatment is possible not earlier than in 30 days after the last administration of 
interferon. 


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13. 
Neutrophil count is <1500 cells/mm3; 
14. 
Platelet count is <60,000 cells/mm3; 
15. 
A patient takes illegal psychiatric drugs at the time of screening; 
16. 
Treatment with Interferon within 30 days before screening; 
17. 
Transplantation of a solid organ in the past history; 
18. 
Patients who abuse alcohol now or have abused it for 6 months before the enrollment; 
19. 
A history of a disease requiring regular use of systemic corticosteroids; 
20. 
Pregnant and lactating women; 
21. 
Participation in other clinical studies within 30 days before screening; 
22. 
Patients who have received Myrcludex B as a part of previous studies. 
Statistical 
analysis 
of 
the Phase II 
and 
III 
study 
results: 
Primary efficacy analysis will be based on the following efficacy endpoint:  
 
The negative PCR result on HDV RNA or decrease by ≥2 log10 at treatment week 24 compared to 
the data obtained before the initiation of treatment with the study drug.  
In Phase II, treatment arms will be compared using the Wald test for Superiority by Margin of 5%; 95% 
Clopper-Pearson confidence interval will also be calculated for treatment response rates (for each treatment 
arm). Each experimental treatment arm (Myrcludex B) will be compared to the control arm receiving 
tenofovir alone. Each Myrcludex B treatment arm will be compared to the control arm separately (Arm A 
vs Arm D, Arm B vs Arm D, Arm C vs Arm D). Hypotheses will be tested sequentially, using Bonferroni-
Holm method. Null hypotheses will be defined for each prior test, and appropriate p-values will be 
calculated (based on data obtained in the study). After that, null hypotheses will be rejected in descending 
order of respective p-values for critical values of type I error (α), calculated as α/(k – i + 1), where k is the 
number of planned comparisons and i is the sequential number of the comparison . 
In Phase III, the hypothesis of statistical superiority will be tested with the help of the two-sided Fisher 
exact test for the primary efficiency index. 
Qualitative secondary endpoints (ALT normalization and disappearance of HBsAg/ seroconversion) will be 
analyzed using the Fisher’s exact test.  Quantitative secondary endpoints (serum fibrosis marker, HBsAg 
and HBV DNA) will be presented as absolute values and changes from baseline. To compare treatment 
arms on the basis of endpoints, two-sided Wilcoxon rank sum test will be employed with adjustment at the 
significance level of 0.0167.  If the assumptions necessary for carrying out parametric approach are not 
violated (will be verified using graphical methods), parametric analogues of the above methods will be 
used: analysis of variance ANOVA/ analysis of covariance ANCOVA, the paired Student’s t-test for 
dependent samples. 
Numerical safety data will be presented as summary tables of descriptive statistics for each treatment arms.  
Descriptive statistics will be provided for each numerical safety endpoint. AEs will be tabulated per 
treatment group and System Organ Class (SOC) at Preferred Term (PT) level of MedDRA. SAEs will be 
reported in form of narratives. Vital sign and laboratory data as well as change from baseline will be 
summarized (where applicable) by visit of assessment and by treatment group. In addition, shifts in 
laboratory parameters will be presented by treatment group. 


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LIST OF ABBREVIATIONS 
AFP - alfa-fetoprotein. 
ALT - alanine transaminase. 
AST - aspartate transaminase. 
UNL - upper normal level. 
WFI - water for injection. 
HPLC - high-performance liquid chromatography. 
HPLC-MS - high-performance liquid chromatography with mass spectrometry. 
HCC - hepatocellular carcinoma 
NOAEL - no observed adverse effect level. 
DLT - dose-limiting toxicity. 
DNA - deoxyribonucleic acid. 
EP - European Pharmacopoeia. 
IL - interleukin. 
IMP - investigational medicinal product. 
INF-α - interferon-alpha. 
SD - study drug. 
CRF - case report form. 
IC - ion chromatography. 
CK - creatine kinase. 
CT - computer tomography. 
LDG - lactate-dehydrogenase. 
IU - international unit. 
MRI - magnetic resonance imaging. 
GCP - good clinical practice. 
IEC - Independent Ethics Committee. 
AE - adverse event. 
RH - relative humidity. 
s/c - subcutaneously. 
SAP - statistical analysis plan. 
RIA - radioassay. 
SCR - screening period. 
Cavg - average concentration. 
Cmax - maximum concentration. 
Cmin - minimum concentration. 
SOC - system organ class. 
SOP - standard operating procedure. 
SAE - serious adverse event. 
cccDNA -cyclic covalently closed deoxyribonucleic acid. 
ICF - informed consent form. 
PK - pharmakokinetics. 
TNF - tumour necrosis factor . 
CHB - chronic hepatitis B. 
CHD - chronic hepatitis B with delta agent. 
AP - alkaline phosphatase. 
ECG - electrocardiogram. 
IRB - Institutional Review Board. 
AUC0-t - area under the curve from the moment of administration of the drug to the determined time point t. 
AUCtau - area under the curve during the dose interval. 
CTCAE - Common Terminology Criteria for Adverse Events. 


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CRP - C-reactive protein. 
DNMEASL - European Association for the Study of the Liver. 
FDA - Food and Drug Administration. 
GCP - Good Clinical Practice. 
GGT - Gamma-glutamyl transferase. 
GMP - Good Manufacturing Practice. 
HBV - hepаtitis B virus. 
HBeAg - Hepatitis B envelope antigen. 
HBsAg - Hepatitis B surface antigen. 
HCC - hepatocellular carcinoma. 
HCV - hepаtitis C virus. 
HDV - hepаtitis Delta virus (D). 
HED - human equivalent dose. 
HLA - human leukocyte antigen. 
ICH - International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. 
INR - international normalized ratio. 
IMPD - investigational medical product dossier. 
IWRS - Interactive Web Response System. 
MCH - mean corpuscular haemoglobin. 
MCHC - mean corpuscular hemoglobin concentration. 
MCV - mean corpuscular volume. 
MDZ – Midazolam. 
MedDRA - Medical Dictionary for Regulatory Activities. 
MRT - mean residence time. 
MXB - Myrcludex B. 
NCI - National Cancer Institute (USA). 
NYHA - New York Heart Association. 
NOAEL - no observed adverse effect level. 
NOEL - no observed effect level. 
NTCP - sodium-taurocholate cotransporting polypeptide. 
PBMC - peripheral mononuclear blood cells. 
PT - Preferred terms 
SOC - System Organ Class 
SUSAR - suspected unexpected serious adverse reaction. 
TEC - target therapeutic effect concentration. 
Tmax - time to maximum concentration. 
TMF - Study Master File (Clinical study Master File). 
TRAE - Therapy related adverse event. 
T1/2 - terminal elimination half-life. 
 


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1. 
BACKGROUND INFORMATION 
 
1.1. 
Protocol Identification 
Title: 
Multicenter, Open-Labeled, Randomized Clinical Study of the Efficacy and Safety 
of 3 Doses of Myrcludex B for the Treatment of Patients with Chronic Hepatitis B 
with delta agent for 24 weeks in Combination with tenofovir to Suppress Hepatitis 
B Virus Replication Vs. the Administration of tenofovir to Suppress Hepatitis B 
Virus Replication 
Protocol No.: 
MYR 202 
Version: 
7.0 
Date: 
September 28, 2017 


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1.2. 
Contact Information about Sponsor 
 
Sponsor: 
Full name of the contact person: Yana Anatolievna Deloveri 
Position: Director General 
Name of the institution: Hepatera LLC, Russia 
Address: 109240, Moscow, Verkhnyaya Radishchevskaya Street, 12/19, bldg. 1 
Tel./fax: +7 (495) 726-52-53 
E-mail: deloveri@ammaxwell.ru. 


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1.3. 
Page of the Protocol Approval by Sponsor 
Protocol No.: 
MYR 202 
The study «Multicenter, Open-Labeled, Randomized Clinical Study of the Efficacy and Safety of 3 Doses of 
Myrcludex B for the Treatment of Patients with Chronic Hepatitis B with delta agent for 24 weeks in 
Combination with tenofovir to Suppress Hepatitis B Virus Replication Vs. the Administration of tenofovir to 
Suppress Hepatitis B Virus Replication» has been approved for conducting in accordance with the Protocol, 
the principles of Good Clinical Practice and applicable regulatory requirements. The signatures of these 
persons guarantee that they have accepted the final version of the protocol: 
Sponsor 
Hepatera LLC 
Sponsor's Representative 1 
Full name: Yana Anatolievna Deloveri 
Position: Director General 
Name of the institution: Hepatera LLC, Russia 
Address: 
109240, 
Moscow, 
Verkhnyaya 
Radishchevskaya Street, 12/19, bldg. 1 
Tel./fax: +7 (495) 726-52-53 
E-mail: deloveri@ammaxwell.ru 
 
 
……………………………. 
Date 
 
……………………………. 
Signature 
 


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1.4. 
Contact Information about Clinical Centers and Investigators 
 
1) List of medical organizations in which the MYR 202 clinical trial will be conducted: 
 
Clinical Site 1 
“Moscow Regional Research Clinical Institute n.a. M.F. Vladimirskiy”, 
61/2, Shchepkina str., 129110, Moscow, Russia 
Principal Investigator 
Pavel Olegovich Bogomolov, MD, PhD 
Clinical Site 2 
State Budgetary Institution of Healthcare  “Stavropol Regional Clinical 
Hospital”, 1, ulitsa Semashko, 355000, Stavropol, Russia  
Principal Investigator 
Nataliya Ioganovna Geyvandova, MD, DMSc 
Clinical Site 4 
State Budgetary institution of the Republic of Sakha (Yakutia) "Yakutsk 
Clinical Hospital" 
677005, Republic of Sakha (Yakutia), Yakutsk, ul. Stadukhina, 81, build. 5 
Principal Investigator 
Snezhana Spiridonovna Slepcova 
Clinical Site 5 
State Budgetary Healthcare Institution "Moscow Clinical Scientific and 
Practical Center of the Department of Public Health of Moscow" 
111123, Moscow, Highway Enthusiasts, 86 
Principal Investigator 
Igor Gennadievich Bakulin 
Clinical Site 6 
State Autonomous Healthcare Institution "Republican Clinical Infectious 
Diseases Hospital named after Prof. A.F. Agafonov "(SAHI RCID) 
420138, Republic of Tatarstan, Kazan, Pobedy Avenue, 83 
Principal Investigator 
Ilsiyar Mansurovna Khaertunova 
Clinical Site 12 
State Budgetary Educational Institution of Higher Professional Education 
“South Ural State Medical university” of the Ministry of Healthcare of the 
Russian Federation, 2 Cherkasskaya str., 454052, Chelyabinsk, Russia 
Principal Investigator 
Olga Igorevna, Sagalova, MD, PhD, DMSc 
Clinical Site 13 
State Budget Health Institution of Moscow "Infectious Clinical Hospital No. 
1 of the Moscow Healthcare Department" 
125367, Moscow, Volokolamskoye road, 63 
Principal Investigator 
Marina Rusanova from January 13, 2017 (Elena Andreevna 
Nurmukhametova, till 13.01.2017) 
Clinical Site 16 
LLC "Clinic of Modern Medicine" 
121293, Moscow, Ploschad Pobedi, 2, bldg. 1 
Principal Investigator 
Tatyana Vladimirovna Stepanova 
Clinical Site 18 
State Budgetary Educational Institution of Higher Professional Education 
"Novosibirsk State Medical University" of the Ministry of Health of the 
Russian Federation 
630091, Novosibirsk, Krasny prospect, 52  
Principal Investigator 
Marina Fedorovna Osipenko 
Clinical Site 19 
Medical Company “Hepatolog” LLC, 36A, Serdobskaya str., 430063, 
Samara, Russia 
Principal Investigator 
Vyacheslav Gennadievich Morozov, MD, PhD, DMSc 
Clinical Site 20 
Federal budgetary research institution Central Research Institute of 
Epidemiology  
111123, Russia, Moscow, ul. Novogireevskaya, house 3а  
Principal Investigator 
Vladimir Petrovich Chulanov 
 
 
 


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2)  List of medical organizations participating in the pharmacokinetic supplementary study: 
 
Clinical Site 1 
“Moscow Regional Research Clinical Institute n.a. M.F. Vladimirskiy”, 
61/2, Shchepkina str., 129110, Moscow, Russia 
Principal Investigator 
Pavel Olegovich Bogomolov, MD, PhD 
Clinical Site 12 
State Budgetary Educational Institution of Higher Professional Education 
“South Ural State Medical university” of the Ministry of Healthcare of the 
Russian Federation, 2 Cherkasskaya str., 454052, Chelyabinsk, Russia 
Principal Investigator 
Olga Igorevna, Sagalova, MD, PhD, DMSc 
Clinical Site 21 
Private institution - educational organization of higher education "Medical 
University "Reaviz " 
443001, Samara, ul. Chapaevskaya, 227 
Principal Investigator 
Kachkovsky Michael Arkadevich 


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1.5. 
Investigator Agreement 
I do confirm that I have read and understood this protocol, the Clinical Investigation Brochure, including the 
potential risks and side effects of the drug, and other information about the medication and study provided by the 
Sponsor. 
I do agree to perform this study in accordance with the requirements of this protocol, and also to protect patient’s 
rights, safety, confidentiality and well-being in accordance with ethical requirements set out in the Declaration of 
Helsinki of the WMA, requirements of Federal Law No. 61-FZ dd. April 12, 2010 “On Medicine Circulation”; 
principles of the National Standard of the Russian Federation GOST 52379-2005 “Good Clinical Practice” 
(hereinafter GCP) and other regulatory requirements of the Russian Federation. 
I do agree to make changes in the protocol only after notifying the Sponsor, unless it is necessary to protect 
safety, rights and well-being of patients. I fully understand that any changes made by an Investigator(s) without 
prior discussion with the Sponsor’s representative will constitute a violation of the protocol, including any 
bridging studies or procedures performed by patients (other than those necessary for patients’ well-being). 
I do agree to perform or monitor the described study personally. 
I do agree to inform patients that the drugs are used for research purposes; I will ensure the compliance with the 
requirements associated with the receipt of an informed consent, following the approval of the Council on Ethics 
and the local Independent Ethics Committee (IEC) and in accordance with the principles of the GCP. 
In accordance with the principles of the GCP, I do agree to inform the Sponsor of the adverse events that have 
developed during the study. 
I do agree to ensure that all employees, colleagues and parties involved in the study are informed of their 
obligations to comply with the arrangements described above. 
I do agree to keep faithful and accurate records, as well as to provide these records for analysis in accordance 
with the principles of the GCP. 
I will ensure that the local IEC, which operates in accordance with the requirements of the GCP, is responsible 
for conducting an ethical review, as well as for approving the clinical study. I do also agree to promptly inform 
the local IEC about all changes in research activities and all unexpected problems, including patient risk and 
other aspects. In addition, I will not make any changes to the study without the approval of the Council on 
Ethics/local IEC, except for necessary cases of eliminating the apparent unexpected threat to patients’ health and 
safety. 
I am ready to provide the direct access to primary documents and agree for the audit held by auditors from the 
Sponsor’s representatives and the regulatory agencies. I do guarantee that the investigational product(s) supplied 
by the Sponsor will only be used in the manner as described in this protocol. 
I do agree to comply with all other requirements regarding the liabilities of clinical investigators, as well as all 
other important requirements of the Good Clinical Practice. 
 
Investigator:  
 
Signature: ________________________________________________________ 
 
Full name: _____________________________________________________________________ 
 
Position: _____________________________________________________________________ 
 
Institution: _____________________________________________________________________ 
 
Address: _____________________________________________________________________ 
 
Date: ___________________________________________ (dd.mm.yyyy) 


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1.6. 
Contact Information about the Central Clinical Laboratory and Other Study Services 
 
1) Central laboratory №1 (Immunogenicity) 
Prolytiс GmbH 
Alt Fechenheim 34 
D-60386 Frankfurt am Main, Germany 
 
Contacts:  
Dr. Elizabeth Wilson, Email:  Elizabeth.Wilson@prolytic.de 
DM, Prof. Dorothee Krone, Email:  Dorothee.Krone@prolytic.de 
Tel:+49 (0) 69 4109 2534, Fax: +49 (0) 69 4269 4784 
 
2) Central laboratory №2 (Virology)  
Medizinische Hochschule Hannover 
Department of Gastroenterology, Hepatology and Endocrinology (Klinik für Gastroenterologie, 
Hepatologie und Endokrinologi) 
 
Carl-Neuberg_Straße 1 
D-30625 Hannover, Germany 
 
Contacts: 
Dr. Patric Lehmann, Email: Lehmann.Patrick@mh-hannover.de 
Dr. Birgit Bremer, Email: Bremer.Birgit@mh-hannover.de  
Tel:+49 (0) 51 1532 3304 
 
3) Central laboratory №3 (HDV and HBV genotyping, resistance, NTCP polymorphism, bile acids) 
Universitätsklinikum Heidelberg 
Department of Infectious Diseases, Molecular Virology University  (Zentrum für Infektiologie, 
Abteilung für Molekulare Virologie) 
 
Im Neuenheimer Feld 672 
D-69120 Heidelberg, Germany 
  
Contacts: 
Dr. Katrin Schöneweis, Email: Katrin.Schoeneweis@med.uni-heidelberg.de 
MD, Prof. Stephan Urban, Email: Stephan.Urban@med.uni-heidelberg.de  
 
4) Central laboratory №4 (PK) 
Universitätsklinikum Heidelberg 
Department of Infectious Diseases, Molecular Virology University (Zentrum für Innere Medizine, 
Abteilung Klinische Pharmakologie und Pharmakoepidemiologie, Analytisch-Chemisches Labor) 
 
Im Neuenheimer Feld 410 
D-69120 Heidelberg, Germany 


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Contacts: 
MSc, PhD., Juergen Burhenne, Email: Juergen.Burhenne@med.uni-heidelberg.de  
 
5) Central laboratory  №5 (biopsy study: immunohistochemical study, intrahepatic options) 
 
Universitätsklinikum Hamburg-Eppendorf 
Zentrum Innere Medizin (Zentrum Innere Medizin, I. Medizinische Klinik, AG Virushepatitis) 
 
Büro: Raum 332, 3.OG, Haus O58 
Martinistraße 52 
20246 Hamburg, Germany 
 
Contacts: 
DM, Prof. Maura Dandri, Email: m.dandri@uke.de 
Dr. Marc Lütgehetmann, Email: m.luetgehetmann@uke.uni-hamburg.de 
 
6) Central laboratory №6 (reception and analysis of the samples on the content of bile acids in the 
blood plasma, of CBC, coagulogram, biochemical blood analysis, urine analysis, determination of 
alpha fetoprotein levels and markers of fibrosis (macroglobulin)) 
 
Independent Laboratory INVITRO  
 
1, bld 33 Nagatinskaya street; 117105;  
Moscow; Russia  www.invitro.ru 
 
Russia, 117105, Moscow,  
Nahagatinskaya St., 1, building 33 
 
Contacts: 
Project Manager Ekaterina Pogodina, Email: epogodina@invitro.ru 
Tel.     + 7 495 258 07 88, доб.5192 / + 7 905 705 11 89  
 
7) Central laboratory № 7 (содержания отдельных желчных кислот в крови) 
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology 
 
Auerbachstr. 112 
70376 Stuttgart, Germany  
 
Contacts: 
Dr. rer. nat. Mathias Haag,  Email: mathias.haag@ikp-stuttgart.de 
Dr. Matthias Schwab, Email: Matthias.Schwab@ikp-stuttgart.de 
Phone +49 (0)711 / 8101-5429        
 
 


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2. 
JUSTIFICATION OF STUDY 
Hepatitis D with delta agent is an inflammatory hepatic disease caused by the hepatitis D virus, which requires 
HBsAg for its replication. Hepatitis D virus (HDV) is a hepatotropic virus with a small RNA genome also 
containing delta antigen. The HDV is at all times associated with HBV infection, since HDV ribonucleoprotein 
is bundled in HBsAg. The HDV genome is a double-stranded RNA with 1680 bases, it is historically 
homogeneous with viroids or with RNA of satellite viruses affecting plants [1]. The HDag consists of 2 isoforms 
– a small 24 kD protein necessary for replication, and a larger 27 kD protein necessary for the virion formation 
[2]. There are eight genotypes of HDV, while virus of genotype 1 is the most common in the world and in 
Europe [3].  
Hepatitis D virus is a highly pathogenic virus that causes acute and chronic hepatic injury. Despite the fact that 
incidents of benign disease have been described [4], patients with hepatitis D usually develop advanced liver 
disease, leading to compensated or decompensated cirrhosis. There is an evidence in the literature that unlike 
HBV, the HDV can lead to direct cytotoxicity, which can lead to the acceleration of fibrosis [5, 6]. However, the 
immune system plays an important role in the eradication of infected hepatocytes; the HDV viremia level has no 
direct connection to histological changes [7]. There are no histological signs that distinguish hepatitis B with 
delta agent from other forms of viral hepatitis. A biopsy sample taken from a patient with chronic hepatitis D 
shows signs of portal and periportal inflammation, fragmentary necrosis, often accompanied by fibrosis and 
cirrhosis. There is a pronounced intraglobular infiltration by mononuclear cells and degenerative changes in 
hepatocytes [8]. Clinically, hepatitis B with delta agentmay become acute or fulminant, the chronic infection can 
lead to symptomatic carriage and worsen rapidly to the chronic liver disease. 
Chronic hepatitis B with delta agent develops in 70-90% of patients with HDV superinfection. A liver disease 
associated with HDV has a more progressive course, compared to the chronic hepatitis B, and can lead to 
cirrhosis in 10-15% of patients in 2 years [9]. Hepatitis B with delta agent is the most severe form of the viral 
hepatitis in human [10], accompanied by the progression of liver disease, development of cirrhosis and 
decompensation [11, 12] 
A study conducted with a patient cohort observed for a long time in a specialized center showed a clear trend 
towards a decreased survivability of HBeAg-negative patients with HDV, compared to patients with HBV 
monoinfection [13]. In endemic populations with HDV infection, liver disease is a serious medical problem. In 
the study performed in Italy in 1987, anti-HDV antibodies were detected in 40% of patients with hepatic 
cirrhosis. Despite the fact that in 2000 their percent was reduced to 11% [14], HDV infection continues to be a 
huge burden for health care service A long-term study showed that 20% of patients suffering from hepatitis B 
with delta agent over an average of 4 years developed adverse events associated with hepatic injury. During the 
same period, only 8.5% of patients with HBV monoinfection developed such events [15]. Initially, cirrhosis was 
diagnosed in 19.8% of patients from this cohort compared to 7.3% of patients with CHB. HDV was the cause of 
death of 60% of patients in the 28-year study conducted in Italy [16]. The HDV co-infection is associated with a 
faster progression to fibrosis and cirrhosis, an earlier onset of hepatic complications and an increase in the 
likelihood of liver transplantation [17-19]. Liver cirrhosis and cancer developed in patients with co-infections 
with HBV/HDV 10-15 years earlier, and 5-year mortality of patients with co-infection twice as high as that of 
those with HBV monoinfection [20]. Chronic HDV infection causes cirrhosis and HCC with an average annual 
rate of 4% and 2.8%, respectively [16]. 
On average, 5-10% of HBsAg-positive patients who had underwent an examination at specialized centers in 
Europe had a positive HDV test result. The number of patients with CHD in the EU is estimated to be 145,000. 
Taking into account that total EU population comprises 505,665,700 people (in 2013), the estimated prevalence 
rate of HDV among residents of the EU countries, with due regard to the assumptions (95% confidence interval), 
is 1.6 and 4.7 per 10,000 people, respectively. The prevalence rate of the disease is below the threshold for 
assigning the drug an orphan product designation, which is 5 cases per 10,000 people. 
The amount of data, allowing to estimate the prevalence rate of HDV in the US, is extremely small. In a recent 
study that evaluated the highly specific center’s database, the prevalence rate of HDV among HBsAg carriers 
was fixed at 8% [21]. 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 [22]. On average, 5-10% of HBsAg-positive 
patients followed up in specialized centers have a positive HDV test result. The total number of patients with 


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CHD in the US is 63,800 (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, showing of a virology and biochemical response in approximately 
25% of cases. Antiviral drugs that are effective in the treatment of HBV are ineffective in the treatment of HDV 
[18]. Several clinical studies have been conducted recently that studied the role of pegylated interferon alfa in the 
treatment of CHD. The two largest studies on this indication, HIDIT-1 and HIDIT-2, have shown very moderate 
long-term virology results. In the clinical study HIDIT-1 involving 91 patients with HDV, the effect of pegylated 
interferon, with adefovir dipivoxil, a nucleotide analogue, and a combination of these two drugs was compared 
[23]. At week 48, the negative reaction on HDV RNA was achieved in 23% of patients receiving combination 
threatment, in 24% of patients receiving pegylated interferon and none of the patients receiving adefovir. The 
effect continued to last until week 24 of the follow-up period. However, in a further follow-up study, it was 
found that out of 16 patients who had induced negative reaction of HDV RNA at the end of the treatment period, 
9 patients had a positive result of the analysis with a median follow-up of 4.5 years (0.5 to 5.5 years) [24]. In the 
clinical study HIDIT-2, 120 patients received pegylated interferon alfa in combination with tenofovir disoproxil 
fumarate or without it for 96 weeks. The prolongation of the period of treatment with interferon for up to 96 
weeks and the addition of a tenofovir nucleotide analogue did not lead to an increase in the stable virology 
response rate: 30% of patients in the combination therapy group and 23% of patients in the monotherapy group 
had negative HDV RNA test results in 24 weeks after the end of treatment. It is remarkable that 20 patients 
(16%) have completed no treatment course until week 80. A study with 49 patients who received pegylated 
interferon alfa-2b showed 33% of the negative reaction of HDV RNA at the end of the treatment period (48 
weeks) and 25% at the end of the follow-up period [25]. 
Thus, there remains an acute unsatisfied medical need for new drugs for the treatment of chronic HDV infection, 
since 75% of patients with co-infection with HBV / HDV have approximately no therapeutic options. 
 
2.1. 
Name and Description of the Study Drug 
2.1.1. Background information 
Myrcludex B (MXB) is a lipopeptide consisting of 47 amino acids, and containing a myristoyl residue in the N-
terminal and an amidated C-terminal. All amino acids have an L-form.  
Molecular formula C248H355N65O72 (net) 
Molecular weight 5398.9 g/mol (average weight, net) 
Salt form Acetate salt 
Physical form white or grayish-white powder 
Appearance of the solution clear and transparent 
MXB is a 47-amino-acid N-myristoylated lipopeptide of the HBV-L protein. It prevents the penetration of HBV 
into hepatocytes by blocking the receptor for HBV and HDV, NTCP/SLC10A1 – a transport protein being in 
charge of the reabsorption of bile acids in the liver. MXV has shown to be efficient against hepatitis B and D 
viruses in the in vitro and in vivo preclinical studies. In a clinical study (HBV infection), a viral load reduction 
was demonstrated, moreover the optimal response was achieved in a patient cohort who received the drug at a 
dose of 10 mg once a day. In vitro studies demonstrated similar efficacy for both HDV and HBV. In the 
simulation study on animals with immunodeficiency, both the prevention of de novo HDV infection and the 
suppression of the spread of HBV were demonstrated. In a clinical study (HDV infection), a significant decrease 
in HDV RNA viremia was demonstrated with the daily dose of 2 mg, and 2 out of 7 patients showed negative 
reaction. This confirms the pronounced dependence of HDV persistence on the ingress of infection of new 
hepatocytes, and consequently, a higher sensitivity to entry inhibitors. This may be due to the pathophysiological 
properties of HDV/HBV co-infection, with a higher degree of immune response and inflammation and a possible 
direct cytopathic effect of HDV, compared to HBV. In addition, the level of HDV RNA is a unique marker of 
the determination of response in clinical studies. Negative reaction of HDV RNA is a widely used criterion for 
evaluating of the results of clinical studies on this indication. 
MXB will be provided in sterile bottles with the label claim of 2.0 mg and 5.0 mg of Myrcludex B. Before use, 
the contents of the vial shall be diluted in 1 ml of sterile water for injection. Containers and caps in use shall be 


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disposable. MXB is intended for parenteral administration. In the Phase I study, healthy volunteers received the 
drug as a single intravenous injection in a volume of up to 20 mg. In the Phase Ib/IIa studies, patients with 
chronic HBV and HDV infection received subcutaneous injections at a dose of up to 10 mg per day for up to 24 
weeks. In this case, the drug showed a good safety profile. 
MXV within the scope of Phase II of this clinical study will be administered at doses of 2, 5 and 10 mg / day / 
subcutaneously for 24 weeks together with the administration of tenofovir, with the follow-up for 24 weeks on 
treatment with tenofovir. 
MXV within the scope of Phase III of this clinical study will be administered at the optimal dosage / 
subcutaneously (the optimal dosage will be determined on the basis of the results of Phase II) for 24 weeks 
together with the administration of tenofovir, with the follow-up for 24 weeks on treatment with tenofovir. 
For more information, see the Clinical Investigation Brochure. 
 
2.2. 
Summary of Preclinical and Clinical Studies 
2.2.1. Preclinical studies 
MXB prevents the penetration of HBV into hepatocytes by blocking the main HBV receptor, recently identified 
as NTCP [26]. MXB acts at the stage after the virus is attached and, possibly, redirects the pathway of HBV 
entry into the unproductive cellular flow. 
The antiviral effect was investigated [36] in studies on the inhibition of HBV and HDV in cell cultures 
susceptible to HBV and HDV infection: the HepaRG cell line, the primary hepatocytes of Tupaia belangeri and 
PHH [27, 28]. HBeAg and HBsAg secreted in a cell culture supernatant were measured as markers of infection 
by ELISA method. The number of infected cells was counted using an immunofluorescence method with the 
determination of the number of HBcAg-positive cells (HBV) and HDV-Ag-positive cells (HDV). The IC50 was 
14.5 pm to 9.5 nm, depending on the viral load and cell culture conditions. When concentrations of MXB were 
up to 50 μm, no in vitro toxicity measured by the release of LDH was detected. 
The in vivo antiviral activity of acetylated HBV peptides similar to MXB were been studied in uPA/RAG-2 mice 
that had been transplanted with Tupaia belangeri hepatocytes and PHH. Mice were injected with HBV, as well 
as an active peptide at various concentrations, or a blank peptide. In this model, the systemic use of peptides 
provided complete prevention of HBV infection at a concentration of 200 μg/kg, the minimum concentration 
studied [29]. MXB is the product of optimization of the peptides studied in this study. Further, MXB was studied 
in uPA/SCID mice with transplanted human hepatocytes after the mice had been infected with HBV. Compared 
with the animals treated with placebo, there was a significant suppression of HBV extension in the liver, 
measured by the serum level of HBV DNA and HbsAg, as well as by the results of immunohistological analysis 
[30]. 
Possible secondary pharmacological effects were studied in a study on a single dosing of the drug to 
chimpanzee. The chimpanzee is the only pharmacologically animal model (relevant species) that fully conforms 
to human, because they have a receptor for HBV and they can develop an acute and chronic infection. With the 
intravenous injection of MXB at a dose of 300 μg/kg, no deviations from clinical or laboratory parameters 
associated with the drug were detected. 
To assess a single dose toxicity, a study was performed on CD® rats (analysis for the maximum tolerated 
concentration of a single dose). The study included an assessment of the pharmacological safety parameters 
(Irwin screen). When 12.5 mg MXV/kg body weight were injected intravenously to rats, no signs of toxicity 
were determined. No animal death cases were reported. 
The evaluation of some toxicological parameters (clinical signs, clinical chemical/haematological parameters) 
was included in the study of pharmacokinetics and secondary pharmacology for a single drug dose delivered to 
chimpanzees. 
A repeated dose toxicity was studied after daily subcutaneous injections to rats (7 days, 4 weeks, 6 months) and 
dogs (3 months). The studies included an evaluation of cytokine levels (rats, a 4-week study) and 
pharmacological safety evaluation parameters (a 3-month study on dogs). 
In all studies conducted until recently, no signs of an increase in the mortality associated with the study drug, 
general or local intolerance, impaired body weight and weight gain, food and water intake, hematological and 
biochemical blood parameters have been determined. Macroscopic analysis and histological evaluation have 


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shown no signs of changes due to the study drug. 
 
2.2.2. Clinical use of MXB 
At the moment, two clinical studies on MXB have been completed, and two more studies are being conducted 
now: 
 Study MYR 101: Phase I study involving healthy volunteers (Germany) – completed. 
 Study MYR 201: Phase Ib/IIa clinical study in the presence of HBV (Russia) – completed. 
 Study MYR 102: Phase I study on drug interaction involving healthy volunteers (Germany) - ongoing. 
 Study MYR 201 (substudy): Phase Ib/IIa study involving patients with CHD (Russia) - ongoing. 
The Phase I study (MYR 101) was conducted with the participation of 36 healthy male volunteers. The drug was 
administered in a dose of 0.3 μg, 3 μg, 10 μg, 100 μg, 800 μg, 3 mg, 5 mg, 10 mg and 20 mg intravenously, and 
in a dose of 800 μg, 5 mg and 10 mg subcutaneously. The drug in each dose was injected to a cohort of 3 
volunteers. For all cohorts and both routes of MXV administration, the drug was well tolerated and did not cause 
adverse events. After the administration, there were no significant changes in vital signs (blood pressure, heart 
rate, respiration rate and body temperature), 12-lead ECG and laboratory safety evaluation parameters. A total of 
85 AEs were registered in 29 participants. No serious adverse event was registered. Adverse events were evenly 
distributed between cohorts, none of the system organ classes prevailed. Seventy four adverse events were of 
mild severity, nine were moderate and only two AEs were severe (grade 3), according to the criteria of CTCAE 
4.0 (increased lipase levels, increased amylase levels). Anti-drug antibodies were determined within up to 6 
months after administration, all participants had a negative antibody test result.  
MXB was well tolerated by all volunteers, there was no evidence of SAEs and dose-limiting toxic reactions. AEs 
were mostly mild and did not require treatment, wherein no association with Myrcludex B or unexpected non-
target effects were detected. No dose dependence of incidence and severity of AE was detected. This 
corresponds to the results of studies in animals in which Myrcludex B showed highly specific exclusive binding 
to hepatocytes. Thus, MXV is characterized by a good safety profile even in cohorts having received the drug in 
high doses.  
Myrcludex B showed a clear dose-dependent pharmacokinetic profile. The area under the time-concentration 
curve in plasma (AUC) increased disproportionately, and the clearance and volume of distribution decreased as 
the dose increased. The drug bioavailability after subcutaneous injections comprised 88%. The release after 
subcutaneous injections is best characterized as part of a parallel slow and rapid first-order process where 59% 
of the bioavailable dose has been rapidly absorbed and the remaining 41% of the dose has been slowly absorbed 
with a half-life of 1.3 and 5.4 hours, respectively. The dose-response simulation on capacity to bind to the target 
receptor showed that at a dose of 10 mg, binding to the target was >80% within a minimum of twenty hours in a 
steady state after subcutaneous injections. 
A Phase 1 study on the drug interaction (MYR 102) with the participation of healthy volunteers is being 
conducted now with the aim to study the dose of MXB, necessary for the saturation of receptors, to effect the PK 
profile of tenofovir for the treatment of HBV infection.  
A 1b/2a phase study involving 48 patients with chronic HBV infection (MYR 201) was completed. Patients with 
negative HBeAg test results with increased ALT levels and viral load higher than 10,000 copies/mL were 
randomized to the following cohorts: 
Cohort A: 0.5 mg MXB/day s/c/12 weeks + 12 follow-up weeks 
Cohort B: 1 mg MXB/day s/c/12 weeks + 12 follow-up weeks 
Cohort C: 2 mg MXB/day s/c/12 weeks + 12 follow-up weeks 
Cohort D: 0.5 mg Entecavir/day per os/24 weeks 
Cohort E 5 mg MXB/day s/c/12 weeks + 12 follow-up weeks. 
Cohort F 10 mg MXB/day s/c/24 weeks + 12 follow-up weeks 
In this study, safety and tolerability, pharmacokinetic parameters of plasma, immunogenicity and virology 
response were studied. To evaluate the effectiveness indicators of HBsAg, HBV DNA and ALT were used. 
In the course of a 12-week treatment, a dose-related decrease in viral load was indicated. In 6 out of 8 patients 
(75%) in the cohort that received the drug at a dose of 10 mg, the serum level of HBV DNA was reduced by 
more than 1 log10, compared to the initial one. Patients in the 10 mg cohort continued treatment for 24 weeks, 


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maintaining during this time the level of HBV DNA at the levels of HBV DNA achieved by week 12. At a lower 
dose, no dose dependence on the cohort was registered, for each cohort, a maximum of 25% of patients from the 
low dose group achieved >1 log10 reduction in the level of HBV DNA at week 12. The normal level of ALT 
was registered in 50-75% of patients who received Myrcludex B at week 12, regardless of the dose. No effect on 
HBsAg was noted. 
In total, 69 adverse events were registered in the study. In general, in the group treated with Myrcludex B, AEs 
were predominantly classified as 4 SOC: general disorders and administration site conditions, investigations, 
skin and subcutaneous tissue disorders, blood and lymphatic system disorders. In the group treated with 
Entecavir, all AEs belonged to 3 SOC: general disorders and administration site conditions, infections and 
infestations, respiratory, thoracic and mediastinal disorders. 45 adverse events were considered associated with 
the treatment (TRAE). In general, AEs associated with treatment were of mild severity (total 41 AEs). Erythema, 
increased levels of gamma-glutamyltransferase, reticulocytes, dermatitis at the injection site were assigned to 
moderate adverse events. None of the treatment groups reported AEs classified as severe. 2 AEs were considered 
serious: withdrawal effect in one patient in the group treated with Myrcludex B 1 mg (Arm B) and one patient in 
the group treated with Myrcludex B 2 mg (Arm C). There were no patients who stopped participating in the 
study due to AEs/SAEs. No death cases was registered in the study. The level of bile acids is an important 
additional pharmacodynamic parameter, since the transporter of bile acids NTPC is the target of MXB. A dose-
dependent asymptomatic increase in the level of bile acids, which are substrates of NTCP (such as taurocholate 
and glycocholate), was detected, and the level of lithocholic acid (not a substrate of NTCP) remained unchanged. 
Anti-MCH antibodies were found in 58% of patients treated with the drug. No relationship between antibodies 
formation and pharmacodynamic parameters has been established. An increased level of bile acids, which are an 
additional pharmacodynamic parameter and indicate the binding of the drug to the target receptor, were 
determined regardless of the positive result of the antibody test. The virology and biochemical response in 
patients with a positive and negative antigen test results was similar. 
There is an ongoing phase IIa study involving patients with CHD. The study includes 24 patients with chronic 
hepatitis B with delta agent that is determined by the presence of anti-HDV antibodies in the serum and a 
positive HBsAg test result within more than 6 months. Patients have been randomized to 3 arms each consisting 
of 8 patients: 
Arm A: Myrcludex B 2 mg once a day for 24 weeks, followed by pegylated interferon alfa, 180 μg/week s/c, for 
48 weeks  
Arm B: Pegylated interferon alfa 180 μg/week s/c for 48 weeks, during the first 24 weeks extra Myrcludex B 2 
mg once a day s/c 
Arm C: Pegylated interferon alfa 180 μg/week s/c for 48 weeks 
At the present day, there are results of the efficacy evaluation for 24 weeks. Six of the seven and 7/7 patients for 
whom data were available, reported a decrease in HDV RNA in >1log10 at week 24 during monotherapy with 
Myrcludex B (A) or combination therapy (B), and this response was observed in 7/7 patients in Arm C. A 
negative result of HDV RNA test was registered in 2 and 5 patients from Arm A and B and 2 patients from Arm 
C. 
The ALT level decreased at week 24 in 6/7 (A), 4/7 (B) and 2/7 (C) patients. One patient in Arm A had a 
negative HDV RNA level and a normal ALT level at week 24. In Arm A, there was a tendency towards a 
decrease in ALT, in comparison with the baseline. It is curious that the median ALT level tended to decrease in 
the group receiving Myrcludex monotherapy, having decreased from 66 units/L to 40 units/L (p = 0.06). In Arms 
B and C, such a trend has not been established. 
Thus, a pronounced anti-viral effect of MXV in relation to HDV when used as monotherapy was shown, as well 
as the possible additive effect to the action of pegylated interferon against HDV. The use of MXV as 
monotherapy led to a pronounced decrease in the activity of hepatitis, measured by a decrease in ALT levels. 
MXV showed a very good safety and tolerability profile in the study, only 4 severe AEs were registered, and 
there was no increase in toxicity due to pegylated interferon. 
Thus, the existing data showed a favorable safety and efficacy profile of MBX and provides a possibility of 
further clinical use of the drug. 
 


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2.3. 
Information on the Drug for Treatment of the Co-Infection with Hepatitus B virus  
According to modern clinical recommendations: 
− 
Recommendations for diagnosis and treatment of adult patients with hepatitis B (2014);  
− 
EASL Clinical Practice Guidelines: Management of chronic hepatitis В virus infection (2012) 
both IF treatment and treatment with nucleoside/nucleotide analogue can be used for the Treatment of Patients 
with Chronic Hepatitis B with delta agent (CHD). 
According to the instructions for medical use (IMU), drugs belonging to both groups of recommended treatment 
(interferons and nucleoside analogues), have no indication for use “chronic hepatitis B with delta agent”, 
concurrently they have an indication “chronic hepatitis B”. The use of the above groups of drugs can be 
explained by the suppression of hepatitis B virus replication (HBV), i.e. Hepatitis D virus (HDV) is certainly 
associated with HBV infection, since HDV ribonucleoprotein is packaged in HBsAg. 
According to clinical studies performed, the IF treatment of patients with CHD is effective only in a small 
number of patients (approximately only 25% of cases have virology and biochemical responses). Thus, in a 
clinical study of HIDIT-2, 120 patients received pegylated interferon alfa in combination with tenofovir 
disoproxil fumarate or without it for 96 weeks. The prolongation of the period of interferon treatment to 96 
weeks and the addition of the tenofovir nucleotide analogue did not lead to an increase in the level of a stable 
virology response: in 30% of patients in the combination therapy group and in 23% of patients in the 
monotherapy group, negative results of HDV RNA analysis persisted 24 weeks after the end of treatment. In a 
study involving 49 patients who received pegylated interferon alpha 2b, a negative PCR result was shown on 
HDV RNA in 33% of cases at the end of the treatment period (48 weeks) and 25% at the end of the follow-up 
period [34]. 
It should also be noted that, according to the study performed, even when HCG patients achieve a long-term 
virology response, the probability of recurrence remains high [35]. 
Thus, the effectiveness of IF treatment in treatment of CHD is not high enough that does not allow to attribute it 
to effective methods of treatment of HGD patients. 
According to the Recommendations for diagnosis and treatment of adult patients with hepatitis B (2014), EASL 
Clinical Practice Guidelines: Management of chronic hepatitis B virus infection (2012): “The feasibility of 
prescription of interferons should be determined individually for each patient”. In accordance with the inclusion / 
exclusion criteria described in the MYR 202 Clinical Study Protocol, patients with liver cirrhosis may be 
included in the study, as well as patients in whom previous interferon therapy ha been ineffective or is currently 
contraindicated, that excludes the possibility of using interferons, but does not exclude the possibility of using 
nucleoside/nucleotide analogue as a treatment aimed at suppressing the replication of the hepatitis B virus in the 
control and study groups. The use of tenifovir also helps to clearly distinguish the effect of Myrcludex B on the 
infection with delta agent and to obtain evidence of the validity of the use of IP in the treatment of hepatitis B 
co-infection. Thus, the use of drugs in the control group to treat co-infection with hepatitis B virus is reasonable 
in ethics and science terms. 
Tenofovir (Viread®) is a highly effective HBV polymerase inhibitor approved for the treatment of chronic 
hepatitis B. Nucleoside / nucleotide analogues are widely 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 Adults with Hepatitis B Patients (2014), EASL Clinical Practice 
Guidelines: Management of chronic hepatitis In virus infection (2012), the use of these drugs is aimed at 
suppressing the replication of the hepatitis B virus, which plays an important role in the progressive liver damage 
in the presence of a delta agent. At the same time dosage strengths and dosing schedules of nucleoside / 
nucleotide analogues do not differ in patients with chronic hepatitis B with and without delta agent. 
Tenofovir will be prescribed to all patients involved in the study as a concomitant treatment of infection of 
hepatitis B virus. The drug will be used in the study in accordance with the instruction for use. 
 
2.4. 
Administration, Dosage and Duration of the Administration of the Investigational Medical 
Product 
MXB in the first (corresponding to phase II) and in the second (corresponding to phase III) parts of the planned 
study is assumed to be used as a part of this Protocol. 


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Phase II of the planned study will evaluate the benefits of 3 doses of MXB before clinical observation in patients 
with hepatitis CHD with limited therapeutic options. Patients will be randomized to one of the 4 treatment 
groups in a ratio of 1:1:1:1. Patients with compensated cirrhosis will be stratified to ensure a uniform assignment 
to each treatment group. If patients have previously received no treatment with a nucleoside/nucleotide analogue, 
a treatment with a group of nucleotide analogues – tenofovir – will be initiated on the first day of the study. 
Patients who have previously received tenofovir will continue to receive it at the same dose. Patients who have 
previously received a different nucleoside / nucleotide analogue will be transferred to tenofovir. 
Phase III of the planned study will evaluate the benefits of the optimal dosage strength of МХВ chosen 
according to the results of the analysis of the efficacy and safety parameters of the Phase II before the clinical 
observation against concomitant chronic hepatitis B treatment with tenofovir in patients with CHD with limited 
therapeutic options. Patients randomized to one of the 2 treatment groups in a ration 1:1. Patients with 
compensated cirrhosis will be stratified to ensure a uniform assignment to each treatment group. If patients have 
previously received no treatment with a nucleoside/nucleotide analogue, a treatment with a group of nucleotide 
analogues – tenofovir – will be initiated on the first day of the study. Patients who have previously received 
tenofovir will continue to receive it at the same dose. Patients who have previously received a different 
nucleoside / nucleotide analogue will be transferred to tenofovir. 
Study groups for Phases II and III has been deemed to be adequate control groups, as daily placebo injections for 
24 weeks have been found to be near-impossible and ethically unacceptable. 
In the Phase 2a study, the effect on HDV RNA, including negative HDV RNA test result, has been observed for 
24 weeks. Consequently, the duration of MXB administration in 24 weeks has been deemed sufficient for 
primary endpoint evaluation. The follow-up period with aim to study the sustainability of responses obtained 
will comprise 24 weeks. 
Phase II and III of this study will not include patients whose ALT is >10 times higher than UGN, creatinine 
clearance is <60 ml/min, total bilirubin is >34.2 μmol/L, who have decompensated liver disease or carcinoma. 
Patients with ant-HCV antibodies, but with negative HCV RNA test results at the screening stage are allowed to 
be enrolled into the study. 
Within the scope of phase II of this clinical study, MXB will be administered at doses of 2, 5 and 10 mg / day / 
subcutaneously for 24 weeks along with the administration of tenofovir, with a 24-week follow-up period on 
treatment with tenofovir. 
A dose of 2 mg is theoretically sufficient to achieve concentrations exceeding IC90 in vitro. In the ongoing 
Phase 2a study involving patients with chronic Hepatitis B with delta agent, Myrcludex B injected at a dose of 2 
mg subcutaneously once a day for 24 weeks, with after or combining treatment with pegylated interferon alpha, 
showed its efficacy and good tolerability. 
In the Phase 2 study involving patients with HBV, a 10 mg dose subcutaneous injections once a day for 24 
weeks resulted in the most pronounced effect on HBV DNA. The use of a 10 mg dose was further confirmed by 
pharmacokinetic modeling, which showed that this dose could result in a minimum of 80% saturation of NTCP 
within a minimum of 20 hours. 
An intermediate dose of 5 mg will also be studied. When using the drug at a dose of 5 mg, you can achieve the 
target level of saturation of the target within several hours. In the in vitro studies, cells that are initially 
susceptible to HBV/HDV infection also became resistant when the exposure of MXB was limited (15-30 
minutes), and maintained their status within at least 24 hours. It can be assumed that if the achievement of the 
target saturation level is important for increasing the antiviral effect, a dose of 5 mg may be sufficient. In 
addition, an increase in the level of bile acid concentration in the groups receiving the drug at a dose of 5 mg and 
10 mg in the Phase 2a study involving patients with HBV was similar, indicating that the drug in both doses had 
the same effect on the function of the transporter of bile acid NTCP. 
The dose of МХВ for Phase III of this clinical study will be determined on the basis of the Phase II results. 
Within the scope of phase III of this clinical study, MXB will be administered at the optimal dosage / 
subcutaneously for 24 weeks along with the administration of tenofovir, with a 24-week follow-up period on 
treatment with tenofovir. 
It is assumed that tenofovir, an inhibitor of HBV polymerase, used individually, will have no effect on HDV 
replication. 


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The objectives and end points for phases II and III of this study are the same. The main objective of the study is 
to study the effect of Myrcludex B on the level of HDV RNA in the setting of effective suppression of HBV 
replication and to study the synergistic effect of two drugs on reducing the HBsAg level. 
The primary endpoint of the study is the negative PCR result on HDV RNA or reduction of HDV RNA by ≥2 
log10 at week 24, compared with the study group, i.e. to show the superiority of MXV in different doses under 
observation. The negative PCR result on HDV RNA is a standard parameter used in clinical studies and routine 
practice to monitor the success of treatment in cases of HDV infection. In the analysis of primary variable for the 
interim analysis during phase II, patients who do not have data at week 24 will be considered as non-responders 
to therapy. Data on patients with a long-lasting response during the follow-up period with no treatment will be 
presented separately. No statistical analysis is planned to determine the sustainability of the response. The most 
important secondary endpoint of the study will be the normalization of ALT, showing a decrease in hepatitis 
activity, which is important for this patient population. 
The analysis of qualitative secondary end points (normalization of ALT and loss of HBsAg/seroconversion) will 
be carried out using the Fisher’s exact test. The analysis of quantitative secondary endpoints (a serum marker for 
fibrosis, HBsAg and HBV DNA) will be presented in dynamics (actual value and change from baseline). 
Comparisons between the groups on endpoints will be conducted using a two-tailed Wilcoxon signed-rank test 
with an adjustment for a significance level of 0.0167. A composite indicator for the control period with no 
treatment will also be presented for each point. As part of the analysis for the control period with no treatment, 
statistical testing is not expected to be performed. 
The sample size calculation has been performed for Phase II and is based on the following results: the study has 
sufficient strength to determine a 34% decrease of HDV RNA or negative PCR result on HDV RNA by 2log 
(304 activity in the study groups) compared to the observation group, taking into account 3% of spontaneous loss 
of HDV RNA or 2log decrease in connection with the primary treatment. To achieve a significance level of 
0.0167 with 80% strength, taking into account multiple comparisons, each group should count 30 patients, given 
that the study is suggested to study 3 doses of the drug. 
No sample size calculation has been performed for Phase III. When the last patient completes a 24-week 
treatment period as a part of Phase II clinical study, patients from all treatment arms will be analyzed for viral 
load based on PCR results on HDV RNA (the negative PCR result on HDV RNA or a decrease by ≥2 log at 
treatment week 24 compared to the results obtained before the initiation of treatment with the study drug will be 
considered as the primary endpoint). Results of the test performed will provide the basis for estimating the 
number of patients needed to confirm the hypothesis of the statistical superiority of the selected dosage strength 
of the study drug over the drug of the standard treatment. When calculating the sample size, the correction for a 
plurality of comparisons (Pocock correction) will be taken into account with due regard to two statistical 
analyzes (at treatment week 24 of phase II and treatment week 24 of phase III). If a statistically significant 
conclusion is obtained based on the results of phase II on the statistical superiority of study drug in chosen 
dosage over the control group with respect to the primary endpoint at the bilateral significance level of 5%, then 
the recruitment of patients into Phase III of the study will not be performed, and the statistical analysis will be 
performed as a part of the Interim Report on Phase II and the Final Report on the Clinical Study Results. 
To monitor safety and missed dose of the study drug, dose modification and treatment discontinuation, standard 
methods will be used that comply with the Good Clinical Practice guidelines. 
 
2.5. 
Study Compliance with Regulatory Requirements 
2.5.1. List of Applicable Standards and Regulatory Requirements 
This study will be conducted in accordance with the protocol, the ethical principles of the Declaration of 
Helsinki of the World Medical Association (WMA) (Fortaleza, 2013), the tripartite guideline on Good Clinical 
Practice (ICH GCP) and the current legislation of the Russian Federation: 
1. 
Federal Law N 61-FZ dd. April 12, 2010 “On Medicine Circulation”;  
2. 
National Standard of the Russian Federation GOSTR 52379-2005 “Good Clinical Practice”; 
3. 
Order of the Ministry of Health of the Russian Federation No. 200н dd. April 01, 2016 “On Approval of 
Rules of Good Clinical Practice in the Russian Federation”; 
4. 
Resolution of the Government of the Russian Federation N 714 dd. September 13, 2010 “On approval of 


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Standard Rules of Compulsory Insurance of Life and Health of the Patient Participating in Clinical studies of 
Medicine” and Resolution No. 393 dd. May 18, 2011 “On Amendments to the Standard Rules of Compulsory 
Insurance of Life and Health of the Patient Participating in Clinical studies of Medicine”; 
5. 
Order of the Ministry of Health of the Russian Federation No. 774n dd. August 31, 2010 “On the Ethics 
Board”; 
6. 
Recommendations for Diagnosis and Treatment of adult Patients with Hepatitis B (2014); 
The Investigator and Sponsor must sign the protocol and the study contract. The Investigator should not deviated 
from the study protocol without the consent of the Sponsor and the approval of the Ethics Committee, unless an 
immediate elimination of an urgent threat to the patient is required, or when the changes relate only to supplies 
or administrative aspects. 
 
2.5.2. Clinical Center’s Responsibilities 
The clinical center shall be responsible for:  
• 
ensuring compliance with the clinical study protocol of clinical research;  
• 
knowledge of and compliance with the GLP and regulatory requirements; 
• 
contacts with the Local Ethics Committee (LEC), providing it with all necessary documents of the study, 
obtaining written and dated approval of the LEC for conducting the study; 
• 
compliance with the conditions for obtaining, storing and consuming the study drugs; 
• 
following the randomization procedure; 
• 
providing the Sponsor with sufficient and accurate information necessary to obtain reliable results; 
• 
storage of documents of the study for a period of 15 years; 
• 
immediate notification of the Sponsor and the Ethics Committee about all serious and adverse events; 
• 
quality control of the data obtained. 
The Investigator is obliged to provide information (for example, data on the work of the center for the previous 
period), confirming the feasibility of timely recruitment of patients in accordance with the criteria as per 
protocol. If, after one month from the planned start of the study in the clinical center, no patient is engaged in the 
study, this center may be closed, about which the Principal Investigator will be notified in writing by the 
Sponsor. 
 
2.6. 
Description of the Study Population 
The selection of the arm of study is based on the requirements of the Federal Law No. 61-FZ dd. 12.04.2010 “On 
Medicine Circulation” and GOST R52379-2005 “Good Clinical Practice”. 
The study will include patients, men and women at the ages from 18 through 65, with chronic HDV infection 
with positive HDV RNA at the screening stage to confirm the efficacy of treatment with Myrcludex B in this 
category of patients. 
The primary data on the efficacy of Myrcludex B in the treatment of patients with chronic viral hepatitis B with 
delta agent was obtained in the Phase IIa clinical study. In the Phase Ib / IIa study, treatment with Myrkludex B 
resulted in reduction of HDV RNA and ALT in patients with HDV infection. Out of 24 subjects in the Phase Ib / 
IIa, 10 patients had hepatic cirrhosis or had previousle undergone the IF treatment. In this population of patients 
with the most limited therapeutic options, the possibility of a positive response to Myrcludex B treatment was 
shown. 
Thus, the present study will include patients suffering from chronic hepatitis B with delta agent in whom the 
prior IF therapy has been ineffective or, in the opinion of the investigating physician, is currently contraindicated 
(including cases of interferon intolerance in the past medical history), as well as patients with hepatic cirrhosis. 
Inclusion of such a patient population is justified both ethically and by the previous study results. 
Phase II of the planned study will be performed on 120 patients. The number of patients required to be enrolled 
in phase III will be calculated on the basis of data of the Interim report on the Clinical Study Results performed 
as a part of phase II. 
Patients will be included in the study only if they have signed the informed consent form and meet all the 
inclusion/exclusion criteria. 
 


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2.7. 
Literary Sources and Data 
References to literature sources and data relevant to the study and its justification are given in section 19 at the 
end of the protocol. 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
Primary objective 
For Phase II: to investigate the efficacy of MXB in patients with chronic hepatitis B with delta agent and 
compare the results of MXB treatment in three doses with a comparison group receiving treatment with tenofovir 
against HBV. 
For Phase III: to investigate the efficacy of MXB in patients with chronic hepatitis B with delta agent and 
compare the results of MXB treatment in the optimal dose with a comparison group receiving treatment with 
tenofovir against HBV. 
Secondary objectives 
For Phase II: to study the safety and tolerability, as well as to assess the pharmacokinetic properties (including 
the effect of MXB on the CYP3A activity) and immunogenicity of MXB in three doses when used in patients 
with chronic hepatitis B with delta agent. 
For Phase II: to study the safety and tolerability, as well as to assess the immunogenicity of MXB in the optimal 
dose when used in patients with chronic hepatitis B with delta agent. 
Primary endpoint for efficacy parameter evaluation for phases II and III: 
 
The negative PCR result on HDV RNA or a decrease by ≥2 log at treatment week 24 compared to the 
results obtained before the initiation of treatment with the study drug. 
Secondary endpoints for efficacy parameter evaluation for phases II and III: 
● 
The duration of the effect (no increase) on HDV RNA at week 24 after treatment (study week 48) 
compared to the results obtained at the end of the treatment period (study week 24). 
● 
The presence of a combined response: the negative PCR result on HDV RNA, or a decrease by ≥2 log 
and normalization of ALT at treatment week 24 compared to the results obtained before the initiation of 
treatment with the study drug. 
● 
Dynamics of ALT activity at treatment week 24 and study week 48 compared to results obtained before 
the initiation of treatment with the study drug. 
● 
Improvement of the histological findings (reduction of necroinflammation, absence of fibrosis 
progression, etc.) according to the liver biopsy study results or the absence of a fibrosis progression according to 
the findings of transient elastometry (fibroscan) at treatment week 24 compared to the results obtained before the 
initiation of treatment with the study drug. 
● 
Dynamics (no increase) of the serum marker for fibrosis – alpha-2 macroglobulin in the serum at 
treatment week 24 and study week 48 compared to the results obtained before the initiation of treatment with the 
study drug. 
● 
Dynamics of HBsAg (decrease in the quantitative content, disappearance of HBsAg, developent of anti-
HBsAg antibodies) at treatment week 24 and study week 48 compared to the results obtained before the 
initiation of treatment with the study drug. 
● 
Decrease in HBV DNA levels at treatment week 24 and study week 48 compared to the results obtained 
before the initiation of treatment with the study drug.  
Criteria for safety parameter evaluation for phases II and III: 
● 
Data on adverse events, physical examination, weight measurement, vital signs examination, 12-lead 
ECG, clinical blood test, coagulation test, blood chemistry, urinalysis, serum bile acid test. 
● 
Antibody response to Myrcludex B. 


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4. 
STUDY DESIGN 
This study will be conducted in accordance with the protocol, the ethical principles of the Declaration of 
Helsinki of the World Medical Association (WMA) (Fortaleza, 2013); National Standard of the Russian 
Federation GOSTR 52379-2005 “Good Clinical Practice”; Federal Law N 61-FZ dd. 12.04.2010 “On Medicine 
Circulation”; Order of the Ministry of Health of the Russian Federation No. 200н dd. April 01, 2016 “On 
Approval of Rules of Good Clinical Practice in the Russian Federation”; Recommendations for Diagnosis and 
Treatment of Adult Patients with Hepatitis B (2014); EASL Clinical Practice Guidelines: Management of 
chronic hepatitis In virus infection (2012); normative standards of regulatory authorities and this study protocol. 
 
4.1. 
Study Design Description 
This study is a randomized, open-labeled, multicenter phase II/III clinical study.  
Justification of a two-phase adaptive design. The following features of the study drug (Myrcludex B): 
− 
it is administrated to treat chronic hepatitis B with delta agent - the most severe form of viral hepatitis; 
− 
it has an orphan status in the European Union and the United States; 
− 
there is currently no effective standard treatment for chronic hepatitis B with delta agent; 
− 
it has the ability to simulate a dose / response reaction based on the viral kinetics 
determine the availability of the possibility of using a two-phase adaptive design for the planned clinical study, 
with its assignment to phase II / III.  
The possibility of using an adaptive design in clinical studies conducted on small patient populations, such as the 
population of patients with chronic hepatitis B with delta agent, is also described in the European Medicines 
Agency (EMA) [GUIDELINE ON CLINICAL STUDIES IN SMALL POPULATIONS. London, 27 July 2006. 
Doc. Ref. CHMP/EWP/83561/2005]. 
The methodology for the planned Phase II / III study is based on EMA guidelines [REFLECTION PAPER ON 
METHODOLOGICAL ISSUES IN CONFIRMATORY CLINICAL STUDIES PLANNED WITH AN 
ADAPTIVE DESIGN. London, 18 October 2007. Doc. Ref. CHMP/EWP/2459/02]. 
 
Phase II. Taking into account the dropout of patients at the stage of Screening, approximately 200 patients will 
undergo Screening procedures, and 120 of them will be randomized into 4 treatment arms in the ratio of 1:1:1:1: 
Arm A (30 patients): Myrcludex B 2 mg/day/subcutaneously (s/c) for 24 weeks +  
tenofovir, with the further follow-up period of 24-weeks of continued tenofovir therapy. 
Arm B (30 patients): Myrcludex B 5 mg/day/subcutaneously (s/c) for 24 weeks +  
tenofovir, with the further follow-up period of 24-weeks of continued tenofovir therapy. 
Arm C (30 patients): Myrcludex B 10 mg/day/subcutaneously (s/c) for 24 weeks +  
tenofovir, with the further follow-up period of 24-weeks of continued tenofovir therapy. 
Arm D (30 patients): tenofovir treatment for 48 weeks. 
The main part of the study includes a Screening period of 28 days (day -28/-1), a pre-treatment periodfor 
patients, who the pre-treatment period with tenofovir is indicated to, lasting up to 84 days, an baseline 
randomization visit (day 1) and a 24-week active treatment period and a 24-week follow-up period.  
 
Phase III. The number of patients required to be enrolled in phase III will be calculated on the basis of data of 
the Interim report performed as a part of phase II. Patients will be randomized to one of 2 treatment groups in the 
ratio of 1:1. 
Group I: Myrcludex B in the optimal dosage /subcutaneously (s/c) for 24 weeks + tenofovir, with the 24-week 
follow-up on treatment with tenofovir. 
Group II: treatment with tenofovir for 48 weeks. 
The main part of the study includes a Screening period of 28 days (day -28/-1), a pre-treatment period for 
patients, who the pre-treatment period with tenofovir is indicated to, lasting up to 84 days, an baseline 
randomization visit (day 1) and a 24-week study period. The follow-up period will be 24 weeks for all treatment 
Arms. 
The graphical scheme of the clinical study is presented in Figures 1a and 1b.  


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Figure 1а. Graphical scheme of the Phase II clinical study. 
 
Screening 
Visit 01 
(Day (-)28/112* - (-)1) 
Preexamination of patients, evaluation of 
compliance with inclusion / non- inclusion 
criteria 
% 
 
Visit 02* 
(Day (-)84) 
Period of pre-treatment 
periodwith tenofovir * 
(Day (-)84 - (-)l) 
Off-site visit 03* 
(Day (-)28) 
Visit 04* 
(Day (-)14 - (-)1) 
 
Randomization visit 
Visit 1 
(day l) 
Arm A 
Arm B 
Arm C 
Arm D 
MXB 2 mg + tenofovir 
MXB 5 mg + tenofovir 
MXB 10 mg + tenofovir 
tenofovir 
 
Study period 
(Treatment according to the randomization scheme) 
Visit 2 (1 week after randomization visit) 
Visit 3 (2 weeks after randomization visit) 
Visit 4 (4 weeks after randomization visit) 
Visit 5 (8 weeks after randomization visit) 
Visit 6 (12 weeks after randomization visit) 
Visit 7 (16 weeks after randomization visit) 
Visit 8 (20 weeks after randomization visit) 
Visit 9 (24 weeks after randomization visit) 
Visit FU1 (25 weeks after randomization visit) 
Visit FU2 (26 weeks after randomization visit) 
Visit FU3 (28 weeks after randomization visit) 
Visit FU4 (36 weeks after randomization visit) 
Visit FU5 (48 weeks after randomization visit) 
Follow-up period 
(All patients take only tenofovir) 
 
End of study 
 
 
* Only for patients who have undergone the pre-treatment periodwith the drug for concomitant hepatitis B infection (Pretreatment period 
- PreT) 
 
 


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Figure 2b. Graphical scheme of the Phase III clinical study. 
 
Screening Visit 01 
(day (-)28/112*-(-1)) 
Preexamination of patients, evaluation of compliance 
with inclusion / non- inclusion criteria 
 
Visit 02* 
(Day (-)84) 
The period of pre-treatment periodwith tenofovir * 
(Day (-)84 - (-)1) 
Off-site visit 03* 
(Day (-)28) 
Visit 04* 
(Day (-)14 - (-)1) 
 
Randomization visit Visit 1 
(day 1) 
Group I  
Group II 
MXB (optimal dose) + tenofovir 
tenofovir 
 
Study period 
(Treatment according to the randomization scheme) 
Visit 2 (1 week after randomization visit) 
Visit 3 (2 weeks after randomization visit) 
Visit 4 (4 weeks after randomization visit) 
Visit 5 (8 weeks after randomization visit) 
Visit 6 (12 weeks after randomization visit) 
Visit 7 (16 weeks after randomization visit) 
Visit 8 (20 weeks after randomization visit) 
Visit 9 (24 weeks after randomization visit) 
Follow-up period 
(All patients take only tenofovir) 
Visit FU1 (25 weeks after randomization visit) 
Visit FU2 (26 weeks after randomization visit) 
Visit FU3 (28 weeks after randomization visit) 
Visit FU4 (36 weeks after randomization visit) 
Visit FU5 (48 weeks after randomization visit) 
 
End of study 
 
 
* Only for patients who have undergone the pre-treatment period with the drug for concomitant hepatitis B infection (Pretreatment period 
- PreT) 
 


 
 
The study procedures and design of are the same for Phases II and III, are presented in Table 1: Study diagram. 
Table 1. Study diagram for Phases II and III. 
Procedures 
SCR 
PreT* 
RV 
Study period 
Follow up 
Early 
Termination 
Visits 
01 
02 
03 
04 
1 
2 
3 
4 
5 
6 
7 
8 
9 
FU1 
FU2 
FU3 
FU4 
FU5 
Study end 
visit 
Day (D)/ Week (W) 
D –
28/-
112* 
-1 
D -
84 
±1D 
D - 
28 
±1D 
D -
14 
- 1 
D1 
±2D 
W1/D8 
±2D 
W2/D15 
±2D 
W4/D28 
±2D 
W8 
±2D 
W12 
±2D 
W16 
±2D 
W20 
±2D 
W24 
±2D 
FUW1/ 
W25 
±3D 
FUW2/ 
W26 
±3D 
FUW4/ 
W28 
±3D 
FUW12/ 
W36 
±3D 
FUW24/ 
W48 
±3D 
D Х 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data and 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
Х 
 
Х* 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
Х 
Body height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
Х 
 
Х* 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
Х 
Vital signs 
X 
Х 
 
Х* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Х 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Urine pregnancy test 1 
X 
 
 
Х* 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Urine drug test (test strip) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine analysis 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
Х 
Serological analysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AFP blood test 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal ultrasound 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol-breath test 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
Х* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver biopsy study 
(2)/Transient elastometry (3) 
Х 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Randomization 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Handing the study product 
for 28 days over 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Handing the nucleotide 
analogue over- tenofovir 
 
Х* 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
Evaluation of compliance 
with the prescribed 
treatment 
 
 
Х* 
Х* 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Issuance and evaluation of 
patient’s diaries 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
PK analysis of Mirсludex B 
(for patients from the PK-
substudy)2 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PK analysis of MDZ 
(CYP3A activity) (for 
patients from the PK-
substudy)3 
 
 
 
X4 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PK analysis (for all study 
 
 
 
 
Х 
 
 
Х 
Х 
Х 
Х 
Х 
Х 
 
 
 
 
 
 
                                                 
 
2 For Phase II only. 
3 For Phase III only. 
4 If a patient does not need a pre-treatment period with tenofovir, but is involved in the PK-substudy, then the following tests are performed during the visit: registration of AEs; collection 
of data on the concomitant treatment; physical examination; vital sings (blood pressure, heart rate, temperature, respiratory rate); urine pregnancy test (only for women of childbearing 
potential). 


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subjects) 
HBV/HDV genotype test 
(frozen samples) 
 
Х 
 
 
X**** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NTCP polymorphism 
(frozen clot of cells) 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical blood test, 
coagulogram 
X 
Х** 
 
Х* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Х 
Blood chemistry (complete 
panel) 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
Х 
Blood chemistry 
(abbreviated panel)) 
 
Х** 
 
Х* 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
 
Serum total bile acids (in the 
central laboratory) 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Х 
Serum bile acids (frozen 
samples) 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Х 
HDV RNA (samples of 
room temperature) 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HDV RNA (frozen samples) 
 
Х* 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Х 
HBV DNA (frozen samples) 
 
Х* 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
Х 
HBsAg (frozen samples) 
 
Х* 
 
 
X 
 
 
Х 
Х 
X 
Х 
Х 
X 
 
 
Х 
X 
X 
Х 
HBeAg и anti-HBeAg 
antibodies 
X 
 
 
 
 
 
 
 
 
 
 
 
X*** 
 
 
 
 
X*** 
 
HBsAg (nonquantitative 
determination in a local 
laboratory 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity(frozen 
samples) 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
Serum marker for fibrosis 
(frozen samples) 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Resistance analysis (frozen 
samples) 
 
Х 
 
 
X**** 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Adverse events 
X 
Х* 
Х* 
Х* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Х 
Concomitant drugs***** 
X 
Х* 
Х* 
Х* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Х 
 
* Only for patients who have undergone the pre-treatment period with the drug for concomitant hepatitis B infection (Pretreatment period - PreT) 
** It shall be performed if more than 14 days have elapsed since the laboratory test was performed at the screening 
*** Only in patients with positive HBeAg during the screening 
****It shall be performed once at the visit_Pre-T 02 in patients who have been indicated a pre-treatment period with tenofovir. If the pre-treatment period with tenofovir 
is not indicated, the analysis shall be performed at the randomization visit only. 
*****Including the previous therapy of hepatitis with interferon medications regardless of treatment prescription 
(1) Only for women of childbearing potential 
 (2) According to the investigator’s decision, it can be replaced with transient elastometry.


 
 
The study includesprocedures that are the same for phases II and III: 
 
Screening period of 28 days duration (Visit 01); 
 
Period of pre-treatment periodwith tenofovir for patients who have been indicated the pre-treatment 
periodwith tenofovir for up to 12 weeks (84 days) (starting from the moment of receiving the results of screening 
procedures that allow assessing the patient’s compliance with inclusion / exclusioncriteria in this clinical study, 
includes: 
 
Visit 02 (face-to-face) - prescription of tenofovir to the patient in 84 days before the proposed 
randomization visit; 
 
Visit 03 (off-site) - phone call to the patient in 28 days before the proposed randomization visit; 
 
Visit 04 (face-to-face) up to 14 days before the proposed randomization visit; 
 
Randomization visit (Visit 1 - day 1); 
 
Treatment period of 24 weeks (Visits 2-9, performed at week 1, 2, 4, 8, 12, 16, 20 and 24 after the 
randomization visit, randomization);  
 
Follow-up period of 24 weeks (Visits FU1-FU5, performed at week 25, 26, 28, 36 and 48 after the 
randomization visit, respectively). 
The screening period (procedures are the same for phases II and III) 
During the screening period, at Visit 01 (up to 112 days before the first administration of MXB if there is a pre-
treatment periodwith tenofovir; up to 28 days before the first administration of MXB for patients whom pre-
treatment periodwith tenofovir has not been presribed) the following examinations will be performed: physical 
examination, laboratory tests, serological tests (HIV, HCV antibodies), HCV RNA in patients with anti-HCV 
antibodies, antibodies to HDV, HDV RNA, evaluation of inclusion/exclusion criteria. 
During the screening, patients will undergo a liver biopsy study, with the determination of the level of hepatic 
necroinflammation and fibrosis. An immunohistochemical analysis of HDV RNA-positive cells will be 
performed. A part of the biopsy material will be frozen to determine intrahepatic parameters. No use of 
maintenance drugs (for example, to stimulate the growth of platelets) is allowed. 
A liver biopsy study may be replaced, by the decision of the investigating physician, with transient elastometry 
(fibroscan)5. 
If a patient needs the pre-treatment periodwith a nucleotide analogue, the patient will receive tenofovir for the 
entire period of pre-treatment period (for 84 days of admission). 
Period of pre-treatment periodwith tenofovir (procedures are the same for phases II and III) 
The period of pre-treatment periodwith tenofovir is introduced in order to enroll patients who have not 
previously received nucleoside analogues but need them, as well as to achieve the greater homogeneity of a 
number of patients enrolled in this clinical study. The total duration will be 12 weeks. 
The period of pre-treatment periodwith tenofovir includes: 
 
Visit 02 (face-to-face) - prescription of tenofovir to the patient in 84 days before the proposed 
randomization visit; 
 
Visit 03 (off-site) - phone call to the patient in 28 days before the proposed randomization visit, it is 
performed to assess the compliance with prescribed treatment, to collect information about concomitant drugs, to 
register AEs; 
 
Visit 04 (face-to-face) is performed up to 14 days before the proposed randomization visit (physical 
examination, weight measurement, laboratory tests, estimation of the taken tenofovir, assessment of the 
compliance with prescribed treatment, re-evaluation of the inclusion / exclusion criteria). 
Randomization visit for Phase II 
All patients who meet the inclusion / exclusion criteria and who have been treated with nucleoside / nucleotide 
analogues for at least 12 weeks before the planned start of study treatmentof the course of treatment with the 
study drug or pre-treated with a nucleotide analogue, tenofovir, as per the protocol will be invited to a 
                                                 
 
5 The possibility of such a replacement is due to the fact that it is possible to enroll patients with advanced stages of the disease, herewith, 
the inclusion of a significant number of patients with hepatic cirrhosis or progressive liver fibrosis is expected. Therefore, a liver biopsy 
study will not be compulsory and can be replaced, by the decision of the physician, with transient elastometry. 


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randomization visit: the following examinations will be conducted: physical examination, weight measurement, 
safety laboratory tests, virology parameters, serum marker for fibrosis, immunogenicity. All evaluations 
performed during this visit should be qualified as the main parameters for safety monitoring and should not be 
qualified as the inclusion/exclusion criteria. During the randomization visit, after the completion of all 
procedures specified in the protocol, patients will be randomized to one of 4 treatment groups and will receive 
the study drug for the first 28 days of use. 
Randomization visit for Phase III 
All patients who meet the inclusion / exclusion criteria and who have been treated with nucleoside / nucleotide 
analogues for at least 12 weeks before the planned start of study treatment with the study drug or pre-treated 
with tenofovir as per the protocol will be invited to a randomization visit: the following examinations will be 
conducted: physical examination, weight measurement, safety laboratory tests, virology parameters, serum 
marker for fibrosis, immunogenicity. All evaluations performed during this visit should be qualified as the main 
parameters for safety monitoring and should not be qualified as the inclusion/exclusion criteria. During the 
randomization visit, after the completion of all procedures specified in the protocol, patients will be randomized 
to one of 2 treatment groups and will receive the study drug for the first 28 days of use. 
Treatment period (procedures are the same for phases II and III) 
The treatment with the study drug and/or tenofovir will last for 24 weeks, followed by a 24-week follow-up 
period. The treatment will be conducted in an outpatient setting. 
The follow-up period (procedures are the same for phases II and III) 
The follow-up period will last for 24 weeks. During this period, patients from all groups will receive treatment 
with tenofovir.  
 
4.2. 
Pharmacokinetic Study  
4.2.1. Pharmacokinetic Substudy (PK-substudy)  
Substudy of the pharmacokinetics of Myrcludex B 
Within the scope of Phase II, 10 patients from each Arm: A, B and C (total 30) will participate in the 
pharmacokinetic substudy. On the eve of the first day of the drug administration (Period I) and on administration 
day 13 (Period II), the drug administration, the patients will be hospitalized to the appropriate study site for 
blood sampling for PK study.  
For the first period of PK study patients will be hospitalized before start of investigational drug therapy, but after 
randomization. 
The next day in the morning, each patient will have a catheter in the elbow vein installed, through which blood 
will be sampled (including sampling of the 24-hour point, after which it will be removed). If the catheter is 
thrombosed and removed a little too soon, Blood sampling should be performed by venipuncture. 
The first blood sampling should be performed before the drug is administered 5-10 minutes after the catheter is 
installed (Point 0). 
The drug should be administered under the supervision of a physician investigator. 
On the dosage day, blood will be sampled from the median cubital vein through a pre-installed catheter. The 
catheter will be removed after collecting 14 blood samples (24 hours after dosing). 
24 hours after the drug administration, patients will be left to go home. 
Patients will return to the clinical center for Period II of the pharmacokinetic study on treatment day 13 (on the 
eve of Visit 3). The next morning, patients will have an intravenous catheter installed and have the first blood 
sample collected. Then the patient will inject the drug, after which the blood samples will be collected, according 
to the bio-sample schedule. 
24 hours after the drug administration, patients will be left to go home. 
In total, in Periods I and II for the pharmacokinetic study, 14 blood samples will be collected from each patient 
at each study period according to the following schedule: 0 h (before the investigational drug and MDZ 
administration), and at 00:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 10:00, 14:00, 24:00 (hh:min) after the 
administration of Myrcludex B. 
In each period, blood samples should be collected at the same time. 
The actual PK sampling time will be recorded. Blood samples should be collected in accordance with the 


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schedule, the following time deviations from the schedule are possible: 
Scheduled hour(s) from the moment of the drug 
administration: 
Deviation (absolute value): 
From 0 to 6 h 
 5 min 
From 10 to 24  
 15 min 
All blood samples collected beyond the abovementioned deviations will be recorded as protocol deviations and 
recorded in the monitor’s report, and actual deviations from the sampling schedule will be corrected during 
pharmacokinetic and statistical calculations. 
The procedures of sampling, storage and processing of blood samples are indicated in paragraph 4.7. 
When hospitalized, patients must follow the internal regulations of the hospital.  
Substudy of the systemic (general) metabolic CYP3A activity 
It is also planned to study the P450 (CYP3A) cytochrome activity in 30 patients from Arms A, B and C (10 
patients from each group), as a part the pharmacokinetic substudy (PK-substudy). 
Performance of this substudy is due to the fact that CYP3A is involved in the metabolism of about 50% of 
currently registered drugs and is the most common isoenzyme from the cytochrome family with localization in 
liver and intestines. 
To study the metabolic CYP3A activity in patients enrolled in the study, it is planned to use data on the 
pharmacokinetics of the benzodiazepine derivative, Midazolam (MDZ). 
In clinical practice, MDZ is used in patients with sleep disturbance, for premedication and sedation, and as an 
initial narcosis. In the planned substudy, patients will be injected with MDZ intravenously (iv) in a microdose 
(10 μg) that is unable to have any therapeutic effect due to the fact that the MDZ microdose is significantly less 
than the no observed adverse effect level (NOAEL) in humans. [Hohmann N. et al. Midazolam microdose to 
determine systemic and pre-systemic metabolic CYP3A activity in humans // Br J Clin Pharmacol 
/2014/79:2/278–285]. 
The possibility of using MDZ as an agent for studying the systemic metabolic CYP3A activity is regulated by 
the EMA guidelines [EMA. Guideline on the investigation of drug interactions. 2012, Available at 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf] and 
FDA [CDER. Guidance for industry drug interaction studies – study design, data analysis, implications for 
dosing, 
and 
labeling 
recommendations. 
2012, 
Available 
at 
// 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/ucm292362.pdf]. 
The introduction of MDZ and its PK study is planned during the following time intervals: 
 day (-13) – day (-12) [Visit 04] apart from the injection and PK-study of Myrcludex B; 
 day 1 – day 2 [Visit 1] together with the injection and PK-study of Myrcludex B; 
 day 14 – day 15 [Visit 3] together with the injection and PK-study of Myrcludex B. 
Patient hospitalization will be carried out on the eve of the day of the PK-study. Thus, patients will be 
hospitalized (including the time of the PK-study: 
 on day (-14) – day (-12) [Visit 04, for 3 days]; 
 on day (-1) – day 2 [Visit 1, for 3 days]; 
 on day 13 – day 15 [Visit 3, for 3 days]. 
On the first day of the PK-study (on day (-13), day 1, day 14, respectively) in the morning, each patient will have 
a catheter in the elbow vein installed, through which blood will be sampled (including sampling of the 24-hour 
point, after which it will be removed). If the catheter is thrombosed and removed a little too soon, Blood 
sampling should be performed by venipuncture. 
The drug should be administered under the supervision of a physician investigator. 
24 hours after the drug administration, patients will be left to go home.  
 
Principles of storage, preparation and terms of administration of MDZ 
MDZ will be administered to patients intravenously (IV) in a microdose of 10 μg before injection of Myrcludex 
B. The drug should be stored at a temperature below 30°C in a dark place. 
The MDZ solution preparation will be performed by a pharmacist in accordance with the method described in 
the laboratory manual for pharmacokinetics substudies. 


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On day (-13-12), the PK of Midazolam is studied before starting the treatment with Myrcludex B at the 
following time points: before the injection of MDZ and in 00:05; 00:15; 00:30; 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 
6:00, 10:00, 14:00, 24:00 (hh:min) after the injection of MDZ.  
To study the PK of MDZ on day 1 and day 14, Midazolam is administered prior to the administration of the 
study drug Myrcludex B, while blood sampling (except for the zero line) is performed after the administration of 
Myrcludex B. The blood sampling for MDZ analysis: before the administration of MDZ and Myrcludex B and in 
00:05; 00:15; 00:30; 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 10:00, 14:00, 24:00 (hh:min) after the 
administration of Myrcludex B.  
In total, for the pharmacokinetic study of MDZ, 14 blood samples will be collected from each patient at each 
study period. 
In each period, blood samples should be collected at the same time. 
The actual PK sampling time will be recorded. Blood samples should be collected in accordance with the 
schedule, the following time deviations from the schedule are possible: 
Scheduled hour(s) from the moment of the 
administration MDZ: 
Deviation (absolute value): 
From 0 to 1 h 
From 1.5 to 3 h 
 1 min 
 2 min 
from 4 to 24 h 
 5 min 
All blood samples collected beyond the abovementioned deviations will be recorded as protocol deviations and 
recorded in the monitor’s report, and actual deviations from the sampling schedule will be corrected during 
pharmacokinetic and statistical calculations. 
The procedures of sampling, storage and processing of blood samples are indicated in paragraph 4.7. 
When hospitalized, patients must follow the internal regulations of the hospital. 
 
4.2.2. Pharmacokinetic main study (PK-main study) 
For a more accurate study of the possible cumulation of the study drug in all patients treated with Myrcludex B, 
blood sampling points for the pharmacokinetic study are assigned: Week 4, 8, 12, 16, 20, 24 (1 hour +/- 15 
minutes after the drug administration). Patients not enrolled in the pharmacokinetic substudy are assigned with a 
blood sampling point at the randomization visit (1 hour +/- 15 minutes after the drug administration). 
 
4.3. 
Randomization 
To minimize an error, randomization will be done in a stratified manner. Patients should be stratified according 
to the presence or absence of hepatic cirrhosis. The aim of stratification is to collect a comparable number of 
patients with cirrhosis in each treatment group. Neither patients nor researchers will go through the blinding 
procedure relating to the prescribed treatment in this open-labeled study. 
Within the scope of Phase II, patients are randomized to Arms A, B, C and D in the ratio of 1: 1:1:1; within the 
scope of Phase III, patients are randomized to Groups I and II in the ratio of 1:1 using an electronic 
randomization protocol. 
Detailed information will be provided in the randomization plan. 
 
4.4. 
Study Stages and Procedures 
Any deviations from protocol procedures should be recorded in the monitor’s report, with notification of the 
sponsor and CRO. The study procedures and visits are described below. Unscheduled visits can be conducted at 
the discretion of the investigator, the data on their conduct should be reported in CRFs. 
The following possible deviations are acceptable in the schedule of patient visits: 
For pretreatment visits ± 1 day; 
For the randomization visit ± 1 day, 
For the treatment period ± 2 days, 
For follow-up period ± 3 days. 
 


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4.4.1. Screening Procedures 
The Screening procedures are the same for Phases II and III. Compliance of the patient with inclusion criteria 
and non-compliance with exclusion criteria will be confirmed during the screening period (maximum 112 days 
before the first day of drug administration in patient subgroups with indications for the treatment therapy with a 
nucleotide analogue; maximum 28 days before the first day of drug administration in patient subgroups without 
appropriate indications). 
During the screening visit (Visit 01) in an outpatient setting, the following procedures will be performed: 
 Providing patients with information on participants and obtaining written informed consent for participation 
in the study with a signature of the participant and the date of signing; 
 Medical history and demographic data; 
 Collection information on medications taken, as well as on previous therapy of hepatitis with interferon, 
regardless of the prescription of treatment; 
 Registration of SAEs; 
 Physical examination; 
 Weight measurement; 
 Body height; 
 Vital signs (blood pressure, heart rate, temperature, respiratory rate); 
 12-lead ECG; 
 Clinical blood test, blood clotting test; 
 Blood chemistry (complete panel); 
 Serological analysis; 
 Urine analysis; 
 Abdominal ultrasound; 
 Liver biopsy study /transient elastometry (fibroscan); 
 AFP blood test; 
 HDV RNA (samples at room temperature, central laboratory); 
 HBeAg and anti-HBeAg antibodies; 
 HBsAg (qualitative determination in a local laboratory); 
 Alcohol-breath test; 
 Urine drug screen (test strip); 
 Urine pregnancy test (only for women of childbearing potential); 
 Evaluation of inclusion/exclusion criteria; 
Patients who meet all inclusion criteria and do not meet any of exclusion criteria must come to the hospital 
within 4 weeks after screening for a randomization visit at the study. 
Only patients with a positive HDV RNA test result can be included in the study. The patient will be considered 
to meet the inclusion criterion of “positive HDV RNA test result” only if the result of the HDV RNA test in the 
central laboratory is positive. 
During the screening period, adverse events should be observed in patients. However, all unfavorable medical 
events (other than serious adverse events) that occurred during the screening period will be recorded as 
indicators to be included in the medical history of patients. 
If there are indications for a pre-treatment period with a nucleotide analogue (the patient have not used any 
nucleoside/nucleotide analogues or have used any nucleoside/nucleotide analogues for less than 12 weeks before 
enrollment), the patient is scheduled to Visit 02 of preliminary tenofovir treatment period. 
 
4.4.2. Procedures and evaluations during the period of pre-treatment period with tenofovir 
Procedures and evaluations during the period of pre-treatment period with tenofovir are same for Phases II and 
III. 
If the patient has confirmed his/her consent to participate in the study and is in full compliance with the inclusion 
criteria, but previously the patient have not taken nucleoside/nucleoside analogues or have used 
nucleoside/nucleoside analogues preparations for less than 12 weeks before enrollemnt, a period of preliminary 


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treament with tenofovir for up to 84 days should be scheduled before the randomization visit. 
Confirmation of compliance of patient subgroup with indications for the pre-treatment period with tenofovir, 
with the participation in the study will be based on results obtained during Visit 04 (maximum 14 days before 
the first day of drug administration). 
Period of pre-treatment periodwith tenofovir includes: 
Visit 02 (face-to-face) – shall be performed in an outpatient setting. The following procedures during the Visit: 
 Data on the drugs being taken; 
 Collection information on medications taken  
 Registration of SAEs; 
 Physical examination; 
 Weight measurement; 
 Vital signs (blood pressure, heart rate, temperature, respiratory rate); 
 Clinical blood test, blood clotting test (if the blood has been sampled at screening for more than 14 days); 
 Blood chemistry (if the blood has been sampled at screening for more than 14 days); 
 HBV/HDV genotype test (frozen samples) shall be performed in patients whom the pre-treatment period with 
tenofovir has been indicated; 
 Resistance analysis (frozen samples) shall be performed in patients whom the pre-treatment periodwith 
tenofovir has been indicated 
 HDV RNA (frozen samples); 
 HBV DNA and HBsAg (frozen samples); 
 Issuance of tenofovir. 
Visit 03 (off-site) – shall be performed by phone call to the patient in 28 days before before the proposed 
randomization visit. The following procedures will be performed during the Visit: 
 Data on the drugs being taken; 
 Collection information on medications taken  
 Registration of SAEs; 
 Evaluation of adherence to prescribed treatment according in patient words. 
Visit 04 (face-to-face) shall be performed in an outpatient setting in 14 days before the proposed randomization 
visit. The following procedures shall bе performed during Visit 04: 
 Registration of SAEs; 
 Collection of data on the concomitant treatment; 
 Physical examination; 
 Weight measurement; 
 Vital signs (blood pressure, heart rate, temperature, respiratory rate); 
 Clinical blood test, blood clotting test; 
 Blood chemistry (abbreviated panel); 
 Urine pregnancy test (only for women of childbearing potential); 
 Calculation of the drug taken (tenofovir); 
 Evaluation of the compliance with the prescribed treatment; 
 Evaluation of inclusion/exclusion criteria. 
 For patients participating in the PK-substudy within the scope of Phase II: hospitalization on the eve of blood 
sampling (day (-14)). Blood sampling should be performed immediately before the administration of MDZ and 
in 00:05; 00:15; 00:30; 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 10:00, 14:00, 24:00 the next day (hh:min) after 
the administration of MZD (days (- 13) and (-12)). 
If a patient does not need preliminary treament with tenofovir, but is enrolled in the PK-substudy, the following 
should be performed during the visit: 
 Registration of SAEs; 
 Collection of data on the concomitant treatment; 
 Physical examination; 


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 Weight measurement; 
 Vital signs (blood pressure, heart rate, temperature, respiratory rate); 
 Urine pregnancy test (only for women of childbearing potential). 
 
The patient should return all used bottles with tenofovir to the clinical center and also bring all the unused bottles 
for recording the drug intake (after that unused bottles will be returned to the patient for continuation of therapy). 
The researcher should enter data on compliance with ttreatment to the CRF.  
The investigator will re-evaluate the patient's compliance with the inclusion/exclusion criteria and, if the patient 
meets all inclusion criteria and does not meet any of the exclusion criteria, he appoints the date of Visit 1 for the 
randomization procedure to be performed. 
During the pre-treatment period with a nucleotide analogue adverse events in patients should be monitored (they 
will be recorded as indicators to be included in a participant's medical history, except for serious adverse events). 
 
4.4.3. Randomization Visit 
All patients who meet the inclusion/exclusion criteria will be invited to the Randomization Visit (Visit 1, day 1). 
During the randomization visit after the completion of the planned procedures, patients will be randomized: at 
Phase II – to one of four treatment groups, at Phase III – to one of 2 treatment groups. 
Treatment and visits will be conducted in an outpatient setting, in the same manner for Phases II and III. As a 
part of Phase II, only patients participating in the pharmacokinetic sibstudy will be hospitalized on the eve of the 
visit during which the PK-study will be performed, and will leave the center the next morning 24 hours after the 
drug administration. Remaining visits during the study will be performed on an outpatient basis. 
Subcutaneous injections of the study drug and oral administration of tenofovir will be performed every 24 ± 1 
hour after the first drug dose administration. In this case patient can adjust the introduction of the second and 
subsequent doses of the study drug under a convenient schedule which should be reflected in the patient's diary. 
Administration of subsequent doses of the drug should be carried out every 24 ± 1 hours from the time set by the 
schedule. 
The following procedures and initial evaluations will be conducted as a part of the randomization visit: 
 Registration of AEs; 
 Certification of inclusion/exclusion criteria based on the screening test results; 
 Randomization; 
 Issuance of patient diaries; 
 Handing the study drug for 28 days over; 
 Handing tenofovir for 28 days over; 
 Collection of data on the concomitant treatment; 
 Physical examination; 
 Weight measurement; 
 Vital signs examination; 
 Clinical blood test and blood clotting test; 
 Blood chemistry (complete panel); 
 Serum total bile acids test (central laboratory); 
 Serum bile acids test (frozen samples); 
 Urine analysis; 
  HDV RNA (frozen samples); 
 HBV DNA and HBsAg (frozen samples); 
 HBV/HDV genotype test (frozen samples) shall be performed in patients whom NO pre-treatment periodwith 
tenofovir has been indicated; 
 Resistance analysis (frozen samples) shall be performed in patients whom NO pre-treatment periodwith 
tenofovir has been indicated; 
 Urine pregnancy test (only for women of childbearing potential); 
 Alcohol-breath test; 


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 Immunogenicity (frozen samples); 
 Serum marker for fibrosis (frozen samples); 
 NTCP polymorphism (frozen clot of cells); 
 For patients participating in the PK substudy within the scope of Phase II (Pharmacokinetic study of 
Myrcludex B): hospitalization on the eve of blood sampling. Blood sampling should be performed immediately 
before the administration of MXB and MDZ and in 00:05; 00:15; 00:30; 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 
10:00, 14:00, 24:00 the next day (hh:min) after the administration of Myrcludex B (days 1-2). 
 For patients participating in the PK-substudy within the scope of Phase II (Study of systemic (general) 
metabolic CYP3A activity): hospitalization on the eve of blood sampling (day (-1)). Blood sampling should be 
performed immediately before the administration of MDZ and in 00:05; 00:15; 00:30; 1:00, 1:30, 2:00, 2:30, 
3:00, 4:00, 6:00, 10:00, 14:00, 24:00 the next day (hh:min) after the administration Myrcludex B (days 1-2). 
 Blood sampling for pharmacokinetic main study (PK-main study). For patients not invovled in the 
pharmacokinetic substudy, a blood sampling point should be scheduled at the randomization visit (1 hour +/- 15 
minutes after the administration of Myrcludex B). 
A patient receives the study drug, tenofovir and all other materials associated with the study, for the 1-28th day 
of the study. 
The tests conducted as a part of this visit represent the next evaluation in safety monitoring and should not be 
considered as inclusion/exclusion criteria. 
 
4.4.4. Procedures and Evaluations during the Treatment Period 
Procedures and Evaluations during the Treatment Period are same for Phases II and III. 
Patients will begin treatment during the randomized visit. Subcutaneous injections of the study drug and oral 
administration of tenofovir will be performed every 24 ± 1 hour after the first drug dose administration. In this 
case patient can adjust the introduction of the second and subsequent doses of the study drug under a convenient 
schedule which should be reflected in the patient's diary. Administration of subsequent doses of the drug should 
be carried out every 24 ± 1 hours from the time set by the schedule. 
Patient visits should occur according to the schedule presented in this section and in the study schedule.  
Randomization visit, visit at week 1, 2, 4, 8, 12, 16, 20, 24; FU (follow-up) at week 1, 2, 4, 12, 24. 
Week 1/day 8 ± 2 days/Visit 2: the following procedures will be performed in an outpatient setting: 
 Registration of AEs; 
 Vital signs examination; 
 Clinical blood test, coagulogram; 
 Blood chemistry (abbreviated panel); 
 Serum total bile acids (central laboratory); 
 Serum bile acids (frozen samples); 
 HDV RNA (frozen samples); 
 Collection of data on the concomitant treatment; 
 Evaluation of the correctness of patient diaries filling (copies of the completed pages should be stored in the 
primary documentation); 
 Evaluation of compliance with the prescribed treatment. 
Investigator must verify records in the patient diary and add data on the compliance with the treatment to the 
CRF. Patient’s diary is classified as the primary documentation. 
2 Week 2/day 15 ± 2 days/Visit 3: the following procedures will be performed: 
 Registration of AEs; 
 Vital signs examination; 
 Clinical blood test, coagulogram; 
 Blood chemistry (abbreviated panel); 
 Serum total bile acids (central laboratory); 
 Serum bile acids (frozen samples); 
 HDV RNA (frozen samples); 


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 Collection of data on the concomitant treatment; 
 Evaluation of the correctness of patient diaries filling (copies of the completed pages should be stored in the 
primary documentation); 
 Evaluation of compliance with the prescribed treatment. 
 For patients participating in the PK-substudy within the scope of Phase II: hospitalization on the eve of day 
14. Blood should be sampled immediately before the administration of MXB and MDZ and in 00:05; 00:15; 
00:30; 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 10:00, 14:00, 24:00 the next day (hh:min) after the 
administration of Myrcludex B. 
 For patients participating in the PK-substudy within the scope of Phase II: hospitalization on the eve of blood 
sampling (day 13). Blood should be sampled immediately before the administration of MDZ and 00:05; 00:15; 
00:30; 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 10:00, 14:00, 24:00 the next day (hh:min) after the 
administration of Myrcludex B (days 14-15). 
Investigator must verify records in the patient diary and add data on the compliance with the treatment to the 
CRF. Patient’s diary is classified as the primary documentation. 
Week 4/day 28 ± 2 days/Visit 4: the following procedures will be performed in an outpatient setting: 
 Registration of AEs; 
 Vital signs examination; 
 Clinical blood test, coagulogram; 
 Blood chemistry (abbreviated panel); 
 Urine analysis; 
 Urine pregnancy test (only for women of childbearing potential); 
 Serum total bile acids (central laboratory); 
 Serum bile acids (frozen samples); 
 HDV RNA (frozen samples); 
 HBsAg (frozen samples); 
 Blood sampling for the pharmacokinetic main study (after 1h ± 15min after administration of Myrcludex B); 
 Collection of data on the concomitant treatment; 
 Evaluation of the correctness of patient diaries filling (copies of the completed pages should be stored in the 
primary documentation); 
 Evaluation of compliance with the prescribed treatment; 
 Handing the study drug for 28 days over; 
 Handing tenofovir over. 
The patient should return the used and unused vials with the study drug, as well as used and unused vials with 
tenofovir to the clinical center. The investigator must verify records in the patient diary and add data on the 
compliance with the treatment to the CRF. The patient diary is classified as the primary documentation. 
Week 8 ± 2 days/Visit 5: the following procedures will be performed in an outpatient setting: 
 Registration of AEs; 
 Vital signs examination; 
 Clinical blood test, coagulogram; 
 Blood chemistry (abbreviated panel); 
 Serum total bile acids (central laboratory); 
 Serum bile acids (frozen samples); 
 Urine pregnancy test (only for women of childbearing potential); 
 HDV RNA (frozen samples); 
 HBsAg (frozen samples); 
 Blood sampling for the pharmacokinetic main study (after 1h ± 15min after administration of Myrcludex B); 
 Collection of data on the concomitant treatment; 
 Evaluation of the correctness of patient diaries filling (copies of the completed pages should be stored in the 
primary documentation); 


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 Evaluation of compliance with the prescribed treatment; 
 Handing the study drug for 28 days over; 
 Handing tenofovir over. 
The patient should return the used and unused vials with the study drug, as well as used and unused vials with 
tenofovir to the clinical center. The investigator must verify records in the patient diary and add data on the 
compliance with the treatment to the CRF. The patient diary is classified as the primary documentation. 
Week 12 ± 2 days/Visit 6: the following procedures will be performed in an outpatient setting: 
 Registration of AEs; 
 Physical examination; 
 Weight measurement; 
 Vital signs examination; 
 12-lead ECG;  
 Clinical blood test, coagulogram; 
 Blood chemistry (complete panel); 
 Urine analysis; 
 Urine pregnancy test (only for women of childbearing potential); 
 Serum total bile acids (central laboratory); 
 Serum bile acids (frozen samples); 
 HDV RNA (frozen samples); 
 HBV DNA (frozen samples); 
 HBsAg (frozen samples); 
 Blood sampling for the pharmacokinetic main study (after 1h ± 15min after administration of Myrcludex B); 
 Immunogenicity (frozen samples); 
 Collection of data on the concomitant treatment; 
 Evaluation of the correctness of patient diaries filling (copies of the completed pages should be stored in the 
primary documentation); 
 Evaluation of compliance with the prescribed treatment; 
 Handing the study drug for 28 days over; 
 Handing tenofovir over. 
The patient should return the used and unused vials with the study drug, as well as used and unused vials with 
tenofovir to the clinical center. The investigator must verify records in the patient diary and add data on the 
compliance with the treatment to the CRF. The patient diary is classified as the primary documentation. 
Week 16 ± 2 days/Visit 7: the following procedures will be performed in an outpatient setting: 
 Registration of AEs; 
 Vital signs examination; 
 Clinical blood test, coagulogram; 
 Blood chemistry (abbreviated panel); 
 Serum total bile acids (central laboratory); 
 Serum bile acids (frozen samples); 
 Urine pregnancy test (only for women of childbearing potential); 
 HDV RNA (frozen samples); 
 HBsAg (frozen samples); 
 Blood sampling for the pharmacokinetic main study (after 1h ± 15min after administration of Myrcludex B); 
 Collection of data on the concomitant treatment; 
 Evaluation of the correctness of patient diaries filling (copies of the completed pages should be stored in the 
primary documentation); 
 Evaluation of compliance with the prescribed treatment; 
 Handing the study drug for 28 days over; 
 Handing tenofovir over. 


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The patient should return the used and unused vials with the study drug, as well as used and unused vials with 
tenofovir to the clinical center. The investigator must verify records in the patient diary and add data on the 
compliance with the treatment to the CRF. The patient diary is classified as the primary documentation.  
Week 20 ± 2 days/Visit 8: the following procedures will be performed in an outpatient setting: 
 Registration of AEs; 
 Vital signs examination; 
 Clinical blood test, coagulogram; 
 Blood chemistry (abbreviated panel); 
 Urine pregnancy test (only for women of childbearing potential); 
 Serum total bile acids (central laboratory); 
 Serum bile acids (frozen samples); 
 HDV RNA (frozen samples); 
 HBsAg (frozen samples); 
 Blood sampling for the pharmacokinetic main study (after 1h ± 15min after administration of Myrcludex B); 
 Collection of data on the concomitant treatment; 
 Evaluation of the correctness of patient diaries filling (copies of the completed pages should be stored in the 
primary documentation); 
 Evaluation of compliance with the prescribed treatment; 
 Handing the study drug for 28 days over; 
 Handing tenofovir over. 
The patient should return the used and unused vials with the study drug, as well as used and unused vials with 
tenofovir to the clinical center. The investigator must verify records in the patient diary and add data on the 
compliance with the treatment to the CRF. The patient diary is classified as the primary documentation. 
Week 24 ± 2 days/Visit 9: the following procedures will be performed in an outpatient setting: 
 Registration of AEs; 
 Physical examination; 
 Weight measurement; 
 Vital signs examination; 
 12-lead ECG;  
 Clinical blood test,  
 Coagulogram; 
 Blood chemistry (complete panel); 
 Urine analysis; 
 Urine pregnancy test (only for women of childbearing potential); 
 Serum total bile acids (central laboratory); 
 Serum bile acids (frozen samples); 
 HDV RNA (frozen samples); 
 HBV DNA (frozen samples); 
 HBsAg (frozen samples); 
 Blood sampling for the pharmacokinetic main study (after 1h ± 15min after administration of Myrcludex B); 
 HBeAg and anti-HBeAg antibodies (frozen samples) – only for patients with positive HBeAg results at 
screening; 
 Liver biopsy study/transient elastometry (fibroscan); 
 Serum marker for fibrosis (frozen samples); 
 Resistance analysis (frozen samples); 
 Immunogenicity (frozen samples); 
 Collection of data on the concomitant treatment; 
 Evaluation of patient diaries; 
 Evaluation of compliance with the prescribed treatment; 


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 Handing tenofovir for 56 days over. 
The patient should return the used and unused vials with the study drug, as well as used and unused vials with 
tenofovir to the clinical center. The investigator must verify records in the patient diary and add data on the 
compliance with the treatment to the CRF. The patient diary is classified as the primary documentation. 
 
4.4.5. Evaluation after the end of the treatment 
At the end of the treatment period, a 24-week follow-up period will start, which procedures are the same for 
Phases II and III. During the follow-up period, all patients will continue to be treated with tenofovir. 
 
FU week 1 – treatment week 25 ± 3 days/ FU visit 1 (follow-up period): the following procedures will be 
performed in an outpatient setting: 
 Registration of AEs; 
 Vital signs examination; 
 Clinical blood test, coagulogram; 
 Blood chemistry (abbreviated panel); 
 Serum total bile acids (central laboratory); 
 Serum bile acids (frozen samples); 
 HDV RNA (frozen samples); 
 Collection of data on the concomitant treatment. 
 
FU week 2 – treatment week 26 ± 3 days/ FU visit 2: the following procedures will be performed in an 
outpatient setting: 
 Registration of AEs; 
 Vital signs examination; 
 Clinical blood test, coagulogram; 
 Blood chemistry (abbreviated panel); 
 Serum total bile acids (central laboratory); 
 Serum bile acids (frozen samples); 
 HDV RNA (frozen samples); 
 Collection of data on the concomitant treatment. 
 
FU week 4 – treatment week 28 ± 3 days/ FU visit 3: the following procedures will be performed in an 
outpatient setting: 
 Registration of AEs; 
 Vital signs examination; 
 Clinical blood test,  
 Coagulogram; 
 Blood chemistry (abbreviated panel); 
 HDV RNA (frozen samples);  
 HBsAg (frozen samples); 
 Collection of data on the concomitant treatment; 
 Handing tenofovir for 56 days over. 
All patients should return packaging of used tenofovir to the clinical center. 
 
FU week 12 – treatment week 36 ± 3 days/ FU visit 4: the following procedures will be performed in an 
outpatient setting: 
 Registration of AEs; 
 Vital signs examination; 
 Clinical blood test; 


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 Coagulogram; 
 Blood chemistry (abbreviated panel); 
 Urine analysis; 
 HDV RNA (frozen samples); 
 HBV DNA (frozen samples); 
 HBsAg (frozen samples); 
 Immunogenicity (frozen samples); 
 Collection of data on the concomitant treatment; 
 Handing tenofovir for 56 days over. 
All patients should return packaging of used tenofovir to the clinical center. 
 
24 FU week 24 – treatment week 48 ± 3 days/ FU visit 5 (study termination visit) the following procedures 
will be performed in an outpatient setting: 
 Registration of AEs; 
 Physical examination;  
 Weight measurement; 
 12-lead ECG;  
 Vital signs examination; 
 Clinical blood test, 
 Coagulogram; 
 Blood chemistry (complete panel); 
 Serum total bile acids (in the central laboratory); 
 Serum bile acids (frozen samples); 
 Urine analysis; 
 HDV RNA (frozen samples); 
 HBV DNA (frozen samples); 
 HBsAg (frozen samples); 
 HBeAg and anti-HBeAg antibodies - only in patients with positive HBeAg resulta at screening; 
 Immunogenicity (frozen samples); 
 Serum marker for fibrosis (frozen samples); 
 Collection of data on the concomitant treatment. 
All patients should return packaging of used and unused tenofovir to the clinical center. 
Upon completion of the visit procedures, the patient is considered to have completed his/her participation in the 
study, according to the protocol. 
 
4.5. 
Premature Drop-out from the Study, Dose Interruption, Dose Correction 
If a study subject stops injecting MXV, for example, due to the development of an adverse event (AE), every 
effort should be made to ensure that the subject continues to participate in the study and to continue to perform 
all study procedures and observation, including administration of tenofovir. If it is not possible or unacceptable 
for the study subject or investigator, the subject may discontinue participation in the study. 
Before withdrawing subjects from the groups receiving MXV at a dose of 5 mg or 10 mg from the study, the 
investigator may consider the possibility of tapering the drug dose: dose should be tapered from 10 mg and 5 mg 
to 5 mg and 2 mg per day. At the same time, monitoring of AEs should be carried out. If in the opinion of the 
investigator it is possible to continue treatment in a dose of 2 mg, the subject should continue treatment with the 
prescribed dose and undergo all the necessary study procedures and follow-up. 
If, in the opinion of the investigator, a subject is indicated an interruption of treatment with MXB or a 
nucleoside/nucleotide analogue, this should be discussed with the sponsor’s medical monitor. 
If a subject from one of the groups treated with MXB discontinues the administration of tenofovir but continues 
treatment with MXB, he/she must continue to participate in the study. If a subject in the study group 
discontinues the administration of tenofovir, efforts should be made to continue his/her participation in the study. 


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Participants dropped out of the study should undergo a visit at the end of treatment, including the following 
evaluations, within 14 days after discontinuation of the administration of the study drug: 
During the final visit, the following procedures will be carried out in an outpatient setting: 
 Registration of AEs; 
 Physical examination; 
 Weight measurement; 
 Vital signs examination; 
 Clinical blood test; 
 Coagulogram; 
 Clinical blood chemistry (full panel); 
 Serum total bile acids; 
 Serum bile acids (frozen samples); 
 HDV RNA (frozen samples); 
 HBV DNA (frozen samples); 
 HBsAg (frozen samples); 
 Urine analysis; 
 Collection of data on the concomitant treatment. 
 
4.6. 
Treatment of the Activation of an Inflammatory Process 
If the activation of the hepatic inflammatory process occurred during the treatment period (during Phase II or III) 
in the absence of signs of depression of liver function (increase in bilirubin level is ≥34.2 mg/dL, INR is ≥1.7), 
the treatment should be continued in connection with a careful monitoring of liver function. The possibility of 
holding unscheduled visits to monitor patients and evaluate laboratory parameters should be discussed with the 
sponsor’s medical monitor. 
In case of impaired liver function, the treatment with MXB should be discontinued, and treatment with the 
nucleotide analogue should be continued. At the investigator’s discretion, the patient can be transferred to 
another registered drug for HBV treatment. 
 
4.7. 
Detailed Description of the Study Procedures 
This section provides a general description of the evaluations conducted as a part of phases II and II of the study. 
A more detailed description will be provided in the laboratory guide. 
 
Patient demographics and medical history 
During the screening period, the following demographics should be recorded: 
 Date of birth, 
 Gender, 
 Race.  
Data on the history of the disease under study, other underlying diseases and previous diseases (at the 
investigator’s discretion), information about the previous treatment with interferon medications that the patient 
receives for the treatment of hepatitis, regardless of the prescription of treatment should also be recorded in the 
CRF. Information on any concomitant treatment / therapy should be collected from the time of screening. 
 
Vital signs 
The respiration rate, blood pressure, heart rate and body temperature will be measured regularly during the 
study. The schedule of the above mentioned measured tests is presented in the study design. The measurement 
data should be recorded in the CRF. 
 
Physical examination 
A complete physical examination of the subjects will be conducted as a part of the study. Its results should be 
recorded in the CRF. 


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Body height and weight 
The measurement of body height and weight should be carried out within the time limits as per the study 
schedule. The measurement results should also be recorded in the CRF. 
 
Urine pregnancy test 
Urine pregnancy test will be conducted in women of childbearing age. The test will be performed at the clinical 
center using test strips. 
 
Drug screening (urine test strips) 
Urine test strips will be used to detect traces of methadone, benzodiazepines, cocaine, amphetamines, 
cannabinoids, opiates, barbiturates, tricyclic antidepressants. 
 
Alcohol-breath test 
Alcohol-breath test will be determined using an alcohol breathalyzer. 
 
Abdominal ultrasound 
During the screening period, an ultrasound of the abdominal cavity will be performed. Particular attention should 
be paid to the evaluation of the liver structure. All disturbances are subject to be registered the CRF in the 
present disease section. 
 
Serum alpha-fetoprotein screening 
A serum alpha-fetoprotein screening will be performed for all patients during the screening stage. The screening 
should be performed in the central laboratory to exclude hepatocellular carcinoma. 
 
Liver biopsy study and transient elastometry 
During the screening stage and the visit at the end of treatment, patients will undergo a liver biopsy study, with 
the determination of the level of hepatic necroinflammation and fibrosis. An immunohistochemical analysis of 
HDV RNA-positive cells will be performed. A part of the biopsy material will be frozen to determine 
intrahepatic parameters. No use of maintenance drugs (for example, to stimulate the growth of platelets) is 
allowed. A liver biopsy study may be replaced, by the decision of the investigating physician, with transient 
elastometry (fibroscan).  
Transient elastometry and biopsy procedures can be performed directly at the clinical site or (if not possible) in 
an authorized medical organization that has the proper equipment and staff qualification. 
 
Laboratory blood tests for safety evaluation 
Laboratory blood tests for safety evaluation will be performed during the study in accordance with the study 
design in the central laboratory. If there is any laboratory abnormality and confirmation of deviations’ clinical 
significance, the investigator should fill in the adverse event registration form in the CRF. 
Clinical laboratory tests that should be performed during the study are listed below: 
 
Clinical blood test, including blood coagulation parameters 
(should be performed in the central laboratory) 
 White blood cell differential count (relative count): neutrophils, eosinophils, basophils, monocytes, 
lymphocytes; 
 White blood cell differential count (absolute count): neutrophils, eosinophils, basophils, monocytes, 
lymphocytes; 
 RBC; 
 WBC; 
 Hematocrit; 
 Hemoglobin; 


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 PLT; 
 Reticulocytes; 
 Prothrombin time; 
 Activated partial thromboplastin time. 
 
Blood chemistry 
(should be performed in the central laboratory) 
Blood chemistry – complete panel: 
 Sodium; 
 Potassium; 
 Chloride; 
 C-reactive protein; 
 Total protein; 
 Albumin; 
 Total bilirubin; 
 Direct (unconjugated) bilirubin; 
 Total cholesterol; 
 Creatinine; 
 Blood urea; 
 Glucose; 
 Gamma-glutamyltransferase; 
 Alanine aminotransferase; 
 Alkaline phosphatase; 
 Aspartate aminotransferase; 
 Lipase; 
 P-amylase; 
 Phosphate; 
Blood chemistry – abbreviated panel: 
 Albumin; 
 Total bilirubin; 
 Direct bilirubin; 
 Creatinine; 
 Gamma-glutamyltransferase; 
 Alanine aminotransferase; 
 Aspartate aminotransferase; 
 Phosphate. 
 
Serum bile acids 
Total bile acids will be tested in the central laboratory. Sampling will be performed in accordance with the 
methodology instructions on laboratory work and stored at -20°C until being sent to the central laboratory. 
Individual bile acids will be tested in the central laboratory in Germany, serum total bile acids – in the central 
laboratory in the Russian Federation. 
 
Serological analysis 
 Anti-HIV antibodies; 
 Anti-HCV antibodies; 
 Anti-HDV antibodies; 
 Non-quantitative HBsAg test to evaluate patient eligibility for participation in the study; 
 Non-quantitative HBeAg test; 


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 Anti-HBeAg antibodies. 
The above mentioned serological analysis should be performed at the local laboratory of the clinical center, 
unless otherwise agreed with the Sponsor. If anti-HCV antibodies are detected, the HCV RNA test should be 
performed. If the HCV RNA test results are negative, the patient may be enrolled in the study. 
 
Urine analysis for safety parameter evaluation 
The urine analysis will be performed in accordance with the study design. The results should be reported in the 
CRF. 
The following parameters will be evaluated: 
 pH; 
 Specific gravity; 
 Protein; 
 Glucose; 
 Bilirubin; 
 Urobilinogen; 
 Ketones; 
 RBC; 
 WBC; 
 Nitrites. 
The urine analysis will be performed at the local laboratory of the clinical center. 
Laboratory tests performed according to the requirements of the Protocol in local laboratories of clinical centers 
will be performed using standard methods adopted in the clinical center laboratories. 
Laboratory tests performed in the central laboratories will be performed using the following methods: 
 
Virology tests 
The virology parameters will be evaluated as a part of the study: HDV RNA, HBsAg and HBV DNA. Blood 
samples from veins will be collected at specified time points. 
The following parameters will be evaluated: 
● HDV RNA using the quantitative PCR; 
● HBsAg level using the quantitative ELISA; 
● HBV DNA using the quantitative PCR; 
● HBV genotype test – using the sequencing method, once as a part of the study during the 02 Pre-T visit for 
patients whom the pre-treatment period with tenofovir has been indicated, or during the randomization visit – if 
no pre-treatment period is indicated; 
● HDV genotype test – using the sequencing method, once as a part of the study during the 02 Pre-T visit for 
patients whom the pre-treatment period with tenofovir has been indicated, or during the randomization visit – if 
no pre-treatment period is indicated; 
● Test on the development of resistance – using the sequencing method, one sample at the initiation of the 
study, one – at the end of the study. The first blood sample should be collected for analysis during the 02 Pre-T 
visit for patients whom the pre-treatment period with tenofovir has been indicated, or during the randomization 
visit – if no pre-treatment period is indicated. The second one – in all patients according to the procedure 
schedule. 
Analysis will be performed in the central virology laboratory. 
The blood samples will be collected in sterile, sealed-off disposable plastic K2-EDTA Vacutainer® tubes. All 
collected samples of plasma /serum are stored in the clinical center at -20°C before sending and then sent to the 
central laboratory in a validated thermal container at -20°C or -80°C (more details about the sampling, bio-
sample storage and transportation conditions are described in the laboratory manual) 
The Blood plasma samples for analysis for the presence of HDV RNA at the screening stage are stored and 
transported to the central laboratory at room temperature. 
Determination of antibodies to HBsAg will be performed at the end of the study in a central virology laboratory 
using appropriate back-up samples (for HBsAg determination) in patients with negative result of quantitative 


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HBsAg determination at Week 24 and Week 48 of active treatment. The samples are not to be taken separately 
for this analysis. 
 
NTCP polymorphism 
NTCP polymorphism will be evaluated once during the study (baseline) in the central laboratory, using the 
sequencing method. 
 
Serum marker for fibrosis 
Serum marker for fibrosis, alpha-2-macroglobulin, will be evaluated at the beginning of the study, at the end of 
the treatment period and at the end of the follow-up period in the central laboratory, using ELISA. 
 
Immunogenicity 
The detection of anti-Myrcludex B antibodies will be performed only in patient groups treated with Myrcludex 
B, using ELISA. 
 
Pharmacokinetic parameters of plasma (as a part of Phase II) 
The blood samples will be collected in sterile, hermetically sealed disposable plastic Li-Heparin Vacutainer® 
tubes. The minimum volume of the blood sample, which is necessary for analytical purposes for the 
pharmacokinetic substudy (PK-substudy) of Myrcludex B and MDZ, comprises 4 ml, and for the 
pharmacokinetic main study (PK-main study) of Myrcludex B comprises 4 ml. 
Blood sampling for studying the pharmacokinetics of Myrcludex B and MDZ is carried out in different tubes. 
The amount of blood sampled to study the concentration of Myrcludex B (as a part of the PK-substudy) in 
plasma will be no more than 112 ml, and to study the concentration of MDZ – 168 ml. 
The pre-printed labels will be pasted onto the tubes. 
Procedures for blood sample processing and storing in the clinical center, as well as transportation of blood 
samples to study the pharmacokinetics of Myrcludex B (PK-main study and PK-substudy), as well as to study 
the systemic (general) metabolic CYP3A activity (MDZ pharmacokinetics study) will be identical. 
Immediately after sampling, tubes with blood samples should be carefully turned upside down for 4-6 times (to 
avoid the clotting reaction). 
In the laboratory, the samples will be centrifuged at 4°C for at least 10-15 minutes at a centrifugal force of 2800-
3000g. The resulting supernatant will be transferred into polypropylene plastic tubes (two tubes per sample, at 
least 1.0 ml of plasma should be placed in each tube) and frozen in a vertical position in the freezer. The samples 
should be stored in the freezer at a constant temperature control of ≤-20°C, until they are sent to the bioanalytical 
laboratory. 
If plasma and blood corpuscles are noted to have mixed during plasma separation process, the tubes should be 
re-centrifuged so that a maximum amount of intact plasma could be obtained from each sample. 
Acceptable time for handling each individual tube, i.e. time between blood sampling and placement the sample 
in the centrifuge, should not exceed 20 minutes, the time between centrifugation and placement of the sample in 
the freezer should not exceed 90 minutes. It is necessary to make every effort to minimize the time interval from 
the moment of blood sampling to the moment of freezing of plasma samples. The site staff should record any 
deviations from this requirement in the case of each sample. 
Tubes should be of room temperature and labeled appropriately. The labelling should represent the time point of 
the blood sampling, the protocol number, the study period, the serial number of the tube for the given point, the 
patient’s randomization number. 
The frozen samples will be transported in a special container with a sufficient amount of dry ice to ensure the 
preservation of freezing during transportation. The frozen samples contained in Aliquots 1 will be sent to the 
central laboratory. Aliquot 2 (reserve aliquot) will be sent to the central laboratory only if necessary.  
Determination of Myrcludex B and MZD plasma level will be performed using validated technique of HPLC-
MS/MS. Quantitative concentration determination will be carried out in the central laboratory. 
For each of the doses studied, for which sufficient information can be obtained on the basis of the plasma 
concentration assessment, an evaluation of the pharmacokinetic parameters will be performed. More detailed 


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information will be provided in the statistical analysis plan.  
The total amount of blood sampled throughout the study will be about 648 ml. If a 12-week pre-treatment period 
with tenofovir is prescribed, the volume of the blood sampled will increase by approximately 30 mL. In patients 
involved in the study if pharmacokinetics of the Myrcludex B and the systemic (total) metabolic CYP3A 
activity, the volume of the blood sampled will increase by approximately 280 ml.  
Clinical events and clinically significant laboratory abnormalities grade 3 and 4 will be classified according to 
National Cancer Institute (NCI) Common Toxicity Criteria (NCI Common Terminology Criteria for Adverse 
Events, version 4.0. In case of inability to analyze the collected sample (hemolysis, transport damage, etc.), 
additional blood volume will be required for re-analyzes. 
If there is a need to conduct re-analyzes or safety monitoring of investigational therapy, additional visits can be 
scheduled. After the unscheduled visit, the next monitoring visit is to be carried out in accordance with 
previously approved plan and protocol. 
To determine Myrcludex B effects or physiological effect of increased level of bile acids on the metabolism or 
inflammation, blood samples collected in the study can be analyzed for parameters that characterize 
carbohydrate and lipid metabolism and also play a role in the development of vascular diseases. 
 
Patient diary 
At randomization period patients will be given diaries in which they will make the following entries during the 
the study drug treatment period: 
 
Adverse events, especially reactions at the injection site, 
 
Day and time of administration of each dose of the study drug and the nucleotide analogue. 
Copies of completed diary pages will be stored in the sourse documentation. 
  
4.8. 
Study Completion, Suspension or Termination and Withdrawal of a Center or a Patient 
4.8.1. Study completion as per protocol 
Study completion as protocol provides for the patient to undergo all the protocol procedures described in Section 
4.4. of the Protocol. 
The study completion date as per protocol should be the date of the last visit or the last planned procedure 
provided for in Section 4.4. of the Protocol. The study completion date as a whole should be the date of the last 
visit of the last patient enrolled in the study. 
The sponsor reserves the right to suspend or terminate the study at any time for certain reasons, which include 
(but are not limited to) safety issues, ethical issues and serious non-compliance with the agreed requirements and 
conditions. If the study is suspended or terminated in connection with safety issues, the Sponsor will promptly 
notify the contracting research organization (CRO), investigators, as well as the IEC and regulatory authorities 
about the study suspension/termination, specifying the reasons for such a measure. 
 
4.8.2. Study Suspension or Termination 
The Investigator and Sponsor reserve the right to terminate the study at any time. If necessary, the procedures 
will be agreed upon after consultation with both parties. If the study is terminated prematurely or suspended, the 
Sponsor shall promptly notify Investigators/organizations and authorized bodies of the termination or 
suspension, as well as indicate the reasons for the termination or suspension. The Sponsor or the 
Investigator/organization (in accordance with regulatory requirements) should also immediately inform LEC 
about it, including the reasons for the study termination or suspension. At the time of study termination, the 
Sponsor and the Investigator will assure the compliance with provisions for the best protection of patient 
interests.  
The main reasons for the suspension or premature termination of the study include the occurrence of serious or 
unlabeled adverse reactions in the majority of patients during the first study days, non-compliance with the rules 
for the conduction of the study, the inability to conduct the study in accordance with the protocol. 
Possible reasons for terminate the Sponsor’s study may include an increase in the risk to the health or life of 
patients, significant violations in the conduct of the study, etc. If the study is terminated by the Sponsor, the 
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(Ministry of Health of the Russian Federation). The Sponsor is authorized to terminate the study at any time. 
The Investigator has the right to terminate the study in case of an increased risk to the health and/or life of 
patients. In this case, the Investigator should inform the CRO/Sponsor and local ethics committee. 
The Ministry of Health of the Russian Federation can temporarily or completely terminate the study if, in its 
opinion, the conditions contained in the application are not met, or the regulatory body has the data that 
challenge the safety of patients or the scientific justification of the study at its disposal. 
If for any reason the study is prematurely discontinued or suspended, the Investigator should immediately inform 
the patients enrolled in the study hereof and provide them with appropriate treatment and supervision. 
If for any reason the study is prematurely discontinued or suspended, the Investigator should immediately inform 
the patients enrolled in the study hereof and provide them with appropriate treatment and supervision. 
 
4.8.3. Premature termination of a center’s participation in the study 
The clinical center may be prematurely closed or its work may be suspended if it is revealed that the 
investigational team of the center significantly violates the requirements of the GCP, protocol and/or regulatory 
authorities, contractual obligations or cannot provide for an adequate study management. 
 
4.8.4. Premature termination of a patient’s participation in the study 
Data on the patients who have been enrolled in the study and have completed the study not in accordance with 
the protocol, i.e. have been dropped out of the study, should be recorded in the Final visit section in the CRF, 
where the reason why the patient has been dropped out of the study should mandatorily be indicated in detail. 
The reasons can include: 
 The case when the Investigator has made a decision that a patient should be dropped out in the very interests 
of the patient; 
 Incorrect inclusion; 
 Serious protocol deviation, protocol violation; 
 Serious adverse event, including death (with the indication of the date of death); 
 Any adverse event; 
 The patient receives/requires supportive treatment, which may affect the study results; 
 Positive pregnancy test results (for women); 
 Failure to appear at the visit and loss of communication of the patient; 
 Refusal or lack of discipline of the patient 
 
4.9. 
List of Data Registered Directly in the CRF 
The source data is all information contained in 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 and 
evaluate it. The source data is kept in the primary documentation (original texts or their certified copies). 
All source data, including information on AEs, will be recorded in the primary documentation (out-patient 
medical record, past medical history) at first, and then it will be transferred to the CRFs. The CRF will not 
contain data that are not displayed in the primary documents, except for cases when the data is available in the 
form of original printouts or can be directly entered into the system according to the monitoring manual. 
The study monitor will be verify the completed CRFs via the source data. All deviations and errors will be 
corrected by the Investigator and reported in the monitor’s report. 


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5. 
PATIENT SELECTION AND DROP-OUT 
This study will include patients with chronic hepatitis B with delta agent and a detectable level of HDV RNA 
replication. 
 
5.1. 
Inclusion Criteria 
The inclusion criteria are the same for phases II and III. 
To be suitable for participation in the study, participants must meet all the inclusion criteria listed below. 
1. 
Age from 18 through 65 years at the time of granting of a written informed consent for the participation in 
the study. 
2. 
Presence of HBsAg in serum within at least 6 months before the screening period. 
3. 
Anti-HDV antibodies in serum within at least 6 months. 
4. 
Positive PCR on HDV RNA in serum during screening. 
5. 
Patients with hepatic cirrhosis, regardless of prior treatment with interferons. 
6. 
Patients without hepatic cirrhosis in whom prior IF treatment was ineffective or, in the opinion of the 
investigator, is currently contraindicated (including cases of interferon intolerance in the past medical history)6. 
7. 
Alanine aminotransferase index is >1 UNL, but less than 10 UNL.  
8. 
Prior treatment with nucleotide / nucleoside analogues for at least 12 weeks prior to the planned start of 
study treatment with the study drug or patient’s consent to take tenofovir for at least 12 weeks before the planned 
start of study treatment. 
9. 
Negative urine pregnancy test in female subjects of childbearing age: 
10. Inclusion criteria for women: 
 
Menopause within at least 2 years, or 
 
Surgical sterilization (complete hysterectomy or bilateral oophorectomy, or ligation of both fallopian tubes, 
staples, or other method of sterilization), or 
 
No heterosexual contactsduring the study period, or 
 
Consent to use a highly effective contraceptive method (a double barrier method or a combination of a 
barrier method with a hormonal or intrauterine contraceptive) during the study period and within 3 months after 
the last dose of the study drug. 
11. Men must agree to use a highly effective contraceptive method (double barrier methods or a combination of 
a barrier method and a hormonal or intrauterine contraceptive used by a female partner) and not be a sperm 
donor during the study period and within three months after the last dose of the study drug. 
5.2. 
Exclusion Criteria 
The exclusion criteria are the same for phases II and III. 
Participants who meet any of the following exclusion criteria can not participate in the study. 
1. 
The Child Pugh score should be B-C or above 6 points; 
2. 
The co-infection with hepatitis C virus (HCV) or HIV. Patients with the presence of anti-HCV antibodies in 
the presence of negative HCV RNA at the stage of screening are considered acceptable to participate in the 
study; 
3. 
Creatinine clearance is <60 ml/min; 
4. 
Total bilirubin is> 34.2 μmol / L. Patients with an increased total bilirubin level may be included in the 
study after consulting with the Medical Research Monitor if it is clearly established that such an increase is an 
evidence of Gilbert’s syndrome. 
5. 
Malignant tumors in any organ system, including hepatocellular carcinoma, in the past or current history.  
6. 
Systemic connective-tissue diseases. 
                                                 
 
6 Inclusion of patients who have previously undergone IF treatment in the study is possible not earlier than 30 days after the last 
administration of interferon. 


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7. 
Chronic heart failure of functional classes III-IV according to NYHA (New York Heart Association) 
classification. 
8. 
Patients with uncontrolled arterial hypertension (BP> 150/100 mm Hg affected by the administration of 
antihypertensive drugs) during previous 3 months before the initiation of the clinical phase. 
9. 
Patients with past or unstable concomitant diseases, or clinical conditions that prevent the inclusion of this 
patient in the study. 
10. Patients with mental disorders or social circumstances that interfere with the requirements of the protocol. 
11. Decompensated liver disease in the current or previous history, including coagulopathy, hyperbilirubinemia, 
hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding esophageal varices; 
12. WBC count is <3000 cells/mm3; 
13. Neutrophil count is <1500 cells/mm3; 
14. Platelet count is <60,000 cells/mm3; 
15. A patient takes illegal psychiatric drugs at the time of screening; 
16. Treatment with Interferon within 30 days before screening; 
17. Transplantation of a solid organ in the past history; 
18. Patients who abuse alcohol now or have abused d it for 6 months before the enrollment; 
19. A history of a disease requiring regular use of systemic corticosteroids; 
20. Pregnant and lactating women; 
21. Participation in other clinical studies within 30 days before screening; 
22. Patients who have received Myrcludex B as a part of previous studies. 
 
5.3. 
Criteria for Premature Withdrawal of Patients from the Study 
5.3.1. Withdrawal criteria 
The withdrawal criteria are the same for phases II and III. 
The study subjects are entitled at any time and for any reason to discontinue participating in the study without 
explaining the reasons. Nevertheless, the Investigator must make every effort to obtain complete information on 
the reasons for the patient’s refusal and to report them in the source data and the CRF.  
The patients can be withdrawn from the study in a number of the following cases: 
1. The Investigator has made a decision that a patient should be dropped out in the very interests of the patient; 
2. 
The Investigator’s decision to withdraw the patient from the study due to a serious protocol 
deviation/protocol violation; 
3. 
Intercurrent disease or progression of the underlying disease, which in the investigator’s opinion, will 
significantly affect the evaluation of the clinical status of the patient. 
4. 
The need to use illegal drugs. 
5. 
Unacceptable toxicity, according to the definition given in the protocol section on toxic reactions, or a 
reaction that, in the investigator’s opinion, makes it impossible to continue the study procedures or does not meet 
the subject’s needs. 
6. 
The subject declares about the desire to drop out the study for any reason. 
7. 
The subject does not adhere to the appointments (unsatisfactory compliance). It is defined as missing the 
dose of the study drug for 3 consecutive days or 4 missed doses of the drug for 28 days. 
8. 
Pregnancy occurred during the study. 
9. 
Termination of participation in the study at the request of the sponsor, regulatory agency or ERB / IEC. 
10. Loss of communication with the patient. 
The protocol violations listed below may be the cause, but do not necessarily lead to the withdrawal of the 
patient from the study. The decision in this case should be made by the Sponsor, both individually and in 
coordination with the investigators: 
 Failure to inform the Sponsor in due time about the development of AEs in patients (in case there is a 
documented fact that the investigator has received information about development of AEs in the patient); 
 Development of a concomitant disease or condition that leads to difficulties in carrying out any mandatory 
study procedure, that, in the opinion of the investigator, can have a significant impact on the objectivity of the 
results in assessing the patient’s condition; 


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 The need to take other medicines other than the study drug that do not have a significant effect on the study 
results. 
 Other study protocol violations, which, in the opinion of the Investigator or Sponsor, are not significant. 
The patient can be withdrawn at any stage of the study without any further delay. 
If there is a serious illness or intolerance to the study drug, the Investigator will make a decision to withdraw the 
subject from the study. Patients who have been withdrawn from the study due to a serious intercurrent disease or 
for safety reasons will be treated in accordance with established medical practice and will be monitored prior to 
resolution or stabilization of their condition. In this case, the Investigator will notify the Sponsor in advance and 
provide for the sufficient medical justification for his decision. 
In addition, patients will be deemed to be dropped out of the study if they are lost for the follow-up, i.e., if the 
patient has discontinued participation without notifying the Investigator. 
Since the excessive number of patients withdrawn from the study may result in the impossibility of interpreting 
the data obtain, it is necessary to avoid an excessive withdrawal of patients. 
 
5.3.2. Data on the patients dropped out 
The Investigator will be responsible for recording the reason(s) of any withdrawal from the study after the 
randomization, as well as for filling all the necessary detailed information in the CRF and completing the “Final 
visit” section in the CRF, where the reason why the patient has dropped out of the study must be recorded in 
detail. If the reason the subject withdrawal is AE, it is necessary to record the main specific event or laboratory 
test in the CRF, and the Investigator should make every effort to record the outcome of the AE in a clear way. 
The Investigator transfers the following data on patients dropped out the study to the Sponsor and study monitor 
within 24 hours, including information on the reason for the premature discontinuation of the patient’s 
participation in the study: 
 investigational error; 
 adverse events; 
 serious adverse events; 
 pregnancy; 
 protocol violations; 
 a patient’s desire to withdraw from the study; 
 due to the absence of the patient and loss of communication with him; 
 other reasons (should be specified). 
 
5.3.3. Subject substitution 
Replacement of study participants in this study is not applicable. 
 
5.3.4. Follow-up of patients dropped out 
If there is any SAE, the patient should be monitored before the resolution of the SAE or it’s transition to a 
chronic condition, by phone calls with an interview for complaints and anamnesis, as well as during visits that 
are not part of the study design but are necessary from the point of view of the patient safety. 
If, in the opinion of the attending physician, AE, which is not a serious one, requires a patient follow-up, this 
observation can also be performed by phone calls and visits, with an interview for complaints and anamnesis. 
If a SAE that has a probable connection with the drug administration as assessed by the investigating physician 
has developed, the observation and necessary treatment should be made regardless of the development period of 
the SAE; monitoring of the patient should also be carried out before the resolution of the SAE. 
If the dropout has occurred due to other reasons, the follow-up will not be carried out. 


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6. 
PATIENT TREATMENT 
6.1. 
Myrcludex B 
6.1.1. Dosage form 
Myrcludex B is manufactured in the form of a lyophilized powder for injection. The drug is supplied in sterile 
vials, the contents of which are diluted before use with 1 ml of water for injection. 
Composition:  
Active ingredient: Myrcludex B acetate, 2.0 mg/vial, 5.0 mg/vial.  
Excipients: water for injection (WFI), sodium carbonate, sodium bicarbonate, mannitol, hydrochloric acid and 
sodium hydroxide are used to dissolve the drug substance before aseptic filling and lyophilization. The 
excipients of pharmaceutical grade are used. 
Physical form: white or grayish-white powder 
Appearance of the solution: clear and transparent. 
6.1.2. Container Closure System 
The study drug Myrcludex B will be administered in the form of a lyophilized powder for injection 2.0 mg/vial 
and 5.0 mg/vial. 
Primary packaging 
Container: 2 R injection vial, colorless glass, EF Hydrolytic class I 
Closure: Lyophilization rubber stopper for 2R vials, E.P. Type I (diameter 13 mm) 
Secondary packaging 
Closure: 13 mm bordered cap, aluminum with plastic disc 
Disposable containers and closures are used. Vials and lyophilization rubber stoppers are sterilized, all materials 
are tested before use. 
6.1.3. Drug Handling and Storage 
In the research center, the drug should be stored at -20±5 °C in the dark place. 
It is allowed to store the drug at + 5°C at home (in the refrigerator). 
The cold chain tolerance is acceptable (storage at room temperature within up to 3 days). 
After reconstitution of the contents of the vial with water for injection, the drug remains stable for 120 minutes at 
room temperature. 
6.2. 
Dose and Administration of Myrcludex B 
The site staff will teach patients the procedure of subcutaneous injections of the drug. Separately, patients will be 
provided with training materials. 
Phase II 
Arm A: 2 mg Myrcludex B once a day s/c 
During the treatment period, at each visit patients randomized to Arm A will be provided with sets of study drug 
for use for 28 days containing: 
 30 vials of 2.0 mg MXB 
 30 vials with sterile water for injection (minimum 2 mL) 
 30 disposable syringes 
Patients will be instructed on the procedure for a dilution of a 2 mg Myrcludex B vial with 1 ml of WFI and self-
administration of the contents of one 2 mg vial once a day. Dilution should be performed immediately before 
injection. The diluted solution remains stable for 2 hours. 
Arm B: 5 mg Myrcludex B once a day s/c 
During the treatment period, at each visit patients randomized to Arm B will be provided with sets of study drug 
for use for 28 days containing: 
 30 vials of 5.0 mg MXB 
 30 vials with sterile water for injection (minimum 2 ml) 
 30 disposable syringes 
Patients will be instructed on the procedure for a dilution of a 5 mg Myrcludex B vial with 1 ml of WFI and self-
administration of the contents of one 5 mg vial once a day. Dilution should be performed immediately before 
injection. The diluted solution remains stable for 2 hours. 


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Arm C: 10 mg Myrcludex B once a day s/c 
During the treatment period, at each visit patients randomized to Arm C will be provided with sets of study drug 
for use for 28 days containing: 
 60 vials of 5.0 mg MXB 
 30 vials with sterile water for injection (minimum 5 ml) 
 60 disposable syringes 
Patients will be instructed on the procedure for a dilution of a 5 mg Myrcludex B vial with 1 ml of WFI and self-
administration of the contents of one 5 mg vial twice a day. Injections should be performed at a 1-30-minute 
interval. 
Dilution should be performed immediately before injection. The diluted solution remains stable for 2 hours 
Dose adjustment 
No dose adjustment in Arm A is allowed. 
In case of any toxicity in Arms B and C, a dose adjustment is acceptable. For more information, refer to 
paragraph 4.5. “Premature Drop-out from the Study, Dose Interruption, Dose Correction”. 
Missing a dose 
If a dose is missed, the following algorithm should be followed: 
If the patient recalled the missed dose no later than 4 hours after the time prescribed during the randomization 
visit, the dose should be injected. The next day, the scheduled dose should be injected at the time prescribed. If it 
has passed more than 4 hours after the scheduled time, the dose should not be injected, it should be considered 
missed, and the next day the next dose should be injected at the time prescribed. 
The data on missing the dose should be registered in the patient diary and in the CFR. The patient should inform 
the investigator about the missed dose by a phone call. 
Phase III 
Group I: optimal dosage (in mg) Myrcludex B per day s / c 
During the treatment period, at each visit patients randomized to Group I will be provided with sets of study drug 
for use for 28 days containing: 
 30 vials of MXB in optimal dosage (in mg) 
 30 vials with sterile water for injection 
 30 disposable syringes 
Patients will be instructed on the procedure for a dilution of a vial with Myrcludex B with WFI and self-
administration of the contents of one vial once a day. Dilution should be performed immediately before 
injection. The diluted solution remains stable for 2 hours 
Dose adjustment 
No dose adjustment in Group I is allowed. 
Missing a dose 
If a dose is missed, the following algorithm should be followed: 
If the patient recalled the missed dose no later than 4 hours after the time prescribed during the randomization 
visit, the dose should be injected. The next day, the scheduled dose should be injected at the time prescribed. If it 
has passed more than 4 hours after the scheduled time, the dose should not be injected, it should be considered 
missed, and the next day the next dose should be injected at the time prescribed. 
The data on missing the dose should be registered in the patient diary and in the CFR. The patient should inform 
the investigator about the missed dose by phone. 
6.3. 
Previous and Concomitant Medication 
Patients treated with nucleoside/nucleotide analogs for HBV treatment should be transferred to entecavir or 
tenofovir at the beginning of the study (randomization visit). 
Tenofovir (VIREAD®) for the study will be studied by Gilead Science (Ireland) in the form of film-coated 
tablets, 245 mg of tenofovir disoproxil, that is equivalent to 300 mg of tenofovir dizoproxil fumarate, in the vial 
N30. Packaging of the drug will be marked in accordance with the requirements of Russian legislation by the 
Heidelberg University Hospital, Germany (see the example of label below). VIREAD® (245 mg of tenofovir 
dizoproxil, that is equivalent to 300 mg of tenofovir dizoproxil fumarate), film-coated tablets. 
Trademark: (VIREAD®) 


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Registration numbers:  
EU/1/01/200/001 
EU/1/01/200/002  
INN: tenofovir dizoproxil (fumarate) 
Chemical name: 9-[(R)-2-[[bis[[(isopropyl carbonyl)oxy]methyl]phosphine]methoxy]propyl] adenine fumarate 
Manufacturer: 
– dosage form and packaging: Patheon Inc., Canada; 
– final quality control and marketing authorisation holder: Gilead Sciences (Ireland) 
– product labeling and release certificate – Heidelberg University Hospital, Germany.  
The drug label, developed in accordance with Art. 13.3 of Directive 2001/20/EC, FZ-61, 2010, as well as Annex 
13 “Production of medicines for clinical studies” of the Good Manufacturing Practices (GMP), 2007, for the 
study, Heidelberg University Hospital, Germany, will be specified as a manufacturer, as the institution that 
conducts the final stage of the drug release. 
Label for tenofovir (example): 
For clinical studies only!  
 
Study No. MYR202 
  
Biread (245 mg of tenofovir dizoproxil, 
that is equivalent to 300 mg of tenofovir dizoproxil 
fumarate), 
30 film-coated tablets  
Batch No. MYR202/2015KW Expiry date: 
06.12.2019 
Randomized patient 
No.:__________________________ 
Full name of the Investigator/Center 
No.___________________________ 
Date of the drug issue «__»________20__ Visit No.: 
 
 
Administration route: oral, with food, with a small 
amount of water. Tablets cannot be chewed or broken. 
Store in the dry and dark place not above 30°C. Keep 
out of reach of children. 
Return empty packaging or unused drug. 
Sponsor: Hepatera LLC, 109240, Moscow, 
Verkhnyaya Radishchevskaya Street, 12/19, bldg. 1, 
Tel. +7 (495) 726-52-53 
Manufacturer: 69120 Heidelberg, Germany, 
Heidelberg University Hospital, Neuerheimer-Feld-
Strasse, 670 
 
Marketing authorization holder: Gilead Sciences, Ireland 
Dosage form 
Film-coated tablets, 245 mg (tenofovir disoproxil) 
Composition 
Each film-coated tablet contains: 
Active ingredient: tenofovir disoproxil, 245 mg, that is equivalent to 300 mg of tenofovir dizoproxil fumarate; 
Excipients: 
Tablet core: pregelatinized starch, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, 
magnesium stearate; 
Coat: glycerol triacetate (Е1518), indigo carmine aluminum lake (Е132), hypromellose (Е464), lactose 
monohydrate, titanium dioxide (Е171). 
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. 
Presentation 
Film-coated tablets 245 mg of tenofovir disoproxil. 30 tablets per a high density polyethylene vial with a child-
proof cap with an embedded moisture absorber (silica gel). 
Storage conditions 
Do not store above 30°C. Store in the dry, dark place. 
Keep out of the reach of children. 


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Shelf life 
5 years. 
Do not use after the expiry date printed on the package. 
 
6.4. 
Excluded medication 
 
Systemic glucocorticosteroids 
 
Illegal psychotropic drugs, drugs and psychoactive drugs. 
 
The use of immunomodulators and antiviral drugs, in addition tenofovir, should be discussed with the 
medical monitor. 
6.5. 
Methods of Monitoring Patient Compliance 
During the screening and at the time of randomization, patients undergo laboratory and instrumental 
examinations, confirming their compliance or incompliance with inclusion/exclusion criteria. Female patients 
are additionally tested for pregnancy. 
Also during the study, at each visit, a collection of data on the concomitant treatment, an assessment of treatment 
regimen adherence and an assessment of the presence of AEs are performed. These procedures additionally 
provide for the confirmation of study inclusion and exclusion criteria and assessment of patient compliance with 
the research procedures. 


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7. 
EFFICACY EVALUATION 
7.1. 
Efficacy Criteria 
Efficacy parameter evaluation criteria are the same for Phases II and III. 
Primary endpoint 
● 
The negative PCR result on HDV RNA or a decrease by ≥2 log at treatment week 24 compared to the 
results obtained before the initiation of treatment with the study drug. 
The reduction in the viral load recorded by the level of HDV RNA (decrease HDV RNA by ≥ 2log10) at 
treatment week 24 compared to the results obtained before the initiation of treatment with the study drug, is the 
primary endpoint in the planned study. 
Due to the fact that Myrcludex B does not directly affect the level of HDV viral replication, but prevents the 
penetration of HBV into hepatocytes, by blocking the HBV and HDV NTCP / SLC10A1 receptor, thereby 
stopping the spread of the virus into the liver, a decrease of HDV RNA by ≥ 2log10 may be indicative of the 
reduction of the number of infected cells by a factor of 100 (this information is needed to evaluate the duration 
of Myrcludex B treatment required for complete virus elimination in a particular patient, depending on the 
dynamics of the decrease in viral load) only. 
Due to the fact that the level of HDV RNA at the time of inclusion into the study may be low, the patients who 
have achieved the virus elimination during the study may not meet the criterion of :HDV RNA reduction by ≥ 
2log10”, herewith, the virus elimination is considered as a positive event. Thus, it becomes necessary to 
supplement the formulation of the main endpoint with information about the negative PCR result on HDV RNA. 
 
Secondary endpoints 
● 
The duration of the effect (no increase) on HDV RNA at week 24 after treatment (study week 48) 
compared to the results obtained at the end of the treatment period (study week 24). 
● 
The presence of a combined response: the negative PCR result on HDV RNA, or a decrease by ≥2 log 
and normalization of ALT at treatment week 24 compared to the results obtained before the initiation of 
treatment with the study drug. 
● 
Dynamics of ALT activity at treatment week 24 and study week 48 compared to results obtained before 
the initiation of treatment with the study drug. 
● 
Improvement of the histological findings (reduction of necroinflammation, absence of fibrosis 
progression, etc.) according to the liver biopsy study results or the absence of a fibrosis progression according to 
the findings of transient elastometry (fibroscan) at treatment week 24 compared to the results obtained before the 
initiation of treatment with the study drug. 
● 
Dynamics (no increase) of the serum marker for fibrosis – alpha-2 macroglobulin in the serum at 
treatment week 24 and study week 48 compared to the results obtained before the initiation of treatment with the 
study drug. 
● 
Dynamics of HBsAg (decrease in the quantitative content, disappearance of HBsAg, development of 
anti-HBsAg antibodies) at treatment week 24 and study week 48 compared to the results obtained before the 
initiation of treatment with the study drug. 
● 
Decrease in HBV DNA levels at treatment week 24 and study week 48 compared to the results obtained 
before the initiation of treatment with the study drug. 
7.2. 
Efficacy Parameter Evaluation Methods and Terms 
Efficacy parameter evaluation methods and terms are the same for Phases II и III. 
According to the requirements of the protocol, the results obtained at the randomization visit (Visit 1) is 
considered to be the source data for determining the therapeutic efficacy of MXB. To evaluate the endpoint on 
the basis of the liver biopsy study results, the results obtained on Visit 01 of the Screening is considered to be the 
source data for determining the therapeutic efficacy of MXB. 
The efficiency parameter evaluation will be performed according to the following schedule: 
● 
The negative PCR result on HDV RNA or a decrease by ≥2 log at treatment week 24 (Visit 9) compared 
to the results obtained before the initiation of treatment with the study drug (Visit 1) will be evaluated using 
virology analysis by PCR. 


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● 
The duration of the effect (no increase) on HDV RNA at week 24 after treatment (FU5 Visit: study week 
48) compared to the results obtained at the end of the treatment period (Visit 9: study week 24) will be evaluated 
using virology analysis by PCR. 
● 
The presence of a combined response: the negative PCR on HDV RNA, or a decrease by ≥2 log and 
normalization of ALT at treatment week 24 (Visit 9) compared to the results obtained before the initiation of 
treatment with the study drug (Visit 1) will be evaluated using virology analysis by PCR. 
● 
Dynamics of ALT activity at treatment week 24 (Visit 9) and study week 48 (FU5 Visit) compared to 
results obtained before the initiation of treatment with the study drug (Visit 1) will be evaluated on the basis of 
results obtained from the blood chemistry. 
● 
Improvement of the histological findings (reduction of necroinflammation, absence of fibrosis 
progression, etc.) at treatment week 24 (Visit 9) compared to results obtained before the initiation of treatment 
with the study drug (Visit 01) or the absence of a fibrosis progression at treatment week 24 compared to the 
results obtained before the initiation of treatment with the study drug (Visit 01) will be evaluated on the basis of 
the results of liver biopsy study/transient elastometry (fibroscan). 
● 
Dynamics (no increase) of the serum marker for fibrosis – alpha-2 macroglobulin in the serum using 
ELISA at treatment week 24 (Visit 9) and study week 48 (FU5 Visit) compared to the results obtained before the 
initiation of treatment with the study drug (Visit 1). 
● 
Dynamics of HBsAg (decrease in the quantitative content, disappearance of HBsAg, development of 
anti-HBsAg antibodies) at treatment week 24 (Visit 9) and study week 48 (FU5 Visit) compared to the results 
obtained before the initiation of treatment with the study drug (Visit 1) will be evaluated using virology analysis 
by the quantitative ELISA. 
● 
Decrease in HBV DNA levels at treatment week 24 (Visit 9) and study week 48 (FU5 Visit) compared to 
the results obtained before the initiation of treatment with the study drug (Visit 1) will be evaluated on the basis 
of results obtained in virology analysis by the quantitative PCR. 


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8. 
SAFETY EVALUATION 
8.1. 
Safety parameter evaluation criteria 
Safety parameter evaluation criteria are the same for Phases II and III  
The safety parameter evaluation criteria include: 
● 
Data on adverse events, physical examination, weight measurement, vital signs examination, 12-lead 
ECG, clinical blood test, coagulation test, blood chemistry, urinalysis, serum bile acid test. 
● 
Antibody response to Myrcludex B. 
8.2. 
Adverse Events 
The study subjects will be carefully monitored for the adverse events (AEs) by interviews, physical examination 
and analyzing laboratory and instrumental indicators from the moment of the first dose of the study drug will be 
used (Randomization visit). All unfavorable medical events which occurred prior to the first dose of the study 
drug administration will be recorded as indicators to be included in patients’ medical history with the exception 
of serious adverse events. Monitoring will be carried out in accordance with the “procedure schedule”. Adverse 
events will be classified and registered in the CRF. The classification will include the following parameters: 
severity, stage, intensity, the presence of a causal relationship with the study drug, the outcome, the actions taken 
and the countermeasures. The classification will be performed by a responsible investigator in accordance with 
the definitions given below.  
In order to identify adverse events in this study assessment of deviations in patients health will be performed 
(based on the results of physical examination, laboratory and instrumental research methods) from the data 
obtained at Screening and at the period before the first dose of study drug administration and the accepted 
reference values. After receiving the necessary information, the investigating physician will classify the patient 
condition as “norm”, “non clinically significant abnormalities” or “clinically significant abnormalities”. If the 
observed abnormalities have been considered by investigators as clinically significant and have not been 
previously recorded, or if there is a deterioration in the patient condition as compared to the findings obtained 
during Screening or before the first dose of study drug administration, the observed abnormalities will be 
classified as adverse events (AEs) and correlated with the severity level according to CT CAE. 
If the observed abnormalities have been recorded during Screening or before the first dose of study drug 
administration and there is no negative dynamics, the observed abnormalities will be classified as non clinically 
significant abnormalities (NCSA). 
The Protocol provides for the registration of all AEs that will occur in the patient after the first dose of study 
drug administration and before completing his/her participation in the study. An adverse event is understood as 
“any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, 
which does not necessarily have to have a causal relationship with this treatment” (National Standard of the 
Russian Federation “Good Clinical Practice” GOST R52379). 
An AE can be any adverse symptom (including laboratory abnormality), a complaint or a disease whose time of 
occurrence does not exclude a causal relationship with the use of the study drug, regardless of the presence or 
absence of such a link. 
All clinically significant laboratory, instrumental and physiological abnormalities and / or deviations from data 
obtained after study drug administration will be recorded by the investigating physician in the AE registration 
form, if the detected deviation falls under the definition of an AE, thereafter, the investigating physician must 
give a medical assessment of the deviations observed. Investigator should register AEs, otherwise, the observed 
abnormality will be treated as a non clinically significant abnormality (NCSA). 
8.2.1. Definitions 
The protocol adopted the following definitions (quotes from the ICH E2A Cclinical Safety Data Management: 
Terminology and Standards for Rapid Reporting guideline, as well as from GOST R 52379-2005 are given in 
italics). 
Adverse event: 
“Any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, 
which does not necessarily have to have a causal relationship with this treatment” (National Standard of the 
Russian Federation “Good Clinical Practice” GOST R52379-2005) 


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AEs include: 
 
New symptom/medical condition, 
 
New diagnosis, 
 
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 adverse event only if there are an 
unfavorable change of their intensity, rate of occurrence or qualitative changes. The responsible investigator will 
register such changes as adverse events. 
Surgical procedures are not AEs, but are measures taken to treat diseases requiring a surgery. A condition 
requiring a surgery can be considered as an AE. 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. 
All AEs (including SAE) will be recorded in the CRF. 
Adverse events will be categorized as “non-serious” or “serious” ones (see below) 
Adverse drug reaction: 
“All noxious and unintended responses to a medicinal product related to any dose should be considered adverse 
drug reactions. The phrase “responses to a medicinal products” means that a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled 
out.” 
Severity 
“A serious adverse event or reaction (SAE) is any untoward medical occurrence that at any dose of a medicinal 
product matches any of the following definitions: 
 
results in death,; 
 
is life-threatening; 
 
requires inpatient hospitalization or prolongation of existing hospitalization; 
 
results in persistent or significant disability/incapacity, 
 
is a congenital anomaly/birth defect.” 
In addition, adverse events or reactions that, in the responsible investigator’s opinion, are significant from a 
medical or scientific point of view will also be classified as “serious” ones. 
Serious adverse events that occur after the termination of participation in the study will NOT be recorded except 
for cases when, in the investigator’s opinion, the event could be caused by the study drug or any protocol 
procedure: 
 
Death is the outcome of an adverse event, not the event itself. Fatal cases reported due to the “progression of 
the disease” in the absence of other information will imply that the death occurred due to the progression of the 
disease, the treatment of which is the target of the drug. 
 
All fatal cases, regardless of their cause or association with the study drug, should be recorded for study 
subjects within 30 days from the administration of the last dose of the study drug or no later than days from the 
last evaluation in the study, whichever comes first. 
 
“Regardless of dose” does not imply that the subject received the study drug at the time of occurrence of the 
adverse event. The drug could be administered as part of a treatment period, the treatment could be temporarily 
suspended until the occurrence of the SAE, but it could affect the occurrence of an adverse event. 
 
“Life-threatening” means that the subject did not have an immediate death risk due to an adverse event. This 
category does not include adverse events that could lead to death if they were more severe. 
 
Sequelae that occurred during hospitalization are AEs. If the sequelae leads to prolongation of 
hospitalization, then it is classified as a SAE. 
 
“Hospitalization” means the official admission of a patient to a hospital on medical indication within any 
period of time. This category does not necessarily include hospitalization for more than a day. This category 


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does not include cases of admission and care provided in an intensive care unit. 
 
The investigator should attempt to diagnose an adverse event based on signs, symptoms and/or other clinical 
data. In such cases, the diagnosis, rather than individual signs/symptoms, should be recorded as an AE or a SAE. 
Expectedness: 
“An adverse reaction, the nature and severity of which is not consistent with the applicable product information 
(i.e., the Investigator's Brochure)”. 
8.2.2. Suspected unexpected serious adverse reaction (SUSAR (SUSAR) 
Suspected Unexpected Serious Adverse Reaction  
Serious adverse events as expected, i.e. (possibly) associated with the study drug, and the “unexpected”, are 
classified as the suspected unexpected serious adverse reactions (SUSARs). 
If the investigator who first reported on the SAE considers the causal relationship of the SAE with the study drug 
at least as “unlikely” and the SAE is the “unexpected” one, this SAE should be classified as SUSAR. 
All SUSARs are subject to expedited communication. Reports should be submitted to the responsible ethics 
committee and the relevant regulatory authorities (detailed information is provided in the “Safety Guide”). 
8.2.3. Follow-up period and recordkeeping 
In this study, adverse events will be registered from the date of the administration of the first dose of the study 
drug (visit on the first day of the study) until the last visit of follow-up. All adverse medical events that occurred 
prior to the first administration of the study drug will be recorded as indicators to be included in the medical 
history of the subject. 
During each study visit, the responsible investigator will interview subjects about the adverse events. If 
necessary, the AEs and SAEs will be registered in the electronic CRF and in paper forms of SAE registration in 
accordance with the principles stated above. 
All subjects with AEs, whether associated with the study drug or not, will be monitored by the responsible 
investigator in order to determine the outcome. The clinical course of AEs will be monitored until complete 
resolution or stabilization of the condition. 
8.2.4. Adverse event characteristics 
All adverse events will be classified according to the following characteristics: 
Intensity/severity 
The severity of AE in the study will be assigned in accordance with the Common Toxicity Criteria (NCI 
Common Terminology Criteria for Adverse Events, Version 4.0, available at http://ctep.cancer.gov)  
 
Mild: presence of signs and symptoms, on the other hand easily tolerable and not affecting daily activity 
ones. Symptoms do not require treatment or medical evaluation, signs and symptoms are temporary, 
 
Moderate: Adverse events lead to inconvenience or anxiety for the subject and can affect the performance 
of daily activities, but are usually reversed with simple therapeutic measures. Moderate adverse events can have 
an impact on body functions to a certain extent, 
 
Severe: Adverse events that cause a subject to interrupt daily activities and usually require systemic drug 
therapy or other treatment. They usually lead to disablement. 
For serious adverse events, there are also possible degrees: Life-threatening and Death. 
The seriousness criterion, not the intensity (severity) of AEs and adverse drug reactions will be used as a guide 
to determine obligations about regulatory authority reporting. 
Causal relationship with the study drug 
The investigator is responsible for the evaluation of the relationship between AEs and the study drug. The 
investigator must determine whether there is a reasonable probability that the study drug has caused or 
contributed to the development of AEs. The evaluation of causal relationship based on a clinical evaluation is 
often based on the following criteria: 
 
Temporal relationship between the onset of AEs and the administration of the study drug; 
 
The likely biological mechanism by means of which the study drug could cause AE; 
 
Other possible etiology of AEs; 
 
Previous reports of similar AEs associated with the study drug or with other drugs of a similar class and 
 
Recurrence of AE after reinitiation of treatment or resolution after discontinuation of treatment, if 
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The following terms are used to evaluate the relationship between the event and the study drug: 
 
Associated – there is an anticipated probability that an AE can be associated with the study drug; 
 
Non-associated – there is no anticipated probability that an AE is associated with the study drug. 
If the event is assessed as “non-associated” with the study drug, an alternative etiology, a diagnosis or 
justification for the development of an adverse event should be identified. 
Outcome 
The outcome of the AE will be classified as follows: 
 
Complete resolution: All signs and symptoms of the AE at the time of the last interview disappear, leaving 
no consequences,  
 
In the process of resolution/recovery: The intensity of signs and symptoms is reduced, their clinical 
character has changed before the last interview according to the scenario typical for the resolution, 
 
No resolution/no recovery: The signs and symptoms of the AE have remained almost unchanged since the 
last interview, 
 
Resolution/recovery with sequelae: The actual signs and symptoms of the AE have disappeared, but has 
had sequelae associated with AEs,  
 
Fatal outcome: The AE has led to death. If a patient has several adverse events, the outcome “death” is 
assigned only to the AE that has led to death, 
 
Unknown: The outcome is unknown or unlikely and the information can not be added or confirmed.  
Acts Relating to the Study Drug 
Acts relating to the study drug must be assigned to one of the following categories: 
 
Dose is not changed: the dose of the study drug is not changed, 
 
Dose is reduced: reduction of the dose of the study drug, 
 
The drug treatment is temporarily suspended: Temporary suspension of the treatment with the study 
drug, 
 
Dechallenge: Complete discontinuation of the treatment with the study drug, 
 
Not applicable: The issue is irrelevant (due to the death of the subject or a single use of the drug, excluding 
the possibility of dose modification). 
Countermeasures: 
The term “countermeasures” refers to special actions taken to treat or alleviate a condition when there are 
adverse events in order to avoid their sequelae. The following categories have been accepted: 
 
Absent: measures have not been taken, 
 
Treatment with the medicinal product: newly prescribed drug or a dose modification of the study drug, 
 
Other: Other countermeasures, such as surgery. 
8.2.5. Investigator’s reports about serious adverse events 
The investigator submits a report about all SAEs to the sponsor within 24 hours after the SAE has occurred by 
sending the SAE form via Fax or email:  
Fax: +7 495 726-52-53 
E-mail: pharmacovigilance@ammaxwell.ru 
Before sending the SAR form, the sponsor’s monitor should be informed about that by phone. 
The initial report should be as complete as possible and include information on the present disease and the event, 
as well as an evaluation of the causal relationship between the adverse event and the study drug. 
Detailed information about the report on the SAE and the SAE form, including instructions for its completion, 
are provided in the “Safety Guide”. 
8.2.6. Emergency notification 
SUSAR should be reported to the ethics committee and to the relevant regulatory authorities within the time 
limits specified by the regulatory documents, i.e. they are subject to emergency notification. 
Investigators involved in this study should report an authorized member of the safety department about all SAEs 
as quickly as possible, but no later than 24 hours after the presence of the relevant information. The report 
should be sent by fax as the completed SAE form. 
The sponsor’s designated employee should make the emergency notification. A more detailed description of the 


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procedures related to pharmacovigilance in this study is presented in the “Safety Guide”. 
8.2.7. Pregnancy 
If a female subject becomes pregnant, discontinue the treatment with the study drug immediately. 
Pregnancy is not an adverse event as such, except cases when there are reasons to believe that the study drug led 
to a decrease in the effectiveness of contraceptives. Congenital abnormalities and developmental disorders in 
patient children are classified as serious adverse events. Medical abortion and other serious complications of 
pregnancy (including spontaneous abortion) are classified as serious adverse events. Artificial abortion in the 
absence of complications is not considered an adverse event. 
All cases of pregnancy (including pregnancy of partners of male patients) should be duly recorded during the 
clinical study. At the time of pregnancy confirmation, the investigator should submit the report to the 
pharmacovigilance department staff of the sponsor. The sponsor should also be informed about the outcome of 
pregnancy. Pregnancy in female patients and partners of male patients is subject to registration, from the first 
day of administration of the study drug to the completion of the final procedures of the study. 
Pregnancy outcome (spontaneous abortion, artificial abortion, the birth of a healthy child or child with 
congenital anomalies or malformations) should be recorded even if the subject(s) has not terminated the clinical 
study. 
8.2.8. After-treatment reporting requirements 
All deaths occurred throughout the study period and within 30 days since the last injection of the drug dose, 
regardless of the cause or association with the study drug, should be recorded. 
8.3. 
Laboratory Abnormalities and Other Deviations Classified as Adverse Events and Serious 
Adverse Events 
In order to identify adverse events in this study assessment of deviations in patients health will be performed 
(based on the results of physical examination, laboratory and instrumental research methods) from the data 
obtained at Screening and at the period before the first dose of study drug administration and the accepted 
reference values. After receiving the necessary information, the investigating physician will classify the patient 
condition as “norm”, “non clinically significant abnormalities” or “clinically significant abnormalities”. If the 
observed abnormalities have been considered by investigators as clinically significant and have not been 
previously recorded, or if there is a deterioration in the patient condition as compared to the findings obtained 
during Screening or before the first dose of study drug administration, the observed abnormalities will be 
classified as adverse events (AEs) and correlated with the severity level according to CT CAE. If a laboratory 
abnormality is a part of the syndrome, this syndrome or diagnosis should be identified. 
The severity of AEs must be indicated in accordance with the common toxicity criteria (CTC AE, NCI Common 
Terminology Criteria for Adverse Events, version 4.0, available at http://ctep.cancer.gov). Particular attention 
should be paid to reactions at the injection site and to dermatitis, as they are expected reactions in the treatment 
with MXB. 
As for adverse events accompanied by a laboratory abnormality, the clinical severity score of the adverse event 
against the background of the underlying disease should be evaluated, wherein the evaluation may differ from 
evaluation of the severity of the laboratory abnormality itself. 
As for the possible nephrotoxicity developed during administration of the nucleotide analogue product Viread 
(tenofovir), adverse events should be recorded if the creatinine clearance is <50 mg/dL – 0.48 mmol/L (two 
independent calculations) or serum phosphate is > 0.5 mg/dL in two separate evaluations. In this case, the 
administration of tenofovir should be discontinued, and renal function evaluation should be performed weekly. 
Further patient treatment should be discussed with the medical monitor of the study. 
The increase of bile acid levels against the background of the use of Myrcludex B is directly related to the 
mechanism the drug effect – blocking NTCP receptor on the liver cells, which functions as a reverse transport of 
bile acids from the bloodstream to the liver. Therefore, an isolated increase in bile acid level in the absence of 
clinical significance should not be classified as an AE. If the investigator considers the increase to be clinically 
significant or it will be associated with the occurrence of clinical symptoms, this increase should be recorded as 
an AE. 
If the observed abnormalities have been recorded during Screening or before the first dose of study drug 
administration and there is no negative dynamics, the observed abnormalities will be classified as non clinically 


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significant abnormalities (NCSA). 
All observed abnormalities, regardless of whether attributed to AEs or NCSAs, will be analyzed when reporting 
clinical study results. 
8.4. 
Managing Toxic Reactions 
 
Clinically significant 3 to 4 Grade laboratory abnormalities should be verified by duplicate analyzes 
within three calendar days from the moment of result generation before the treatment with the study drug is 
terminated, if such a delay does not meet the requirements of good medical practice (central laboratory). 
 
Clinical events and clinically significant laboratory abnormalities will be classified according to National 
Cancer Institute (NCI) Common Toxicity Criteria (NCI Common Terminology Criteria for Adverse Events, 
version 4.0, are available at http://ctep.cancer.gov) 
 
When the treatment with the study drug is reinitiated after an adverse event has been resolved, the study 
drug will be administered in full or in a modified dose, as agreed with the medical monitor. 
 
Recurrence of a clinical or clinically significant 3 to 4 Grade laboratory abnormality, after the 
reinitiation of treatment following its suspension, requires the complete discontinuation of treatment with the 
study drug. 
 
Any questions regarding the managing toxic reactions should be directed to the medical monitor. 
The classification of skin adverse events, possible to occur with the use of the study drug, is given in the table 2. 
Table 2 Classification of Skin Adverse Events, Associated with the Study drug Injections 
Parameter 
Grade 1 
(mild) 
Grade 2 
(moderate) 
Grade 3 
(severe) 
Grade 4 
(potentially life-threatening) 
Skin 
Reaction/ 
Rash/ 
Dermatitis 
Hyperemia, 
skin itch 
Diffuse 
maculopapular rash 
OR 
dry 
peeling 
skin 
Vesiculation OR 
moist 
peeling 
skin 
OR 
ulceration 
ANY OF THE STATED BELOW: 
mucous membrane lesions, suspicion 
of 
Stevens-Johnson 
syndrome, 
erythema 
multiforme, 
necrosis 
requiring 
surgical 
treatment, 
exfoliative dermatitis  
Local 
reactions 
Hyperemia 
Induration <10 mm 
OR 
inflammation 
OR phlebitis 
Induration 
≥10 
mm 
OR 
ulceration 
Cutaneous necrosis 
8.4.1. Grade 1 to 2 laboratory abnormalities 
 
Continuation of treatment with the study drug at the discretion of the investigator. 
8.4.2. Laboratory abnormality or Grade 3 clinical event 
 
If a clinically significant laboratory abnormality or a Grade 3 clinical event develops, the treatment with 
the study drug can be continued if this event was found not to be associated with the study drug. 
 
If there is a Grade 3 clinical event or a clinically significant laboratory abnormality confirmed by a 
duplicate analysis, considered to be associated with the study drug, the treatment should be discontinued until the 
toxic reaction is reduced to Grade 2 and below. 
 
If, after the reinitiation 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 should be completely discontinued, and 
subjects should be treated according to the local practice accepted in the institution. Recurrence of adverse 
events considered not to be associated with the study drug does not require the irrevocable termination of 
treatment with the study drug. 
8.4.3. Laboratory abnormality or Grade 4 clinical event 
 
If a clinically significant laboratory abnormality or a Grade 4 clinical event develops, the treatment with 
the study drug should be discontinued and subjects should be treated according to the local practice accepted in 
the institution. The subjects should be monitored in accordance with clinical indications before resolution to 
baseline values. A clinically significant Grade 4 laboratory abnormality, not confirmed by duplicate analyzes, 
should be adjusted in accordance with the algorithm for a new degree of toxicity. 
 
If there is a clinically insignificant Grade 4 laboratory abnormality (for example, a Grade 4 QC deviation 
after intense physical activity or an increase in the nonfasting triglyceride level or in the triglyceride level not 
subject to medical correction) or a Grade 4 clinical event, considered not associated with the study drug, 


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treatment with the drug can be continued without interruption. 
8.5. 
Risks for Women of Childbearing Age and Risks during Pregnancy 
No evaluations of the risks associated with MXB treatment during pregnancy was not performed. Studies in 
animals have not shown the presence of direct or indirect adverse events of MXB on pregnancy. For more 
information, see the latest version of the Investigator’s Brochure. Women of childbearing age and women whose 
menopause occurred less than 2 years before should use barrier methods of contraception in combination with 
other methods of contraception (for example, oral or other hormonal contraceptives) during the period of 
participation in the study and within 3 months after administration of the last dose of the study drug. Sexually 
active male subjects should use barrier methods of contraception during the same period of time upon contact 
with partners of childbearing age, or they should keep themselves from heterosexual contacts. 
The subjects should be aware of the need to stop taking all the drugs and immediately inform the investigator 
about pregnancy during the study. 
The investigator must inform the sponsor about all cases of pregnancy no later than 24 hours from the time he 
has learnt about pregnancy. The investigator should inform the subject about the possible effects of the previous 
intake of the study drug on the fetus and about the need to inform the clinical center about the outcome of 
pregnancy. 
Pregnancy complications, as well as the planned termination of pregnancy on medical indications should be 
reported as an AE or a SAE. 
Spontaneous abortion is always considered as SAE, it should be reported in accordance with the requirements set 
out in the section on serious adverse events. In addition, any SAE that has occurred as an adverse event of 
pregnancy after the study should be reported to the sponsor. 
In addition, all cases of pregnancy that occurred during the study should be reported on the CRF “Report on 
pregnancy”. Monitoring of the study subject should be performed until the end of pregnancy. The outcome of 
pregnancy should be reported to the sponsor using the CRF “Pregnancy outcome” page (including, if applicable, 
the section “Complicated outcome of pregnancy”). If the termination of pregnancy occurs at the time after the 
study termination, the sponsor should be informed about the outcome directly. The cases of pregnancy that 
occurred after the study subject has stopped to take the study drug, do not require monitoring. 


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9. 
STATISTICS 
9.1. 
Documentation of Statistical Methods 
9.1.1. General principles 
The statistical analysis will be carried out under supervision of the responsible biostatistician in accordance with 
the requirements of the National Standard of the Russian Federation “Good Clinical Practice” and other 
applicable requirements and laws. 
Before the statistical analysis is carried out, data from different centers will be combined into a common data set. 
If the assumptions made in the preliminary planning of the study prove to be erroneous, the analysis methods 
will be changed for a more appropriate analysis to be carried out. If the change in the statistical analysis is 
significant and affects the study results or their interpretation, an amendment to this study protocol will be issued 
in advance. 
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. 
9.1.2. Demographic and baseline characteristics 
The descriptive statistics will be used to describe baseline demographic parameters and characteristics for the 
analysis population in general and for treatment subgroups. The arithmetic mean (with a 95% confidence interval 
for the mean), the standard deviation, the median, 25- and 75-percentiles will be calculated for interval variables. 
The frequency rates, rates of the categories and the confidence intervals for rates(95% confidence intervals 
according to the Clopper-Pearson method) will be calculated for nominal variables. 
9.1.3. Efficacy analysis methods 
Primary efficacy analysis for Phase II and III will be based on the following efficacy endpoint:  
 
The negative PCR result on HDV RNA or a decrease by ≥2 log at treatment week 24 compared to the 
data obtained before the initiation of treatment with the study drug.  
This endpoint will be analyzed in modified Intent-to-Treat Set (mITT), which includes all randomized subjects 
who started study treatment (Myrcludex B or Tenofovir) in study period after randomization.  Additionally these 
data will be analyzed in the Per Protocol (PP) set that includes subjects with available Week 24 efficacy results 
(see below for PP set definition).  
In Phase II, treatment arms will be compared using the Wald test for Superiority by Margin of 5%; 95% 
Clopper-Pearson confidence interval will also be calculated for treatment response rates (for each treatment 
arm). Each experimental treatment arm (Myrcludex B) will be compared to the control arm receiving tenofovir 
alone. Each Myrcludex B treatment arm will be compared to the control arm separately (Arm A vs Arm D, 
Arm B vs Arm D, Arm C vs Arm D). Hypotheses will be tested sequentially, using Bonferroni-Holm method. 
Null hypotheses will be defined for each prior test, and appropriate p-values will be calculated (based on data 
obtained in the study). After that, null hypotheses will be rejected in descending order of respective p-values for 
critical values of type I error (α), calculated as α/(k – i + 1), where k is the number of planned comparisons and i 
is the sequential number of the comparison [31]. 
In Phase III, the hypothesis of statistical superiority will be tested with the help of the two-sided Fisher exact test 
for the primary efficiency index. 
Qualitative secondary endpoints (ALT normalization and disappearance of HBsAg/ seroconversion) will be 
analyzed using the Fisher’s exact test.  Quantitative secondary endpoints (serum fibrosis marker, HBsAg and 
HBV DNA) will be presented as absolute values and changes from baseline. To compare treatment arms on the 
basis of endpoints, two-sided Wilcoxon rank sum test will be employed with adjustment at the significance level 
of 0.0167.  If the assumptions necessary for carrying out parametric approach are not violated (will be verified 
using graphical methods), parametric analogues of the above methods will be used: analysis of variance 
ANOVA/ analysis of covariance ANCOVA, the paired Student’s t-test for dependent samples.   
9.1.4. Safety analysis methods 
MXB safety (Phase II and III) will be analyzed for the following evaluation parameters:  
The main safety evaluation parameter: 


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 
The incidence of adverse events associated with the administration of the study drug, estimated from 
Visit 1 to the end of study visit (EOS visit) 
Secondary safety evaluation parameters:  
 
Type and severity of AEs associated with the administration of the study drug, estimated from Visit 1 to 
the final visit. 
 
Rate of occurrence, type and severity of any other AEs, as well as evaluation of physical examination 
findings, vital signs, 12-lead ECG, clinical blood test, coagulation test, blood chemistry, urine analysis, serum 
bile acid test, antibody response to Myrcludex B. 
These evaluation parameters will be analyzed in the safety population (refer to paragraph 9.7).  
The AE associated with the administration the study drug is defined as any AE started after administration 
the study drug or before administration the study drug, but the severity of which has increased after the 
administration, that has any connection with the study drug, with the exception of “not associated”. The severity 
of AEs will be presented in the number of subjects with different severity of AEs (mild, moderate and severe).  
The AEs, including serious adverse events, will be classified according to the latest version of the Medical 
Dictionary for Regulatory Activity Terminology (MedDRA) available at the time the database freeze. Further 
analysis of AEs and SAEs will include the calculation of the number of AEs, the number of subjects with AEs, 
the number of AEs associated with the study drug, the number of AEs requiring discontinuation of therapy, the 
number of WAE. 
The rate of occurrence and severity of all AEs and AEs associated with the study drug will be presented for all 
system organ classes (SOC MedDRA). SAE will also be presented in the form of descriptions (narratives). 
Numerical safety data will be presented as summary tables of descriptive statistics for each treatment arms. Descriptive 
statistics will be provided for each numerical safety endpoint. Vital sign and laboratory data as well as change from baseline 
will be summarized (where applicable) by visit of assessment and by treatment group. In addition, shifts in laboratory 
parameters will be presented by treatment group. 
The safety data sheets will also be included in the final analysis. 
9.2. 
Scheduled Number of Subjects 
For Phase II. This study is scheduled as a comparative parallel group clinical study with three groups of the 
study drug (of a dosage strength of 2 mg, 5 mg and 10 mg) and one comparison group (all three comparisons 
will be conducted as independent ones) to study the hypothesis of superiority of the study drug with the 
reference drug.  
The basic variable of the study is the response rate, defined as decrease in the level of HDV RNA by at least 2 
log10 (assay) or lack of HDV RNA (in 24 weeks after the initiation of treatment). It is a frequency index. 
In accordance with the study aim and objectives, the null hypothesis (H0) will be formulated as follows: 
H0: ε ≤ δ  
and an alternative hypothesis (Ha) will be as follows  
Ha: ε > δ 
where ε – an expected difference between the response rates in the treatment group with the study drug and the 
reference drug, δ – a limit of clinically significant differences (superiority limit). 
Given the study design, type and nature of the basic variable (parallel group comparative study), the size of each 
group can be estimated by the formula: 
 
where: 
z and 
z  — corresponding values of the z-function for the planned values of I and II type error; p1 and 
p2 – a response rate in the treatment and control groups respectively;  — estimated differences between groups 
with respect to the basic variable of the study; k — coefficient when number of subjects in groups is unequal (in 
this study k=1); n1 and n2 – scheduled number of subjects in the main and control groups, respectively.  
Thus, the sample size was calculated on the basis of the following parameters:  
1. 
Critical significance level for the null hypothesis testing α = 0.0167 (using the Bonferroni amendment). 
2. 
The power of the study is not less than 0.8 (80%), the probability of II type error (), thus, will not 


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exceed 0.2. 
3. 
The superiority limit (clinical significance of differences)  will be taken as 5%; 
4. 
The estimated difference between groups in the basic variable of the study will be at least 34.0%. The 
performed phase 1b/2a clinical study in patients with CHD showed efficacy in the monotherapy group in 57% of 
patients after 24 treatment weeks, with the lower limit of the confidence interval in~ 37%.  
5. 
The estimated response rate in the control group does not exceed 3% (when there was no treatment, as 
well as when patients with hepatitis delta were prescribed nucleoside/nucleotide analogues registered for the 
treatment of CHD, the investigators observed no positive dynamics; for example, the HIDIT-1 study in 90 
patients with CHD did not show an effect on HDV RNA when monotherapy with a nucleotide analog adefovir 
was prescribed). It is assumed that there may be a spontaneous decrease in the HDV RNA level by 2log10 in no 
more than 3% cases.  
The sample size was calculated as follows: 
 
 
Thus, to test the hypothesis of the superiority of the study drug (each dosage group should be tested separately) 
against the control group, it is necessary to include at least 28 subjects in each group in the efficacy analysis. 
Assuming the drop-out is no more than 5% subjects in each study group, each group arm should be at least 30 
subjects. 
 
For Phase III. When the last patient completes a 24-week treatment period as a part of Phase II clinical study, 
patients from all treatment arms will be analyzed for viral load based on PCR data on HDV RNA (the negative 
PCR result on HDV RNA or a decrease by ≥2 log at treatment week 24 compared to the data obtained before the 
initiation of treatment with the study drug will be considered as the primary endpoint). Results of the test 
performed will provide the basis for estimating the number of patients needed to confirm the hypothesis of the 
statistical superiority of the selected dosage strength of the study drug over the drug of the standard treatment. 
When calculating the sample size, the correction for a plurality of comparisons (Pocock correction) will be taken 
into account with due regard to two statistical analyzes (at treatment week 24 of phase II and treatment week 24 
of phase III). 
If a statistically significant conclusion is obtained based on the results of phase II on the statistical superiority of 
study drug in chosen dosage over the control group with respect to the primary endpoint at the bilateral 
significance level of 5%, then the recruitment of patients into Phase III of the study will not be performed, and 
the statistical analysis will be performed as a part of the Interim Report on Phase II and the Final Report on the 
Clinical Study Results. 
 
9.3. 
Applicable Significance Level 
In Phase II, for testing the main variable of the study, the significance level will be a one-sided one (a superiority 
test is planned). Non-inferiority test will be performed in series, according to the Bonferroni-Holm method. This 
method allows you to monitor the FWER (Familywise error rate) for a family of null hypotheses. In the course 
of the planned comparisons, the type I error probability will not exceed 0.05, and the significance levels for each 
successive comparison will be calculated individually according to the Bonferroni-Holm method (see above). 
If Phase II results require the inclusion of additional patients in Phase III, when calculating the sample size, the correction 
for a plurality of comparisons (Pocock correction) will be taken into account with due regard to two statistical analyzes (at 
treatment week 24 of phase II and treatment week 24 of phase III).  
 
9.4. 
Study Termination Criteria 
Interim and final data analysis as a part of Phase II 
When the last patient completes a 24-week treatment course as a part of Phase II clinical study, patients from all 
treatment arms will be analyzed for viral load based on PCR data on HDV RNA (the negative PCR result on 


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HDV RNA or a decrease by ≥2 log at treatment week 24 compared to the data obtained before the initiation of 
treatment with the study drug will be considered as the primary endpoint). The results of this study will be used 
to draw up the Interim report on the results of the Phase II clinical study, herewith, all patients will continue to 
be treated with tenofovir. During the Interim analysis, the recruitment of new patients into the clinical study will 
be suspended. 
Based on the data from the Phase II Interim Report, the optimal (based on efficacy and safety analysis) dosage 
for the second part of the clinical study (corresponding to phase III) will be selected, and the required number of 
patients to be enrolled in Phase III will be calculated. When calculating the sample size, the correction for a 
plurality of comparisons (Pocock correction) will be taken into account with due regard to two statistical 
analyzes (at treatment week 24 of phase II and treatment week 24 of phase III). The results of the Phase II 
Interim analysis will be submitted to the Ministry of Health of the Russian Federation.  
If a statistically significant conclusion is obtained based on the results of phase II on the statistical superiority of 
study drug in chosen dosage over the control group with respect to the primary endpoint at the bilateral 
significance level of 5%, then the recruitment of patients into Phase III of the study will not be performed, and 
the statistical analysis will be performed as a part of the Interim Report on Phase II and the Final Report on the 
Clinical Study Results. 
When the last patient completes the follow-up period of the first part of the clinical study, the data on the 
treatment studied will be analyzed in all patients who have completed the 48-week treatment course in phase II, 
the Final Report on the Results of the Phase II Clinical Study will be drawn up and submitted to the regulatory 
authorities. 
Interim and final data analysis as a part of Phase III 
When the last patient completes a 24-week treatment course as a part of Phase II clinical study, patients from all 
treatment arms will be analyzed for viral load based on PCR data on HDV RNA which results will be used to 
draw up the Interim report on the results of the Phase III clinical study, herewith, all patients will continue to be 
treated with tenofovir. The negative PCR result on HDV RNA or a decrease by ≥2 log at treatment week 24 
compared to the data obtained before the initiation of treatment with the study drug will be considered as the 
primary endpoint. The results of the Interim Report on the Results of the Phase III Clinical Study will be 
submitted to the regulatory authorities with the aim of the study drug marketing authorization. 
When the last patient completes the follow-up period of the first part of the clinical study, the data on the 
treatment studied will be analyzed in all patients who have completed the 48-week treatment period, the Final 
Report on the Clinical Study Results will be drawn up and submitted to the regulatory authorities. 
9.5. 
Procedures for Accounting Missing Data not to be Analyzed 
If there are any missing, not to be analyzed and spurious data, the randomness of such data will be evaluated. An 
analysis of the stability of the results obtained and the conclusions drawn from them will be made. During 
interim analysis after the last patient will complete 24-week therapy within Phase II of the clinical trial for the 
primary efficacy parameter, if there is no HDV RNA data at the 24-week Visit, the patient will be considered as 
non-responder to therapy. The procedure for restoring missing values will be described in more detail in the 
Statistical Analysis Plan. 
9.6. 
Procedures for Reporting Any Deviations from the Original Statistical Plan 
Detailed information about the statistical analysis will be presented in the statistical analysis plan. The statistical 
analysis plan will be consummated before the database freeze. All deviations from the final version of the 
statistical analysis plan will be justified in the final study report. 
9.7. 
Selection of participant for the statistical analysis 
The statistical analysis will include the following populations: 
Safety Set: all subjects who received at least one dose of the study medication in Myrcludex B groups or   
Tenofovir in group of observation after randomisation.  
Full set of data for efficacy analysis (Modified Intent-to-Treat Set (mITT): all randomized subjects who  
received at least one dose of the study medication in Myrcludex B groups or who was randomized in observation 
group and received Tenofovir after randomisation.  
Per Protocol Set (PP): subjects from full set of data for efficacy analysis who completed 24-week treatment 
period without major protocol deviations and with efficacy results for 24-week time point.  


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10. 
DIRECT ACCESS TO SOURSE DATA/DOCUMENTS 
10.1. 
Access and Verification of Source Data and Records 
All the information contained in the original records and certified copies of the clinical data, observations and 
other activities in the study, and which is necessary for the reconstruction and evaluation of the study, is the 
source data. The investigator permit study-related monitoring, audit(s), IEC review, and regulatory inspections, 
as well as to provide direct access to source data/records and study documents. 
Direct access to source data and documentation should be provided to the Sponsor’s clinical research associate 
and its authorized representatives (CROs), the Sponsor/CRO auditor, the regulatory inspector, ethical reviewers, 
the insurance company representatives. 
10.2. 
Access to Additional Information 
Upon request, the Investigator provides the Sponsor with additional data regarding the study, or copies of the 
related source records, after proper processing of the data to achieve anonymity of the participant’s data. This is 
important when case report form are filled in illegible, or if there are errors in data recorded. In special cases or 
when requested by governmental organizations, it is also necessary to have access to the full study records, 
provided that the patient’s confidentiality complies with applicable regulations. 
 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. 
Periodic Monitoring 
Monitoring is the process of supervision of the progress of a clinical study, designed to ensure that it is 
conducted, documented and information about it is transmitted to the appropriate authorities in accordance with 
the Protocol and the rules. The Sponsor appoints the person conducting the monitoring. The monitor is the main 
link between the Sponsor and the Investigator. The monitor, in accordance with the requirements of the Sponsor, 
must ensure the proper conduct and documentation of the study 
The CRO and the Sponsor will carry out monitoring in the center before, during and after the study. The monitor 
will check that the study is being conducted, the data is recorded and presented in accordance with the protocol, 
SOP, GRP and applicable regulatory requirements. The monitor will check the accuracy and integrity of the data 
entered in the CRF, the primary documentation, and other records related to the study, compared to each other. 
The Principal Investigator provides quality control of the study, and quality inspection is performed by 
monitoring visits, the terms of which are determined by the Sponsor. 
The Sponsor representative or specially designated person will monitor the study to ensure that: 
 
data is true, accurate and complete; 
 
safety and rights of the study subjects are protected; 
 
the study is conducted in accordance with the currently approved protocol version and any other study 
agreements, ICH GCP, and all applicable regulations. 
The monitor, in accordance with the requirements of the Sponsor, must ensure the proper conduct and 
documentation of the study. With that in mind, the monitor performs the following actions: 
 
Verifies the correspondence of the Investigator’s qualifications and resources, as well as the sufficiency 
of available human and material resources, including laboratories, equipment and personnel, for the safe and 
appropriate conduct of the study, at the beginning and throughout the study 
 
Verifies that storage period and conditions of the IMP are acceptable and the amount is sufficient until 
the end of the study 
 
Verifies that the IMP is received only by those patients whom it is prescribed, and at the doses 
established by the protocol; 
 
Verifies that patients are provided with the necessary instructions for the correct use of the 
investigational products, for their handling, storing, and returning them; 
 
Verifies that the receipt, application and return of the products in the clinical center are properly 
monitored and documented; 
 
Verifies that the Investigator complies with the approved protocol and all approved amendments to it, if 
any. 
 
Verifies that the written informed consent of each patient has been received before conduct of the study. 


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 
Ensures that the Investigator has an up-to-date version of the Investigator’s Brochure, all other 
documents and materials required to conduct the study in an appropriate manner and in accordance with 
regulatory requirements. 
 
Ensures that the Investigator and his staff involved in the study are sufficiently informed about the study. 
 
Verifies that the Investigator and his staff involved in the study exercise the study-related duties in 
accordance with the protocol and all other written agreements between the Sponsor and the Investigator/Center 
and do not transfer their functions to unauthorized persons. 
 
Verifies that the Investigator complies with the enrollment criteria when patients are included in the 
study. 
 
Reports the enrollment rate. 
 
Verifies the accuracy, integrity and timeliness of data registration in primary and other documents 
related to the study, as well as the procedure for their entry. 
 
Verifies the accuracy and integrity of the data in the CRFs, the primary documents and other records 
related to the study by comparing them with each other. 
 
Informs the Investigator about any errors made in the CRFs, omissions and illegible records. The 
monitor should ensure that appropriate corrections, additions or deletions are made, dated, explained (if 
necessary) and signed by the Investigator himself or by a member of the research team authorized to sign 
changes for him in the CRFs. These powers must be documented. 
 
Verifies the compliance with the deadlines for reporting adverse events identified by GCP, protocol, 
IEC, Sponsor and regulatory requirements. 
 
Verifies that the Investigator maintains the basic documents. 
 
Informs the Investigator about deviations from the protocol, SOP, GCP and regulatory requirements, as 
well as takes the necessary actions to prevent the recurrence of such deviations. 
The monitor will periodically contact the Investigator and perform visits to analyze all the source data/records 
relevant to the study, verify compliance with the protocol, and the integrity, validity and accuracy of all records 
in the CRFs in comparison with the source data. The Investigator will cooperate with the monitor in order to 
eliminate all identified discrepancies. 
The Monitor will submit a written report to the Sponsor after each visit to the clinical center and/or contact with 
the investigators in accordance with standard operating procedures (SOPs). 
In this study, it is planned that monitoring visits will take place before the initiation of the study (preliminary 
visit and initial visit) and during the study (routine visits every 4-6 weeks and final visit). The first routine visit 
will be scheduled within 2 weeks after the first patient is randomized in the center. 
11.2. 
Audit and Inspection 
The Sponsor provides for such a quality control system that will guarantee the conduct of this clinical study in 
accordance with the study protocol, the principles of the GCP and the current requirements of the legislation of 
the Russian Federation. 
If a situation arises that requires an on-site inspection during the study, the Sponsor initiates an audit conducted 
by its representatives or independent auditors. Comments and conclusions of the audit should be documented. 
The objective of the audit is a comprehensive and independent verification of the activities and documentation 
related to the study performed to confirm the compliance with this activity, as well as with procedures for data 
collecting, analyzing and reporting, with the Sponsor’s standard operating procedures, with the Good Clinical 
Practice principles and regulatory requirements. 
Inspection is the actions of the authorized body for the official verification of documents, premises, quality 
assurance measures, as well as all other materials that, in the opinion of the authorized body, are related to the 
conduct of a clinical study and that may be on a clinical site. 
After the audit is completed, a report should be prepared, which must be available to the Sponsor provided that 
the confidentiality is respected. 
In order to ensure compliance with the ICH GCP and all applicable regulations, at any time during or after the 
end of the study, the Sponsor or regulation authorities may conduct an audit or inspection to control the quality 
of the records of the medical center. In the case of an audit or inspection, the Ivestigator (as well as the 
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relevant documents and to appoint them and the center staff time to discuss the results or issues. 
The Investigator will ensure that all source data and records relevant to the study are accessible to a qualified 
auditor authorized by the Sponsor or to inspectors from regulators after due notice. The main objectives of audits 
and inspections are to confirm that the rights and well-being of the patients involved in the study are protected, 
and that all data relevant to the evaluation of the study drug have been processed and reports on them have been 
submitted in accordance with the GCP and applicable regulatory requirements. 


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12. 
LEGAL AND ETHICAL ISSUES IN STUDY MANAGEMENT 
12.1. 
General requirements 
The participation of patients in the study is voluntary. The patient has the right to reject participation in the study 
at its any stage. 
The study should be carried out in accordance with ethical principles set forth in the Declaration of Helsinki of 
the WMA (adopted at the 18th WMA General Assembly in Helsinki in June 1964, the latest edition was adopted 
at the 64th WMA General Assembly in Fortaleza, in October 2013). 
Ethical standards for clinical studies are regulated by the relevant documents: Art. 21 of the Constitution of the 
Russian Federation, Federal Law No. 61-FZ dd. 12.04.2010 “On Medicine Circulation”, National Standard of 
the Russian Federation GOSTR 52379-2005 “Good Clinical Practice”, Principles of Good Clinical Practice in 
the Russian Federation (approved by Order of the Ministry of Health N 200н dd. April 04, 2016). 
The Investigators involved in the clinical study prior to the initiation of the study should provide the Sponsor 
with signed and dated summaries that contain the description of clinical practice, data on professional and 
scientific activities. 
12.2. 
Ethical Conduct of the Study 
The approval of the study by an independent ethical committee and the patient’s signature on the informed 
consent are the guarantees of compliance with ethical standards during the study. 
Each patient will be informed that a study monitor, a quality assurance department auditor or a health inspector, 
in accordance with applicable regulatory requirements, can review his/her personal data, including the study-
related ones. 
12.3. 
Council on Ethics and Local Ethics Committee 
Ethical review of clinical study of drugs is carried out by the Council on Ethics of the Ministry of Health and the 
Local Ethics Committee (LEK). The Council on Ethics and LEC are intended to protect the rights, safety and 
well-being of all study subjects. The Council on Ethics and LEC should evaluate the conformity of the 
Investigator’s qualifications to the proposed study on the basis of his curriculum vitae. Prior to the initiation of 
the study, the approval of the protocol, the informed consent form and any other document handed over the 
patient, should be obtained from the LEC of those institutions where the clinical study will be conducted. The 
findings of the Council on Ethics and LEC must be dated, signed and issued in writing. Clinical study can be 
initiated only after obtaining the approval of the relevant Council on Ethics and the local EC. 
The Investigator, the head of the medical institution or other responsible person must submit the required 
documentation to the local ethics committee for consideration in time. Documents submitted to the local ethics 
committee may vary in different institutions, but must necessarily include the final version of the clinical study 
protocol, information for patient and informed consent, the Investigator’s Brochure with information about the 
study drug. 
A list of all members of the Council on Ethics who have conducted consultations or participated in voting, as 
well as of the Council President(s), will be included in the study report. 
12.4. 
Regulatory Approval 
An approval to conduct the clinical study is issued by the Ministry of Health of the Russian Federation (MoH of 
the RF) subsequent to the results of the expert review of documents required to obtain an approval to conduct the 
clinical study, and ethical review conducted in accordance with the procedure established by Article 20 of 
Federal Law No. 61-FZ dd. April 12, 2010 “On Medicine Circulation”. 
In accordance with the current legislation, the clinical study protocol and other necessary documents will be 
submitted to the Ministry of Health of the Russian Federation for obtaining an approval to conduct the study. 
Clinical study can be initiated only after the approval from the Ministry of Health of the Russian Federation has 
been obtained. The approval for all documents and for the study should be obtained before the patient undergoes 
any study procedures, including screening tests for acceptability appraisal. 
12.5. 
Periodic Informing of the Independent Ethics Committee 
In accordance with federal law No. 61-FZ “On Medicine Circulation” and GCP principles, the IEC and the 
competent regulatory authorities should be informed of all suspected unexpected serious adverse drug reactions 
(SUSAR) occurred during the study. Both institutions should be informed of changes in the risk/benefit ratio or 


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about a significant new health and safety risk of the subjects. 
The IEC and regulatory authorities should be informed of the end of the study. Not later than one year after the 
end of the clinical phase of the study, they should be provided with generalized data on the study results. 
12.6. 
Notification to Regulatory Authorities 
Local regulatory authorities responsible for each investigator must receive information before initiation, during 
and at the end of the study in accordance with the applicable law.  
12.7. 
Information for the Patient and Informed Consent Form 
Prior to the initiation of the study, the Investigator will receive a voluntary signed and dated informed consent 
from each patient after properly explaining the aims, methods, potential benefits, possible risks and all other 
aspects of the study that may influence the patient’s decision to participate in the study, and the patient will get 
acquainted with a patient information leaflet that includes information for the patient and an informed consent 
form. The informed consent form must be signed and dated by the patient prior to undergoing any study-related 
procedures, including screening tests for acceptability appraisal. 
The Investigator will explain that patients have the full right to refuse to participate in the study or to withdraw 
their consent at any time, without any consequences for their further treatment and without explaining the 
reasons. 
The consent should be signed by both the patient (or his legal representative) and the Investigator in duplicate. 
One copy is given to the patient or his legal representative, and the other remains with the Investigator. 
The signed informed consent form must be stored in the clinical center and be available for inspection by the 
study monitor or by the auditors upon request. All information on the process of obtaining of the informed 
consent must be reflected in the primary documentation. 
Each patient will be informed that a study monitor, a quality assurance department auditor or a health inspector, 
in accordance with applicable regulatory requirements, can review his/her personal data, including the study-
related ones. 


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13. 
DATA MANAGEMENT AND RECORDKEEPING 
13.1. 
Clinical Study Documents 
The sponsor company submits the following basic documents and materials to the clinical center: 
 Study protocol (and amendments thereto, if any); 
 Investigator’s Brochure; 
 CRF; 
 Information for patients with the informed consent form; 
 Scales, questionnaires, enquirers (if any); 
 Investigator File (Study Documentation Log); 
 The study drug; 
 Agreement; 
 Approval of regulatory bodies and the Ethics Committee; 
 Documents required for submission to the local ethics committee. 
The Investigator provides the Sponsor with the following basic documents before the study begins:  
 Referral letter to the local ethics committee; 
 Signed confidentiality agreement; 
 Signed investigator agreement with the terms of the protocol; 
 Protocol approval by the local ethics committee members; 
 List of the local ethics committee members; 
 Recently compiled scientific Curriculum Vitae of all investigators and co-investigators (signed and dated); 
 Laboratory norms with the signature and date of the designated employee from the laboratory (using a local 
laboratory); 
 Medical/laboratory equipment certificates (at the request of the Sponsor). 
The Investigator must store the documentation related to the clinical study (primary documentation, copies of 
CRFs and the Investigator File) for 15 years after the end of the study. 
13.2. 
Presentation (Delivery) of Study Documents and Materials 
The Sponsor should provide the Investigator with the investigational product, the Clinical Study Protocol, the 
Investigator's Brochure, the CRFs and other documents, materials and equipment (where applicable) required for 
the study. 
The Investigator must provide the Sponsor with a signed clinical study agreement, a signed confidentiality and 
non-disclosure agreement, a copy of the local EC approval, a list of LEC members, signed and currently dated 
Curriculum Vitae of the principal investigator and research team, and other documents (where applicable). 
All deliveries to the center and withdrawal of study materials from the center will be documented using the 
Study Material Transfer/Return Forms. 
13.3. 
Primary Documentation 
The presence of primary documentation in the clinical center is necessary to confirm the existence of subjects 
and to confirm the truth of the information collected. Primary documentation includes original documents that 
are relevant to the study, treatment, anamnesis and description of the patient’s condition. For example, such 
documents include the past medical history and extracts (printouts) with laboratory study results. 
The primary medical documentation should include the following information:  
 
Demographic data; 
 
Information on inclusion and exclusion criteria; 
 
Evidence of participation in the study, indicating the study number and the patient number; 
 
Date and time of all visits; 
 
Historical and physical examination data; 
 
Adverse events; 
 
Prior therapy and concomitant treatment; 
 
Examination results; 
 
Laboratory test results; 


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 
Information on the administration of the study drug.  
The reason for the premature dropout (when applicable).  
13.4. 
Data Collection: Case Report Forms (CRFs) 
All the data obtained, including the study results, will be recorded for each patient in the electronic CRF (eCRF). 
For patients prematurely withdrawn from the study for any reason, all necessary documentation should be filled 
out completely with the indication of a reason for the early withdrawal. 
The Principal Investigator or an authorized Co-investigator will fill in eCRFs for each patient enrolled and 
endorse them by their electronic signature.  
Case Report Forms are used to complete several task:  
 
provide for data collection in accordance with the Protocol; 
 
ensure the compliance with the requirements of the control and permission system authorities for 
information collecting; 
 
contribute toward efficient and complete data processing, analysis and reporting on results; 
 
contribute toward the exchange of safety data among the project team and other organization units. 
The data collected during the study at the clinical center should be complete and accurately represent what has 
happened to each subject.  
The monitor should verify the information recorded in eCRFs for compliance with the primary documentation, 
which will allow confirming the absence of discrepancies in various documents during data registration. If the 
monitor reveals inconsistencies, necessary changes will be made in the eCRF. If any discrepancies are revealed, 
the monitor should discuss this issue with the investigator to ensure timely introduction of appropriate alterations 
in the eCRF. 
The monitor must follow up the completeness and accuracy of the eCFR completion. The monitor does not have 
the right to alter the eCRF in his own hand. 
The Investigator or other person authorized to fill eCRFs out must fill in eCRFs with data during or immediately 
after each visit in accordance with the source documents. 
13.5. 
Data Processing and Introduction of Amendments to eCRFs 
Data processing will be coordinated by the Sponsor. All information for each patient that is registered in 
accordance with the protocol must be timely entered in CRFs, which design is developed in accordance with this 
protocol. 
In order to ensure the most efficient data collection and transmission, the investigator or the authorized clinical 
center employee should record the information in eCRFs as soon as possible immediately after the patient’s visit. 
The access to CRFs, all primary documentation should be available for verification by the monitor.  
The Sponsor or his representative will verify eCRFs during data processing. If any inconsistencies and/or errors 
that could affect the analysis and interpretation of results are found during data processing, data refinement 
requests will be sent to the clinical center (data discrepancy resolution forms). The investigator must reply to 
them in accordance with the established procedure. 
13.6. 
Confidentiality of Patient Data 
The personal medical information of the patient obtained during the study is considered confidential and can not 
be disclosed to third parties. This information can be communicated to the attending physician of the patient or 
other health care provider responsible for the health of the patient after the submission of the patient’s consent. 
An identification number will be assigned to each patient, this number will be used instead of the patient’s name 
to preserve patient confidentiality during the transfer of information about adverse events or other data related to 
the ongoing study. 
Complete identification information about each patient will be stored only by the investigator who must provide 
it at the request of the auditor, insurance company or competent authorities. This information should be stored 
taking into account its confidential nature. With that in mind, the Clinical Center will fill out and keep the 
Patient Identification Log, which contains information about the patient (name, date of birth, medical record 
number in the institution, etc.) and the randomization code assigned to it. The identification Log or its copy will 
not be transferred to the Sponsor/CRO and will be kept in the archive of the clinical center after the end of the 
study. This Log will ensure the identification of coded information about the study subject with his/her 
individual data and medical record. 


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All persons involved in the study process must ensure the maintenance of patient’s confidentiality, not allowing 
the use of any information that can identify the patient (for example, his name or address). 
13.7. 
Investigator File (Study Documentation Log) 
The Investigator must keep all records to ensure full documentation of the study progress, in accordance with 
Good Clinical Practice standards. The Investigator must store all necessary study documentation for 15 years, 
unless otherwise required by the Sponsor; the Investigator must take measures to prevent the accidental or 
premature destruction of this document. 
The Investigator must maintain a confidential patient identification code list, which provides a unique link 
between the primary records which indicate the name, and the anonymous data of CRFs for the Sponsor. The 
Investigator must arrange for the storage of this confidential code for at least 15 years after the study completion 
or termination. 
No study documents can be destroyed without a prior written agreement between the Sponsor and the 
Investigator. If the Investigator wishes to transfer the study documentation to another party, or to transport it to 
another location, the Sponsor must be notified of this. 
The Study Documentation Log includes the following documents that are mandatory for detailed examination:  
 
Investigator’s Brochure; 
 
Clinical Study Protocol; 
 
Information for the study subject and informed consent form; 
 
Clinical Study Reports; 
 
Case report form of the subject (CFR) 
 
Responsibility assignment matrix; 
 
Patient Identification Log; 
 
IMU log/IMU issue log; 
 
Screening and randomization log. 
13.8. 
Data Archiving 
Electronic copies of the CRFs and the primary documentation relevant to the study, the subject identification list 
and the informed consent form should be stored by the investigator for 15 years. In case of the Investigator’s 
moving, retirement or other changes related to the archiving of the documentation during the mentioned time (15 
years), the Sponsor should be notified of who will be responsible for storing the CRFs and other study 
documentation. An inventory of the stored data will be stored by the Investigator, a copy will be provided to the 
Sponsor. 
The Clinical Study Protocol and Protocol Amendments, all editions of the Investigator’s Brochure, the CRFs, 
copies of regulatory permits, all correspondence and reports relevant to the study, as well as other documents 
relevant to the study will be stored by the Sponsor or his authorized representative for 15 years. 
14. 
FINANCING AND INSURANCE 
The Sponsor will fund the study management and performance. 
The financial aspects of the study will be documented in the form of an agreement between the Sponsor and the 
clinical center. 
If the patient follows the investigator’s instructions and if a harm is inflicted on his/her health as a result of the 
drug administration or procedures performed in accordance with the study design, the Sponsor will pay for all 
medical treatment costs. No other compensation from the Sponsor is forthcoming, except for compensation for 
travel expenses of patients (if applicable). 
In accordance with Article 44 of the Federal Law “On Medicine Circulation” No. 61-FZ dd. 12.04.2010 prior to 
the beginning of the study, a procedure for the insurance of patient health and civil liability of persons 
conducting clinical studies should be carried out. If a harm associated with a clinical study is inflicted on patient 
health, the Insurance Company through which the Sponsor has concluded an insurance contract undertakes to 
reimburse all costs for the necessary medical examination and treatment that will be required as a direct result of 
the study drug and/or medical procedures performed in accordance with the Study protocol. 
The Sponsor of the clinical study is Hepatera LLC, Russia. The Sponsor takes over the responsibility for 
insuring each study subject in accordance with the requirements for conducting clinical studies in the Russian 
Federation. The Sponsor effected a life insurance policy for patients participating in the study of drugs intended 


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for medical use, in accordance with the current legislation of the Russian Federation, with an insurance 
company: IPJSC INGOSSTRAKH, Russia, 127994, Moscow, Lesnaya str., 41, Office of Claims Settlement and 
Property and Casualty Insurance. 
Tel./Fax: 8 (495) 641-41-01, 725-73-25, 234-36-00. 
All discussions (if any) will be subject to the terms of the local insurance policy signed by the Sponsor and the 
Insurance Company. 


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Date: September 28, 2017 
 
 
 
15. 
PUBLICATION AND STUDY RESULT USAGE 
Information regarding the study drug and/or the conditions for conducting this study or the study results, as well 
as unpublished scientific data on the investigational product, is considered confidential and is the property of the 
Sponsor. This information can only be transferred to the authorities that approve the study, or to those parties 
that participate in the study on a confidentiality basis. The investigator must use this information only for the 
purpose of carrying out this study, unless otherwise provided by a separate written permission of the Sponsor. 
The Investigator agrees that the Sponsor can use the information obtained during the clinical study for 
publication and, thus, make it available to other investigators or regulatory authorities. 
The results of this study can be published or presented at scientific conferences. Publication or presentation of 
the study results by the Investigator is possible only after obtaining approval from the Sponsor. In this case, the 
Investigator must provide the Sponsor with all scripts and abstracts of the planned publication for getting an 
approval prior to submission to the editorial board or scientific expert advice. This will allow the Sponsor to 
protect the information that is its property and to supplement the report with comments based on information that 
may not yet be available to the Investigator. 
In accordance with publishing practice standards, the Sponsor is usually in favor of the publication of 
multicenter study results from cover to cover, and not as data from individual clinical centers. Any publication of 
the study results in which the Sponsor’s expert took a part greater than just standard monitoring should be 
regarded as a co-publication of the Investigator and this person. 
Before presentation of the results (written or oral), the material of the clinical study should be submitted for 
consideration and approval by Hepatera LLC. The authorship of materials for an oral report or article should be 
established as agreed by the Sponsor and the Investigator. 
 
16. 
FINAL REPORT 
The final study report should be written after the database freeze and data has been statistically proceeded when 
the study is completed in accordance with the protocol. 
No matter whether the study has been completed as per protocol or terminated prematurely, the Sponsor will 
ensure that a clinical study report is compiled and submitted to regulatory authorities and the IEC in accordance 
with the ICH guidelines on “Structure and content of clinical study reports”. In some cases, abbreviated reports 
may be acceptable. 
The final report on the clinical study results should contain (but not be limited to) the following information: 
• 
Synopsis; 
• 
List of abbreviations; 
• 
Ethical aspects of the study management; 
• 
Investigators and the administrative structure of the study; 
• 
Introduction; 
• 
Objectives of the Study; 
• 
Plan and design of the study; 
• 
Names of medicinal products-objects of the study and names of manufacturers; 
• 
Numbers of a series of medicinal products-objects of the study, data on their shelf life; 
• 
Demographic and anthropometric patient data; 
• 
Patient screening; 
• 
Route of administration of the study drugs and their doses; 
• 
Patient randomization schedule; 
• 
Protocol amendments; 
• 
Efficacy and safety evaluation criteria; 
• 
Information on the safety and tolerability of the study drugs, adverse reactions/events, including AE lists 
for each patient; 
• 
Final estimates of the parameters analyzed in this test, both for the study drug and for the reference 


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product, including arithmetic means, standard deviations; 
• 
ANOVA results, the values of the corresponding coefficients of variation; 
• 
Evaluation criteria and results of statistical analysis of relevant parameters together with comparisons of 
the study drug with the reference product; 
• 
Data on patients who were discharged or were dropped out the study; 
• 
Data on protocol deviations and the original statistical plan; 
• 
Discussion and conclusions. 
The report should clearly state the conclusion about the efficacy and safety of investigational medicinal product. 
Conclusions and recommendations should be consistent with the results obtained.  
The final report should be sent to the Sponsor for approval. The final report, as well as other study documents, is 
confidential information that can not be disclosed by investigators without the relevant permission of the 
Sponsor. The report will be prepared in accordance with regulatory requirements. 
17. 
CONFIDENTIALITY 
The information contained in this document is the property of the Sponsor, and its transfer to the third parties is 
permitted with the written permission of the Sponsor only. Only the Investigator(s) and staff of the clinical 
center(s) participating in the study, members of the independent ethics committee(s) and employees of the health 
administrations authorized to monitor the study are entitled to familiarize with this information. The information 
on the study, in the amount necessary for making a decision to grant consent for participation, is given to 
patients whom the Investigator plans to enroll in the study. 
 
18. 
PROTOCOL AMENDMENTS AND/OR PROTOCOL REVIEW 
Any protocol amendment will be agreed to between the Investigator and the Sponsor before it is accepted valid. 
Any changes in the study that occurred after the protocol has been approved should be registered as additions or 
amendments to the protocol and/or an updated version of the protocol. Depending on the nature of the 
amendment, approval or notification of the Council on Ethics and regulatory authorities will be required. Ethical 
approval will be required for any protocol amendment that may affect the patient safety, the scope/design of the 
study, cause any increase in the dosage or duration of administration of the study drug, an increase in the number 
of patients treated, the addition of a new analysis/procedure or the exclusion of analysis designed to monitor 
safety. Amendments may go into effect only after being approved by the Sponsor, the Investigator and, if 
necessary, the Council on Ethics and regulatory authorities, unless there is an immediate threat to the life or 
health of patients enrolled in the clinical study, or when the protocol amendment(s) refer to administrative 
aspects or supply matters only. 


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Date: September 28, 2017 
 
 
 
19. 
REFERENCES 
1. 
Radjef, N., Gordien, E., Ivaniushina, V., Gault, E., Anaïs, P., Drugan, T., … De, P. (2004). Molecular 
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; 
2. 
Taylor, J. M. (2006). Hepatitis delta virus. Virology, 344(1), 71–76. doi:10.1016/j.virol.2005.09.033; 
3. 
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; 
4. 
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; 
5. 
Cole S., Gowans E., M. T. (1991). Direct evidence foe cytotoxicity accociated with expression of 
hepatitis delta virua antigen. Hepatology, 13(5), 845–51; 
6. 
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; 
7. 
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; 
8. 
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; 
9. 
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; 
10. 
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; 
11. 
Rizzetto, 
M. 
(2009). 
Hepatitis 
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doi:10.1016/j.jhep.2009.01.004; 
12. 
Wedemeyer, H., & Manns, M. P. (2010). Epidemiology, pathogenesis and management of hepatitis D: 
update 
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challenges 
ahead. 
Nature 
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Gastroenterology 
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Hepatology, 
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13. 
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; 
14. 
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; 
15. 
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; 
16. 
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; 
17. 
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; 
18. 
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; 
19. 
Niro, G. A., Smedile, A., Ippolito, A. M., Ciancio, A., Fontana, R., Olivero, A., … Andriulli, A. (2010). 
Outcome of chronic delta hepatitis in Italy: A long-term cohort study. Journal of Hepatology, 53, 834–840. 


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doi:10.1016/j.jhep.2010.06.008; 
20. 
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; 
21. 
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; 
22. 
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; 
23. 
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; 
24. 
 Heidrich, B., Yurdaydın, C., Kabaçam, G., Ratsch, B. a, Zachou, K., Bremer, B., … Wedemeyer, H. 
(2014). Late RNA HDV 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; 
25. 
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 
study. Journal of Gastrointestinal and Liver Diseases : JGLD, 20(4), 377–82. Retrieved from 
http://www.ncbi.nlm.nih.gov/pubmed/22187703; 
26. 
Yan, J., and Burgess, S.M. (2012) Using a yeast inverse one-hybrid system to identify functional binding 
sites of transcription factors https://zfin.org/cgi-bin/webdriver?MIval=aa-pubview2.apg&OID=ZDB-PUB-
111011-13 
27. 
Gripon P1, Cannie I, Urban S. (2005 Feb; 79 (3); 1613-22; Efficient inhibition of hepatitis B virus 
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Glebe D1, Urban S, Knoop EV, Cag N, Krass P, Grün S, Bulavaite A, Sasnauskas K, Gerlich WH., 
(2005 Jul;129(1):234-45) Mapping of the hepatitis B virus attachment site by use of infection-inhibiting preS1 
lipopeptides and tupaia hepatocytes. http://www.ncbi.nlm.nih.gov/pubmed/16012950/ 
29. 
Thomas C. Peterson, William M. Connolley, and John Fleck, 2008: The Myth of the 1970s Global 
Cooling Scientific Consensus. Bull. Amer. Meteor. Soc., 89, 1325–1337. Volz et al 2012. The Myth of the 1970s 
Global Cooling Scientific Consensus http://journals.ametsoc.org/doi/abs/10.1175/2008BAMS2370.1 
30. 
Dose Finding in Drug Development. Naitee Ting (Editor). - Springer-Verlag New York. – 2006; 
31. 
S.C. Chow, J. Shao, H.Wang. Sample Size Calculations in Clinical Research. — London: 
Taylor&Francis, 2003; 
32. 
Recommendations for Diagnosis and Treatment of Adult Patients with Hepatitis B. - Moscow, 2014; 
33. 
EASL Clinical Practice Guidelines: Management of chronic hepatitis В virus infection. - Journal of 
Hepatology, vol. 57; 167–185 – 2012. 
34. 
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 study. 
Journal 
of 
Gastrointestinal 
and 
Liver 
Diseases : 
JGLD, 
20(4), 
377–82. 
Retrieved 
from 
http://www.ncbi.nlm.nih.gov/pubmed/22187703. 
35. 
Heidrich, B., Yurdaydın, C., Kabaçam, G., Ratsch, B. a, Zachou, K., Bremer, B., Wedemeyer, H. (2014). 
Late RNA HDV 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. 
36. 
In vitro Inhibition of HBV and HDV Infection by Myrcludex B in HepaRG cells. OMZ Study Report 
No. 201. Code number: OMZ 201. – University Hospital Heidelberg, 2010. 


 
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Statistical Analysis Plan 
Study information 
Sponsor study code: 
MYR 202 
Study title: 
Multicenter, open-label, randomized clinical study to assess efficacy and safety of three 
doses of Myrcludex B for the treatment of patients with chronic hepatitis B with delta 
agent for 24 weeks in combination with Tenofovir to suppress hepatitis B virus replication 
vs. the administration of Tenofovir to suppress hepatitis B virus replication 
Protocol version and date: 
Version 3.0 (2017-12-25; Germany) 
Version 7.0 (2017-09-28) 
PCG study ID: 
MYR002 
 
 


 
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Document control 
Document Name 
Statistical Analysis Plan 
Version 
2.0 
Status 
final 
Author 
Fredrik Thunarf 
PCG Clinical Services AB 
Kungsängsvägen 19 
SE-753 23 Uppsala, Sweden 
e-mail: Fredrik.Thunarf@pcg-clinical.com 
phone: +46 18 430 31 00 
mobile: +46 73 502 77 64 
Document history 
Version 
Modified by (name and role) 
Date 
Description of Changes 
1.0 
Fredrik Thunarf 
2018-10-24 Initial version 
2.0 
Fredrik Thunarf 
2018-11-13 Final version. 
Updated after comments from the sponsor. 
 
 


 
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Table of contents 
1 
Abbreviations ............................................................................................................................................. 6 
2 
Introduction ................................................................................................................................................ 8 
3 
Study objectives .......................................................................................................................................... 8 
3.1 
Primary objective ............................................................................................................................................................ 8 
3.1.1 
Primary variables ........................................................................................................................................................................ 8 
3.2 
Secondary objectives ...................................................................................................................................................... 8 
3.2.1 
Secondary efficacy variables ....................................................................................................................................................... 8 
3.2.2 
Safety variables ........................................................................................................................................................................... 8 
3.2.3 
Pharmacokinetic variables .......................................................................................................................................................... 9 
4 
Study design ............................................................................................................................................. 10 
5 
Study population ...................................................................................................................................... 10 
5.1 
Sample size ................................................................................................................................................................... 11 
6 
Assessments ............................................................................................................................................. 11 
6.1 
Demographics and medical history assessments ......................................................................................................... 11 
6.2 
Efficacy assessments .................................................................................................................................................... 11 
6.2.1 
Histological findings .................................................................................................................................................................. 11 
6.3 
Pharmacokinetic assessments ...................................................................................................................................... 12 
6.3.1 
Main study ................................................................................................................................................................................ 12 
6.3.2 
Pharmacokinetic sub-study ....................................................................................................................................................... 12 
6.4 
Safety assessments ....................................................................................................................................................... 13 
6.4.1 
Adverse events .......................................................................................................................................................................... 13 
7 
Method of analysis ................................................................................................................................... 13 
7.1 
General ......................................................................................................................................................................... 13 
7.1.1 
Presentation of results .............................................................................................................................................................. 13 
7.1.2 
Baseline ..................................................................................................................................................................................... 14 
7.1.3 
Analysis relative day .................................................................................................................................................................. 14 
7.1.4 
Analysis visit .............................................................................................................................................................................. 14 
7.1.5 
Handling of missing data and non-quantifiable values .............................................................................................................. 14 
7.1.6 
Interim analyses ........................................................................................................................................................................ 15 
7.1.7 
Multiplicity ................................................................................................................................................................................ 15 
7.1.8 
Subgroups ................................................................................................................................................................................. 15 
7.2 
Analysis sets ................................................................................................................................................................. 16 
7.2.1 
Modified intention-to-treat analysis set ................................................................................................................................... 16 
7.2.2 
Per-protocol analysis set ........................................................................................................................................................... 16 
7.2.3 
Safety analysis set ..................................................................................................................................................................... 16 
7.2.4 
Pharmacokinetic analysis sets ................................................................................................................................................... 16 
7.3 
Disposition of subjects .................................................................................................................................................. 16 
7.4 
Protocol deviations ....................................................................................................................................................... 17 
7.5 
Demographics and baseline characteristics.................................................................................................................. 17 
7.6 
Medical history and concurrent diseases ..................................................................................................................... 17 


 
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7.7 
Prior and concomitant medication ............................................................................................................................... 18 
7.8 
Efficacy evaluation ........................................................................................................................................................ 18 
7.8.1 
Primary efficacy variable: HDV RNA response ........................................................................................................................... 19 
7.8.2 
Change from baseline in HDV RNA levels .................................................................................................................................. 19 
7.8.3 
Durability of HDV RNA response ............................................................................................................................................... 20 
7.8.4 
Combined response .................................................................................................................................................................. 20 
7.8.5 
Change from baseline in ALAT................................................................................................................................................... 20 
7.8.6 
Change in fibrosis marker ......................................................................................................................................................... 20 
7.8.7 
Change in hepatitis B surface antigen ....................................................................................................................................... 20 
7.8.8 
Change from baseline in HBV DNA ............................................................................................................................................ 21 
7.8.9 
Improvement of the histological findings.................................................................................................................................. 21 
7.8.10 
Other efficacy variables ............................................................................................................................................................ 22 
7.9 
Pharmacokinetic evaluation – main study .................................................................................................................... 22 
7.10 
Pharmacokinetic evaluation – sub-study ...................................................................................................................... 22 
7.10.1 
Plasma concentrations .............................................................................................................................................................. 22 
7.10.2 
Pharmacokinetic parameters .................................................................................................................................................... 23 
7.10.3 
Dose proportionality ................................................................................................................................................................. 23 
7.10.4 
Multiple dosing versus single dose............................................................................................................................................ 23 
7.10.5 
PK data for midazolam for investigation of the metabolic activity of CYP3A ............................................................................ 24 
7.11 
Safety evaluation .......................................................................................................................................................... 24 
7.11.1 
Extent of exposure .................................................................................................................................................................... 24 
7.11.2 
Adverse Events .......................................................................................................................................................................... 24 
7.11.3 
Laboratory ................................................................................................................................................................................. 25 
7.11.4 
Urine pregnancy test ................................................................................................................................................................. 25 
7.11.5 
Physical examination................................................................................................................................................................. 25 
7.11.6 
Vital signs .................................................................................................................................................................................. 26 
7.11.7 
Electrocardiogram ..................................................................................................................................................................... 26 
7.11.8 
Immunogenicity ........................................................................................................................................................................ 26 
7.12 
Other analyses .............................................................................................................................................................. 26 
7.13 
Changes to planned analysis ........................................................................................................................................ 26 
7.13.1 
HDV RNA levels ......................................................................................................................................................................... 26 
7.13.2 
Combined response .................................................................................................................................................................. 26 
7.13.3 
Development of antibodies to HBsAg ....................................................................................................................................... 26 
8 
Derived variables ...................................................................................................................................... 26 
8.1 
General ......................................................................................................................................................................... 26 
8.1.1 
Change from baseline ............................................................................................................................................................... 26 
8.1.2 
Durations .................................................................................................................................................................................. 26 
8.2 
Disposition of subjects .................................................................................................................................................. 26 
8.3 
Demographics and baseline characteristics.................................................................................................................. 27 
8.3.1 
Age ............................................................................................................................................................................................ 27 
8.3.2 
Body mass index ....................................................................................................................................................................... 27 
8.4 
Efficacy variables .......................................................................................................................................................... 27 
8.4.1 
HDV RNA response (primary efficacy variable) ......................................................................................................................... 27 


 
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8.4.2 
Durability of HDV RNA response ............................................................................................................................................... 27 
8.4.3 
Combined response .................................................................................................................................................................. 27 
8.4.4 
Histological findings .................................................................................................................................................................. 27 
8.5 
Safety variables ............................................................................................................................................................ 27 
8.5.1 
Exposure ................................................................................................................................................................................... 27 
8.5.2 
Physical examination................................................................................................................................................................. 28 
8.5.3 
Immunogenicity ........................................................................................................................................................................ 28 
8.6 
Pharmacokinetic variables ............................................................................................................................................ 28 
8.6.1 
Accumulation ratio .................................................................................................................................................................... 28 
8.6.2 
AUC ratio ................................................................................................................................................................................... 28 
8.6.3 
Dose-normalisation ................................................................................................................................................................... 28 
9 
References ................................................................................................................................................ 28 
10 
Signoff....................................................................................................................................................... 29 
Appendix A: Schedule of assessments ................................................................................................................. 30 
 
 


 
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1 
Abbreviations 
Abbreviation 
Explanation 
1-OHMDL 
1-hydroxymidazolam 
ALAT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
ASAT 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical [classification system] 
AUC 
Area under the curve 
BLQ 
Below the limit of quantification 
BMI 
Body mass index 
cccDNA 
Cyclic covalently closed deoxyribonucleic acid 
CHD 
Chronic hepatitis D 
CI 
Confidence interval 
CV% 
Coefficient of variation, expressed as a percentage 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
FU 
Follow-up 
GGT 
Gamma glutamyl transferase 
HAI 
Histological activity index 
HBeAg 
Hepatitis B envelope antigen 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HDV 
Hepatitis delta (D) virus 
ICH 
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use 
LLOQ 
Lower limit of quantification 
LS 
Least squares 
MDZ 
Midazolam 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intention-to-treat analysis set 
MMRM 
Mixed-effects model for repeated measures 
MXB 
Myrcludex B 
NOA 
Not analysed 
NOP 
No peak detectable 
NOR 
No valid result 
NOS 
No sample 
NTCP 
Sodium-taurocholate co-transporting polypeptide 


 
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PK 
Pharmacokinetic 
PPAS 
Per-protocol analysis set 
RNA 
Ribonucleic acid 
SAP 
Statistical analysis plan 
ULOQ 
Upper limit of quantification 
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 in-
cludes 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. 
This SAP is mainly based on the German protocol version 3.0 (2017-12-25), and partly on the Russian 
protocol version 7.0 (2017-09-28). 
If the SAP suggests changes to the principal features stated in the protocol, these should also be docu-
mented in a protocol amendment. Otherwise, it will suffice to record the changes in the SAP. 
3 
Study objectives 
3.1 Primary objective 
The primary objective is to investigate the efficacy of Myrcludex B (MXB) and to compare three doses 
of MXB versus observation on background therapy with tenofovir in hepatitis delta patients. 
3.1.1 Primary variables 
The primary efficacy variable is hepatitis delta (D) virus (HDV) RNA response, defined as HDV RNA nega-
tivation or a decrease in HDV NRA by at least 2 log10 from baseline to Week 24. 
3.2 Secondary objectives 
The secondary objective is to investigate further efficacy parameters as well as safety and tolerability, 
as well as to assess pharmacokinetics (PK) and immunogenicity, of three doses of MXB in hepatitis delta 
patients. 
3.2.1 Secondary efficacy variables 
The secondary efficacy variables are: 
• Change from baseline in HDV RNA levels at Week 24 and Week 48. 
• Durability of HDV RNA response to 24 weeks post treatment (from Week 24 to Week 48). 
• Combined response: HDV RNA response and normal alanine aminotransferase (ALAT), at Week 
24 and Week 48. 
• Change from baseline in ALAT at Week 24 and Week 48. 
• Lack of fibrosis progression based on transient elastometry (Fibroscan) at Week 24 compared 
to baseline. [German protocol] 
• Changes (absence of increase) in fibrosis marker: serum alpha-2-macroglobulin at Week 24 and 
Week 48 compared to baseline. 
• Changes in hepatitis B surface antigen (HBsAg) (decreased level, disappearance of HBsAg, 
antibodies to HBsAg) at Week 24 and Week 48 compared to baseline. 
• Change from baseline in hepatitis B virus (HBV) DNA levels at Week 24 and Week 48. 
• Improvement of the histological findings (reduction of necroinflammation, absence of fibrosis 
progression, etc.) according to the liver biopsy study results or the absence of a fibrosis prog-
ression according to the findings of transient elastometry (Fibroscan) at Week 24 compared to 
baseline. [Russian protocol] 
3.2.2 Safety variables 
The safety variables are: 


 
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• Adverse events. 
• Physical examination. 
• Vital signs. 
• 12-lead electrocardiogram (ECG). 
• Laboratory parameters (haematology, coagulation panel, blood chemistry, urinalysis, blood bile 
acid levels). 
• Development of anti-Myrcludex B antibodies. 
3.2.3 Pharmacokinetic variables 
Plasma concentrations (main study): 
• Myrcludex B 
Plasma concentrations (PK sub-study): 
• Myrcludex B 
• Midazolam and its main metabolite, 1-hydroxymidazolam (1-OHMDL). 
PK parameters for Myrcludex B (PK sub-study): 
• 𝐶av: average concentration during dosing interval 𝜏= 24ℎ (for subperiod II). 
• 𝐶min: minimum concentration during dosing interval 𝜏= 24ℎ. 
• 𝐶max: maximum concentration during dosing interval 𝜏= 24ℎ. 
• 𝑇max: time to reach maximum concentration. 
• PTF: peak to trough fluctuation within a dosing interval (for subperiod II). 
• PTS: peak to trough swing – the degree of fluctuation over a dosing interval (for subperiod II). 
• 𝜆𝑧 (𝑘𝑒𝑙): terminal elimination rate constant. 
• 𝑇1 2
⁄ : terminal elimination half-life. 
• 𝐶𝐿𝐹
⁄ : total body clearance 
• 𝑉𝑧𝐹
⁄ : apparent volume of distribution based on terminal phase. 
• 𝐴𝑈𝐶0–24: area under the plasma concentration curve from drug administration (time zero) to 
the end of dosing interval 𝜏= 24ℎ (for subperiod II). 
• 𝐴𝑈𝐶0–𝑡: area under the plasma concentration curve from drug administration to the last mea-
surable concentration 
• 𝐴𝑈𝐶0–∞: area under the plasma concentration curve from drug administration to infinity. 
PK parameters for midazolam (MDZ) and 1-OHMDL (PK sub-study): 
• 𝐴𝑈𝐶0–𝑡: area under the plasma concentration curve from drug administration to the last mea-
surable concentration 
• 𝐴𝑈𝐶0–∞: area under the plasma concentration curve from drug administration to infinity. 
• 𝐶max: maximum concentration during dosing interval 𝜏= 24ℎ. 
• 𝑇max: time to reach maximum concentration. 
• 𝜆𝑧 (𝑘𝑒𝑙): terminal elimination rate constant. 
• 𝑇1 2
⁄ : terminal elimination half-life. 
• CL: total body clearance. 
• 𝑉𝑠𝑠: volume of distribution at steady-state. 
• The 𝐴𝑈𝐶0–∞ ratio of 1-hydroxymidazolam/midazolam. 


 
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4 
Study design 
This is a randomised, open-label, multicentre phase II clinical study. 
The main part of the study includes: 
• Screening period of 28 days (visit 01). 
• Tenofovir pre-treatment period, for subjects requiring preliminary therapy with tenofovir for up 
to 12 weeks (84 days), starting from the moment that screening results allowing assessment of 
inclusion and exclusion criteria become available. This period includes the following visits: 
o visit 02 (site visit) – start of tenofovir treatment 84 days before planned randomisation visit 
o visit 03 (telephone contact) – telephone call to the subject 28 days before planned randomi-
sation visit 
o visit 04 (site visit) – up to 14 days before the planned randomisation visit. 
• Randomisation visit (visit 1, day 1). 
• Treatment period of up to 24 weeks (visits 2–9 at weeks 1, 2, 4, 8, 12, 16, 20 and 24 after the 
randomisation visit). 
• Follow-up (FU) period of 24 weeks for all treatment arms (visits FU1–FU5 at weeks 25, 26, 28, 
36 and 48 after the randomisation visit). 
Pre-treatment is required for subjects who have not received nucleotide/nucleoside analogues for at 
least 12 weeks prior to enrolment. 
At the randomisation visit, subjects will be randomly assigned to one of the four treatment arms: 
A. Myrcludex B 2 mg/day subcutaneously and tenofovir for 24 weeks + follow-up period of 24-
weeks of continued tenofovir therapy. 
B. Myrcludex B 5 mg/day subcutaneously and tenofovir for 24 weeks + follow-up period of 24-
weeks of continued tenofovir therapy. 
C. Myrcludex B 10 mg/day subcutaneously and tenofovir for 24 weeks + follow-up period of 24-
weeks of continued tenofovir therapy. 
D. Tenofovir treatment for 48 weeks. 
The randomisation will be stratified by presence of cirrhosis, and allocation will be done according to a 
ratio of 1:1:1:1. 
A sub-study on pharmacokinetics will be performed, including 30 subjects from the 3 MXB treatment 
arms (10 subjects per arm). In this sub-study. In addition to evaluation of the pharmacokinetic profile 
for Myrcludex B, PK data for midazolam, a benzodiazepine derivative, and its main metabolite will be 
used to investigate the metabolic activity of cytochrome P450 (CYP3A). 
5 
Study population 
The study population consists of male and female subjects aged 18–65 years old with chronic HDV in-
fection and positive HDV RNA results at screening, who failed previous interferon therapy or for whom, 
in the opinion of the investigator, such therapy is contraindicated (including history of interferon intole-
rance), as well as cirrhotic subjects. Only subjects who sign the informed consent form and who meet 
all eligibility criteria will be enrolled into the study. 
Up to 200 subjects will be screened for inclusion into the study, and 120 subjects (up to 30 of which in 
Germany) will be randomised. 


 
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5.1 Sample size 
The previous phase Ib/IIa clinical study in subjects with chronic hepatitis D (CHD) showed efficacy in the 
monotherapy group in 57 % of subjects after 24 treatment weeks, with a lower limit of the confidence 
interval (CI) of approximately 37 %. 
It is believed that spontaneous decrease in the HDV RNA level by 2 log10 occurs in no more than 3 % of 
cases (in the absence of treatment and with nucleoside/nucleotide analogue therapy approved for 
hepatitis B in subjects with CHD, no response was observed; e.g. study HIDIT-1 in 90 subjects with CHD 
showed no effect on HDV RNA with monotherapy with adefovir, a nucleotide analogue). 
Using a two-sided test with a power of 80 %, a significance level of 𝛼= 0.05 3
⁄
≈0.0167 (using Bon-
ferroni correction to adjust for multiple testing; the 3 active treatment groups will be tested separately 
against the control group), and a superiority limit (test margin) of 5 %, a sample size of 28 subjects per 
group will be sufficient to detect a 34 % increase in response compared to the control group, assuming 
a response rate of 3 % for the control group. 
The sample size for each treatment arm was calculated according to the following formula: 
𝑛=
(𝑧1−𝛼+ 𝑧1−𝛽)
2
(𝑝1 −𝑝0 −𝛿)2 (𝑝1(1 −𝑝1) + 𝑝0(1 −𝑝0)), 
where 𝑧𝑥 is the value of the normal distribution quantile function, 𝛼 is the type I error, 𝛽 is the type II 
error (1 −𝛽 is the power), 𝑝1 and 𝑝0 are the response rates in the test group and the control group, 
respectively, and 𝛿 is the superiority limit (clinically significant difference in proportions). 
Assuming a drop-out rate of 5 %, a total number of 30 subjects per treatment arm will be needed. 
6 
Assessments 
This section gives a brief summary of a selection of the assessments in the study; see the study protocol 
for more details on all assessments. 
A schedule of assessments for the study is presented in Appendix A: Schedule of assessments. 
6.1 Demographics and medical history assessments 
Date of birth 
6.2 Efficacy assessments 
6.2.1 Histological findings 
The histological activity index (HAI), also known as the Knodell score, is an additive score calculated as 
the sum of the semi-quantitative scores for four individual features: periportal and/or bridging necrosis, 
hepatocyte degeneration and/or focal necrosis, portal inflammation, and fibrosis. In clinical trials, the 
first three categories are often totalled to give a necro-inflammatory score (0–18), while the fibrosis 
score (0–4) is reported separately. 
The Knodell fibrosis score stages fibrosis in a 5-tier system (with stage 2 eliminated to overstate the 
difference between mild and severe disease): 
0. No fibrosis 
1. Fibrous portal expansion 
3. Bridging fibrosis 


 
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4. Cirrhosis. 
The Ishak fibrosis score is part of the Ishak score, a modified form of the HAI, and has 7 stages: 
0. No fibrosis 
1. Fibrous expansion of some portal areas, with or without short fibrous septa 
2. Fibrous expansion of most portal areas, with or without short fibrous septa 
3. Fibrous expansion of most portal areas with occasional portal to portal bridging 
4. Fibrous expansion of portal areas with marked bridging (portal to portal as well as portal to 
central) 
5. Marked bridging (portal–portal and/or portal–central) with occasional nodules (incomplete 
cirrhosis) 
6. Cirrhosis, probable or definite 
The METAVIR scoring system is used to assess the extent of inflammation and fibrosis by histopatho-
logical evaluation in a liver biopsy. It comprises two scores, the fibrosis stage representing the amount 
of fibrosis or scarring, and the activity grade indicating the degree of inflammation. 
Fibrosis stage: 
F0: No fibrosis 
F1: Portal fibrosis without septa 
F2: Portal fibrosis with few septa 
F3: Numerous septa without cirrhosis 
F4: Cirrhosis 
Activity grade: 
A0: No activity 
A1: Mild activity 
A2: Moderate activity 
A3: Severe activity 
6.3 Pharmacokinetic assessments 
6.3.1 Main study 
In the main study, blood samples for PK analysis are collected at the randomisation visit and then every 
4th week during the treatment period, at 1 hour ± 15 minutes after administration of Myrcludex B. 
6.3.2 Pharmacokinetic sub-study 
The PK sub-study comprises two subperiods during the treatment period: subperiod I (Day 1–2), and 
subperiod II (Day 14–15). For the PK evaluation for MDZ, samples will also be collected during the pre-
treatment period (at Day -13 – -12) 
Midazolam will be administered before Myrcludex B, and PK blood sampling (except pre-dose) will be 
done after MXB dosing. 
PK samples are collected pre-dose and at 5, 15 and 30 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6, 10, 14 and 24 
hours after dosing, with allowed windows of ±5 minutes up to 6h and ±15 minutes thereafter for the 
MXB samples, and allowed windows of ±1 minute up to 1h, ±2 minutes up to 3h and ±3 minutes there-
after for the MDZ samples. Blood samples should be drawn at the same time in each period. 
In the pre-treatment period, the planned sampling times are the same as in the subperiods, but in rela-
tion to the administration of MDZ (since MXB is not administered during the pre-treatment period). 


 
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6.4 Safety assessments 
6.4.1 Adverse events 
In this study, adverse events will be recorded from the first dose of the study medication to the last visit 
of the follow-up period. All adverse medical events present before the first administration of the study 
medication (including the screening period) will be reported as part of subject’s medical history. 
Already present diseases and symptoms will be considered as adverse events only if their severity or 
rate worsens, or they change in nature. The responsible investigator will document such changes as 
adverse events. 
7 
Method of analysis 
7.1 General 
All statistical analyses will be performed in accordance with the ICH E9 guideline for Statistical Principles 
for Clinical Trials (1), using SAS® (Version 9.4 or higher, SAS Institute Inc., Cary, NC, USA). 
7.1.1 Presentation of results 
All results will be presented by treatment group, in total across all three MXB groups (regardless of 
dose), and in total (all 4 groups), unless stated otherwise. 
Continuous data will be summarised using descriptive statistics, and the following parameters will be 
reported: 
• number of subjects with evaluable observations and missing observations, respectively 
• arithmetic mean and standard deviation 
• confidence interval for the mean 
• median 
• first and third quartiles 
• minimum and maximum. 
Categorical data will be presented using absolute frequency and percentage and Clopper–Pearson exact 
confidence intervals for binomial proportions. 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 vari-
ables with missing values, the number and percentage of subjects with missing values will be presented. 
Significance tests will be two-sided and performed at the 5 % significance level, unless stated otherwise. 
When reporting the results of significance tests, p-values will be presented. 
All confidence intervals presented will be two-sided with a nominal confidence level of 95 %, unless 
stated otherwise. 
Data will be presented using an appropriate number of decimal places, to ensure that undue precision 
is not implied (e.g. the number of decimals should not exceed the accuracy of the measuring instru-
ment). 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 


 
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proportions will be presented with one decimal. Odds ratios and hazard ratios will be presented with 3 
decimals, and small and large values will be presented as ‘<0.001’ and ‘>999.999’ respectively. 
Confidence interval bounds will be presented with the same number of decimals as the corresponding 
point estimate, and p-values will be presented with 4 decimals or as ‘<.0001’. 
Mock tables and graphs are presented in the Data Display Plan (DDP), which is a supplementary docu-
ment to this analysis plan. Individual subject data listings will be presented according to the ICH E3 
guideline for Structure and Content of Clinical Study Reports (2), unless stated otherwise. 
7.1.2 Baseline 
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 ran-
domisation 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 variable 
into temporal or conceptual groups used for analyses. 
The study 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 ana-
lysis 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 and non-quantifiable values 
In general, no imputations of missing data will be performed, and the analyses will be performed on 
the observed cases, unless stated otherwise. In analyses using a mixed-effects model for repeated mea-
sures (MMRM), missing values are handled by means of built-in maximum-likelihood based methods in 
the SAS procedure used for the analysis, under the 'missing at random' assumption. 
For all response parameters, the missing equals failure (MEF) approach will be used for the main ana-
lysis (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. 
7.1.5.1 
Virology 
For the virology results, the following rules will be applied: 
• Values below the limit of detection will be collected in the database 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. 


 
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7.1.5.2 
Pharmacokinetics 
Concentration data identified with 'NOS' (no sample), 'NOR' (no valid result), 'NOA (not analysed), or 
'NOP' (no peak detectable) will be ignored and not replaced by zero at any time point. 
For descriptive statistics, values reported as below the limit of quantification (BLQ) will be imputed as 
half the LLOQ value. The lower limit of quantification is 1 ng/mL for Myrcludex B, 0.093 pg/mL for mida-
zolam, and 0.255 pg/mL for the midazolam metabolite (1-OHMDL). 
In the non-compartmental analysis, concentration data identified with 'NOS', 'NOR', 'NOA', and 'NOP' 
will not be considered. Pre-dose BLQ values and BLQ values in the lag phase (MXB, 1-OHMDL) will be 
set to LLOQ/2. The lag phase is defined as the period between time zero and the first time point with a 
concentration above the quantification limit. All other BLQ values of the profile will be ignored and set 
to missing. For 𝐴𝑈𝐶0–𝜏 estimation, all BLQ values in the terminal phase will be set to LLOQ/2. 
Every effort will be made to include all concentration data in the analysis. If not possible, a case to case 
decision is required whether the value should be excluded from the analysis. 
If a concentration value is excluded from all calculations, it will not be presented graphically or used for 
the calculation of descriptive statistics and parameter determination. However the excluded concen-
tration itself will be listed and associated with an appropriate flag. 
If the actual sampling time will not be recorded or will be missing for a certain time point, the planned 
time will be used for this time point instead. 
Pharmacokinetic parameters which cannot be determined will be identified by 'not calculated' (NC). 
7.1.5.3 
Safety laboratory test results 
For safety laboratory parameters, the following rules will be applied: 
• Values reported as '<x' (below the LLOQ), will be imputed as half the LLOQ value. 
• Values reported as '>x' (above the ULOQ), will be imputed as the ULOQ value. 
7.1.6 Interim analyses 
An interim safety analysis was performed when 10 subjects of each arm had completed 28 days of 
treatment. Based on the results of the analysis, it was decided that cirrhotic subjects could be included 
in the study. 
When all randomised subjects had completed the 24-week treatment period, an interim analysis on 
efficacy and safety of the study treatment was performed and documented in an interim study report. 
7.1.7 Multiplicity 
Correction for multiple testing will be done by sequential testing of hypotheses using the Bonferroni–
Holm method. This will be done for all hypothesis testing of efficacy variables, and adjusted p-values 
will be presented in addition to the raw unadjusted p-values. 
7.1.8 Subgroups 
The following subgroups will be defined: 
1. Subjects with cirrhosis at baseline. 
2. Subjects with no cirrhosis at baseline. 
3. Subjects with normal ALAT levels at baseline. 
4. Subjects with abnormal ALAT levels at baseline. 
5. Subjects who attended at least one follow-up visit. 


 
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6. Subjects who tested positive for hepatitis B envelope antigen (HBeAg) at screening. 
7.2 Analysis sets 
The decision on the classification of subjects to each analysis set will be taken at the clean file meeting 
and documented in the clean file report together with the reasons for excluding subjects from the ana-
lysis sets. 
7.2.1 Modified intention-to-treat analysis set 
The modified intention-to-treat (mITT) analysis set is defined as all randomised subjects who received 
at least one dose of the study treatment. 
Analysis on 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 mITT analysis set who 
completed the 24 week treatment period with efficacy results for Week 24 and for whom no major 
protocol deviations were reported. When determining if a subject has evaluable data for the primary 
efficacy variable, HDV RNA assessments from study weeks 24 to 26 (day 166–185, taking visit windows 
of ±2 and ±3 days, for visits 9 and FU2 respectively, into account) will be considered as valid. 
Exclusion of subjects from the per-protocol analysis set was decided upon at the data review meeting 
before the final analysis of the treatment period. In addition, subjects with violation of any inclusion 
and/or exclusion criterion will be excluded from the PPAS. Cases where subjects took regularly pre-
scribed tenofovir instead of study tenofovir during the study will not be considered as a reason for 
exclusion from the PPAS. All other reasons, which were used in the interim analysis, will still be used 
for exclusion from the PPAS in the final analysis. 
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 treatment. 
Analysis on the safety analysis set will be based on the actual treatment (‘as treated’). 
7.2.4 Pharmacokinetic analysis sets 
The pharmacokinetics concentration analysis set (PKCAS) is defined as the subset of all subjects in the 
safety analysis set who have at least one measured concentration. 
The pharmacokinetics analysis set (PKAS) is defined as the subset of all subjects in the PKCAS who are 
included in the PK sub-study and have at least 1 estimated PK parameter and no major protocol viola-
tions relevant to the evaluation of pharmacokinetics. 
Analysis on the PK analysis sets will be based on the actual treatment ('as treated'). 
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. 


 
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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 treatment. 
• Number and percentage of subjects who received at least one dose of study treatment. 
• Number and percentage of subjects who completed the treatment period. 
• 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. 
The tables on the disposition of subjects will be presented in total as well as per country and study site. 
7.4 Protocol deviations 
The number and percentage of randomised subjects with at least one protocol deviation, in total and 
per deviation category will be presented. 
7.5 Demographics and baseline characteristics 
The following parameters will be summarised descriptively on the safety analysis set: 
• Demographics: Age, age groups ('<65 years' and '≥65 years'), sex, and race. 
• 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): 
o Urine drug test (positive/negative): amphetamine, barbiturates, benzodiazepine, cannabin-
oids, cocaine, methadone, opiate, and tricyclic antidepressants. 
o HDV RNA (positive/negative) 
o Serology test: HBeAg and anti-HBeAg antibodies, HBsAg, hepatitis C virus (HCV) RNA and 
HCV antibodies, HDV antibodies, and human immunodeficiency virus (HIV) antibodies. 
o Creatinine clearance [mL/min]. 
o Serum alpha fetoprotein (AFP) test [IU/mL] 
o Abdominal ultrasound (normal/abnormal). 
o Substance abuse: Alcohol breath test (positive/negative), subject status (alcohol: drinker, 
ex-drinker, non-drinker; drugs: current user, ex-user, non-user; nicotine: current user, ex-
user, non-user). 
o sodium-taurocholate co-transporting polypeptide (NTCP) polymorphism. 
7.6 Medical history and concurrent diseases 
Medical history and concurrent diseases will be coded according to the Medical Dictionary for Regula-
tory Activities (MedDRA) and summarised by system organ class and preferred term, on the safety 
analysis set. 
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 con-
current diseases will be presented in separate tables, based on the safety analysis set. 


 
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Medical history is defined as events stopped prior to baseline. Concurrent diseases are defined as 
events reported as ongoing and events stopped at 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 event based on the reported and/or imputed start and end dates, the 
event 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 sum-
marised by therapeutic subgroup (ATC level 2) and preferred name, on the safety analysis set. 
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. Separate 
tables will be presented for prior medications, concomitant medications during the treatment period, 
and concomitant medications started during the follow-up period. 
Midazolam will be presented separately only (with no distinction between prior and concomitant use). 
If a reported medication cannot be coded, it will be presented as 'non-appropriated'. 
Prior medication is defined as medication stopped prior to baseline. Concomitant medication during 
the treatment period is defined as ongoing medication or medication stopped on or after baseline, with 
a start date before the end of the treatment period. 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, 
the medication will be considered as concomitant during the treatment period. In data listings, the 
reported dates will be presented. 
7.8 Efficacy evaluation 
All analyses of efficacy variables will be performed on both the mITT analysis set (main analysis) and 
the per-protocol analysis set (supportive analysis). 
In addition to the statistical hypothesis testing described in the subsections below, all efficacy variables 
will be summarised descriptively, on both the mITT analysis set and the per-protocol analysis set. For 
continuous variables, both the actual values at each visit as well as the change from baseline will be 
summarised. All descriptive presentations of efficacy data will be done for all subjects as well as for the 
subgroups based on presence of cirrhosis at baseline. 
Whereas the hypothesis testing will be performed only for the timepoints specified in section 3, descrip-
tive presentations will be based on data from all analysis visits at which the variable can be evaluated. 
Assumptions for statistical models will be evaluated using graphical methods. 


 
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7.8.1 Primary efficacy variable: HDV RNA response 
For each of the three MXB treatment groups (arms A–C), a null hypothesis of no clinically significant 
difference in proportion of responders compared to the control group (tenofovir only; arm D), at Week 
24, will be tested using the one-sided Wald test for superiority, at a one-sided overall significance level 
of 0.05 adjusted for multiple testing according to Bonferroni–Holm, with the superiority limit (test 
margin) set to 5%: 
𝐻0: 𝑝𝐴−𝑝𝐷≤𝛿,
𝐻𝐴: 𝑝𝐴−𝑝𝐷> 𝛿
𝐻0: 𝑝𝐵−𝑝𝐷≤𝛿,
𝐻𝐴: 𝑝𝐵−𝑝𝐷> 𝛿
𝐻0: 𝑝𝐶−𝑝𝐷≤𝛿,
𝐻𝐴: 𝑝𝐶−𝑝𝐷> 𝛿
 
where 𝑝𝑋 is the proportion of responders in treatment group X, and 𝛿 is the superiority limit. 
As supportive analysis, Fisher's exact test will be used to test a null hypothesis of no difference in pro-
portions against a two-sided alternative hypothesis. Separate tests will be performed for each of the 
three MXB treatment groups against the control group, at Week 24. 
For each of the three MXB treatment groups, the difference in proportions of responders compared to 
the control group will be presented together with the corresponding confidence interval. 
7.8.2 Change from baseline in HDV RNA levels 
A null hypothesis of no difference between the MDX treatment groups and the control group in the 
change from baseline in HDV RNA levels will be tested against a two-sided alternative hypothesis using 
a mixed-effects model for repeated measures. Assessments from all post-baseline analysis visits up to 
Week 48 will be considered for the dependent variable, and tests will be performed at Weeks 24 and 
Week 48. The model will include baseline HDV RNA as a fixed covariate; treatment group, analysis visit, 
the interaction between treatment group and analysis visit, and presence of cirrhosis (the stratification 
factor) will be included as fixed factors. An appropriate covariance structure will be selected 
(unstructured, Toeplitz, auto-regressive and compound symmetry structures will be considered, and 
the selection will be based on the Akaike information criterion, AIC), and the Kenward–Rogers approxi-
mation will be used to estimate the denominator degrees-of-freedom and adjust standard errors. 
Adjusted least square (LS) means and corresponding 95 % confidence intervals for the change from 
baseline for each of the treatment groups and the pairwise differences between the MXB treatment 
groups and the control group (on the log-10 scale, as well as anti-log transformed into geometric means 
and geometric mean ratios) will be presented together with the p-values corresponding to the tests of 
difference. 
If the assumptions for the MMRM are not-fulfilled, a non-parametric analysis will be performed instead, 
using two-sided van Elteren tests (stratified Wilcoxon rank sum tests) adjusted for the stratification 
factor. Separate pairwise comparisons of the MDX treatment groups against the control group will be 
made at each of Week 24 and Week 48. The p-values from the tests will be presented. 
All analyses on HDV RNA levels will be based on log-10 transformed data. Descriptive statistics will be 
presented for non-transformed data as well. Descriptive statistics for the follow-up visits will include 
the change from Week 24 as well. 
Data will also be presented graphically, in line charts displaying the mean log-transformed HDV RNA 
levels over time. 


 
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7.8.3 Durability of HDV RNA response 
Fisher's exact test will be used to test a null hypothesis of no difference in proportions of subjects with 
HDV RNA response at both Week 24 and Week 48 against a two-sided alternative hypothesis. Separate 
tests will be performed for each of the three MXB treatment groups against the control group. 
7.8.4 Combined response 
Fisher's exact test will be used to test a null hypothesis of no difference in proportions against a two-
sided alternative hypothesis. Separate tests will be performed for each of the three MXB treatment 
groups against the control group, at Week 24 and Week 48. 
This analysis, and presentation of descriptive statistics, will be repeated for the subgroups of subjects 
with normal/abnormal baseline ALAT values. 
7.8.5 Change from baseline in ALAT 
The change from baseline to Week 24 and Week 48 in ALAT levels will be analysed in the same way as 
the change from baseline in HDV RNA, using MMRM or van Elteren tests. 
Fisher's exact test will be used to test a null hypothesis of no difference in proportions (of subjects with 
normal ALAT values) against a two-sided alternative hypothesis. Separate tests will be performed for 
each of the three MXB treatment groups against the control group, at Week 24 and Week 48. 
The descriptive presentation will include summary statistics on the ALAT levels and change from base-
line, as well as change from Week 24, the number and percentage of subjects with normal ALAT levels, 
and shift tables on the shift from baseline, and the shift from Week 24 in normal/abnormal status of 
ALAT. 
Data will also be presented graphically, in line charts displaying the mean ALAT levels over time. 
7.8.6 Change in fibrosis marker 
The change from baseline to Week 24 and Week 48 in fibrosis marker (alpha-2-macroglobulin) will be 
analysed in the same way as the change from baseline in HDV RNA, using MMRM or van Elteren tests. 
Descriptive presentation will include summary statistics on percentage change from baseline as well. 
Data will also be presented graphically, in line charts displaying the mean alpha-2-macroglobulin levels 
over time. 
7.8.7 Change in hepatitis B surface antigen 
The change from baseline to Week 24 and Week 48 in HBsAg will be analysed in the same way as the 
change from baseline in HDV RNA, using MMRM or van Elteren tests. 
Fisher's exact test will be used to test a null hypothesis of no difference in proportions (of subjects with 
a decrease by at least 1 on the log-10 scale or disappearance [value is zero]) against a two-sided alterna-
tive hypothesis. Separate tests will be performed for each of the three MXB treatment groups against 
the control group, at Week 24 and Week 48. 
The number and percentage of subjects with a decrease by at least 1 on the log-10 scale or disappear-
ance will be presented. 
All analyses on HBsAg levels will be based on log-10 transformed data. Summary statistics will be pre-
sented for non-transformed data as well. 


 
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Data will also be presented graphically, in line charts displaying the mean log-transformed HBsAg levels 
over time. 
7.8.8 Change from baseline in HBV DNA 
The change from baseline to Week 24 and Week 48 in HBV DNA will be analysed in the same way as 
the change from baseline in HDV RNA, using MMRM or van Elteren tests. 
All analyses on HBV DNA levels will be based on log-10 transformed data. Descriptive statistics will be 
presented for non-transformed data as well. 
Data will also be presented graphically, in line charts displaying the mean log-transformed HBV DNA 
levels over time. 
7.8.9 Improvement of the histological findings 
Summary statistics on liver stiffness (as measured in kPa using transient elastometry) will be presented 
for baseline and Week 24, as well as for the change from baseline. In addition, the number and percent-
age of subjects with lack of progression in fibrosis (no increase in liver stiffness) and with progression 
will be presented, in total and by baseline value categories ('<12', '12–20', and '>20'). 
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 pre-
sented 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 expression level of HDV RNA 
o HBV RNA (S region) [copies/cell] 
o HBV RNA relative expression level (S region) 
o relative expression level of total HBV RNA (X region) 
o relative expression level of HBV pregenomic RNA 
o HBV DNA (S region) [copies/cell] 
o total HBV DNA (X region) [copies/cell] 
o HBV cccDNA [copies/cell] 
• 
Molecular analysis using immunofluorescence staining: 
o HDAg, % of positive hepatocytes 
• 
Gene expression: 
o relative expression level of NTCP 
o relative expression level of CYP7A1 
o relative expression level of CXCL10 
o relative expression level of ISG15 
The following parameters of molecular analysis and gene expression will be reported in listings only: 


 
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• 
Molecular analysis: DNA content [ng/µl], RNA content [ng/µl], HDV RNA [CT], HDV RNA [copies/cell], HBV 
RNA (S region) [CT], total HBV RNA (X region) [CT], total HBV RNA (X region) [copies/cell], HBV pre-
genomic RNA [CT], HBV pregenomic RNA [copies/cell], HBV DNA (S region) [copies], total HBV DNA (X 
region) [copies], beta globin [copies], cccDNA [copies], housekeeping gene GAPDH [CT]. 
• 
Gene expression: CXCL10 [CT], CYP7A1 [CT], GAPDH [CT], mean of GAPDH and RPL30 [CT], ISG15 [CT], 
NTCP [CT], rpl30 [CT]. 
7.8.10 Other efficacy variables 
HBV and HDV genotyping, and resistance testing data will be presented descriptively by visit. 
7.9 Pharmacokinetic evaluation – main study 
All analyses and summaries of PK data for the main study will be based on the PK concentrations ana-
lysis set. 
Summary statistics (including the geometric mean, and the arithmetic and geometric coefficients of 
variation [CV%]) on the Myrcludex B plasma concentrations will be presented by visit. Data will also be 
presented graphically, in line charts where the mean plasma concentration is plotted against time. 
Additionally, for each arm, the attainment of steady state will be analysed exploratorily using linear 
mixed effect models. The log-transformed concentration values will be used as dependent variable and 
the model will include subject as a random factor and week of dosing as a fixed categorical effect. The 
following contrasts will be tested sequentially: 
• Week 20 vs Week 24 
• Week 16 vs Week 24 
• Week 12 vs Week 24 
• Week 8 vs Week 24 
• Week 4 vs Week 24 
• Randomisation vs Week 24. 
Geometric mean ratios for each comparison against week 24 will be presented together with 90% confi-
dence intervals, as well as the p-value. 
All main study PK analyses and summaries will be based on the PK concentrations analysis set. 
7.10 Pharmacokinetic evaluation – sub-study 
In the PK sub-study, all analyses and summaries will be based on the PK concentrations analysis set 
(concentrations) or the PK analysis set (PK parameters). 
7.10.1 Plasma concentrations 
Summary statistics, including the geometric mean and arithmetic and geometric CV%, on plasma con-
centrations (MXB, MDZ, 1-OHMDL) will be presented by visit and timepoint. 
Plasma concentrations will be presented graphically against time in line charts, both individual curves 
for each subject and mean profiles for each treatment group. In the graphs for individual subjects, the 
actual sampling times will be used, whereas the mean profile graphs will be based on the planned 
sampling times. Mean profiles will be plotted using both linear and semi-logarithmic scales. 
Summaries of plasma concentrations will be based on the PK concentrations analysis set. 


 
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7.10.2 Pharmacokinetic parameters 
Summary statistics, including the arithmetic CV%, on PK parameters for MXB will be presented. For 
concentration and area under the curve parameters, the geometric mean and CV% will be presented 
as well. 
7.10.3 Dose proportionality 
Dose proportionality for MXB will be evaluated separately after single dose (subperiod I) and multiple 
dosing (subperiod II) for each arm. 
The proportionality relationship between AUC (𝐴𝑈𝐶0–24, 𝐴𝑈𝐶0–𝑡, and 𝐴𝑈𝐶0–∞) and 𝐶max parameters 
and daily dose is described as a power function 𝑦= 𝑎𝑥𝑏, where 𝑎 is a constant, 𝑥 is the daily dose, and 
𝑏 is a proportionality constant. The power model assumes a linear relationship between natural log-
transformed pharmacokinetic exposure parameter and natural log-transformed dose. The dose 
proportionality will be assessed from the 90 % confidence interval for the 𝑏, where 𝑏 equal to 1 indi-
cates the dose proportionality. The proportionality constant and its corresponding confidence interval 
will be compared with the modified acceptance range. 
According to the Smith criteria, dose proportionality is declared when the 90 % CI for 𝑏 lies completely 
within the critical region defined as 
(1 + 𝑙𝑛(𝜃𝐿)
𝑙𝑛(𝑅) ; 
1 + 𝑙𝑛(𝜃𝐻)
𝑙𝑛(𝑅) ), 
where 𝑅 is the ratio of the highest to lowest administered doses, and 𝜃𝐿= 0.8 and 𝜃𝐻= 1.25 are the 
lower and upper critical limits of the ratio of dose-normalised mean values for highest dose relative to 
lowest dose. 
If dose proportionality is not declared for any of the PK parameters based on the Smith criteria, the 
90 % CI for 𝑏 would be compared to a less stringent critical region based on 𝜃𝐿= 0.5 and 𝜃𝐻= 2.0 
(Hummel criteria). 
Additional analysis will be performed to test dose-normalised AUC parameters and 𝐶max using an ana-
lysis of variance (ANOVA) model on log-transformed exposure measures between arms. Point estimates 
and 90 % CI of geometric mean ratios between arms (anti-log transformed LS mean differences from 
the model) will be presented and judged by bioequivalence acceptance criteria of 80–125 %. Dose 
proportionality will be concluded if all 90 % CIs fall within 80–125 %. 
AUC parameters and 𝐶max will also be presented graphically in scatterplots, where the PK parameter 
value will be plotted against the daily dose. 
7.10.4 Multiple dosing versus single dose 
To determine whether multiple-dose pharmacokinetic behaviour of Myrcludex B (with concomitant 
MDZ administration) is predicted by single-dose pharmacokinetics, the 𝐴𝑈𝐶0–24 and 𝐶max accumulation 
ratios will be calculated (on the log-scale and back-transformed for reporting) and compared to 100 %. 
The geometric mean will be presented together with the corresponding 90 % CI. 
In addition, summary statistics on the changes from subperiod I to subperiod II in 𝑇max, 𝑇1 2
⁄ , CL/F, and 
𝑉𝑧𝐹
⁄  will be presented. Data will also be presented graphically, in scatterplots where the subperiod II 
values are plotted against subperiod I values. 


 
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7.10.5 PK data for midazolam for investigation of the metabolic activity of CYP3A 
The effect of Myrcludex B on the natural log-transformed 𝐶max, 𝐴𝑈𝐶0–∞, and 𝐴𝑈𝐶0–𝑡 of midazolam and 
its main metabolite (1-hydroxymidazolam) will be analysed by treatment arm using ANOVA models. 
Comparisons will be made for each of the two subperiods versus the pre-treatment period. 
Adjusted least square means and corresponding 95 % confidence intervals for the change from baseline 
for each of the treatment groups and the pairwise differences between the subperiods versus the pre-
treatment period will be anti-log transformed (into geometric means and geometric mean ratios) and 
presented together with the p-values corresponding to the tests of difference. 
In addition, summary statistics on the changes from the pre-treatment period in in 𝑇max, 𝑇1 2
⁄ , CL, 𝑉𝑠𝑠 
and the 𝐴𝑈𝐶0–∞ ratio of 1-hydroxymidazolam/midazolam will be presented. Data will also be presented 
graphically, in scatterplots by subperiod, where the subperiod values are plotted against pre-treatment 
values. 
7.11 Safety evaluation 
All evaluations of safety data will be performed on the safety analysis set. 
7.11.1 Extent of exposure 
Exposure to Myrcludex B will be presented for each of the three MXB treatment groups, separately and 
in total. Summary statistics on the treatment duration, cumulative dose, dose intensity and compliance 
will be presented, as well as the number and percentage of subjects with at least one injection inter-
ruption. 
Exposure to tenofovir will be presented for each of the treatment groups, and in total across the three 
MXB treatment groups. Summary statistics on the duration of exposure will be presented. 
7.11.2 Adverse Events 
Adverse events will be coded according to MedDRA. 
Only treatment-emergent adverse events will be summarised in tables. Pre-treatment serious adverse 
events will be presented in listings only. 
A treatment-emergent adverse event is defined as an event with a time of onset after administration 
of the first dose of study medication, and a pre-treatment event is defined as an event starting before 
the first dose. Events starting on the date of the first dose for which the onset time is not known will be 
considered as treatment-emergent (i.e., the time of onset will be imputed as 23:59). 
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, broken down by severity 
• Adverse events, broken down by causality assessment 
• Adverse events leading to withdrawal of the study treatment 
• Fatal adverse events 
The incidence of adverse 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 percent-
age of subjects with at least one adverse event within that system organ class or preferred term will be 
presented. Serious adverse events will be summarised in the same way. 


 
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In the same way, the incidence of adverse events broken down by causality assessment, adverse events 
broken down by severity, and related adverse events broken down by severity will be presented by 
system organ class and preferred term. Serious adverse events will be summarised in the same way. 
All presentations described above will be repeated for the following subsets of adverse events: 
• Adverse events started during the treatment period. 
• Adverse events started after the end of treatment period, for the subgroup of subjects who 
attended at least one follow-up visit. 
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. 
7.11.3 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, 
reported values 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: leukocytes [10^9/L] with absolute [10^9/L] and relative [%] differentials: basophils, 
eosinophils, lymphocytes, monocytes, neutrophils; erythrocytes [10^12/L], haematocrit [%], haemo-
globin [g/dL], platelets [10^9/L], reticulocytes [‰]; coagulation panel: prothrombin time [sec], activated 
partial thromboplastin time [sec]. 
• 
Blood chemistry: chloride [mmol/L], C-reactive protein [mg/L], albumin [g/L], alkaline phosphatase [U/L], 
alanine aminotransferase (ALAT) [U/L], aspartate aminotransferase (ASAT) [U/L], creatinine [umol/L], 
direct (unconjugated) bilirubin [umol/L], phosphate [mmol/L], gamma glutamyl transferase (GGT) [U/L], 
glucose [mmol/L], lipase [U/L], pancreatic amylase [U/L], potassium [mmol/L], sodium [mmol/L], total 
bilirubin [umol/L], total cholesterol [mmol/L], total protein [g/L], urea [mmol/L]. 
• 
Blood bile acids: total bile acids [umol/L]. 
Urinalysis data will be presented in listings only. 
7.11.4 Urine pregnancy test 
Urine pregnancy test results (positive/negative) will be presented by visit for female subjects of child-
bearing potential. The number and percentage of female subjects of childbearing potential will also be 
presented. 
7.11.5 Physical examination 
Physical examination data will be summarised by visit for each of the examined body systems (ab-
domen, general appearance, hair/eyes/ear/nose/throat, heart, lungs, lymph nodes, musculoskeletal, 
neurological, skin, thyroid, and vascular) as the number and percentage of subjects with normal/
abnormal findings. The shift from baseline will also be presented. 


 
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7.11.6 Vital signs 
Summary statistics on vital sign parameters (respiration rate, blood pressure, heart rate, and body tem-
perature), body weight and BMI will be presented by visit. For post-baseline visits, the change from 
baseline will also be summarised. 
7.11.7 Electrocardiogram 
A frequency table on the overall ECG evaluation (assessment of normality) will be presented by visit. 
For post-baseline visits, the shift from baseline will also be presented. 
7.11.8 Immunogenicity 
Summary statistics on the anti-MXB antibodies concentration values and change from baseline will be 
presented by visit for the three experimental treatment groups. The number and percentage of positive 
subjects will also be presented. 
7.12 Other analyses 
Frequency tables, including confidence intervals, on HBeAg laboratory results will be presented by visit, 
for the subgroup of subjects in the safety analysis set who were HBeAg-positive at screening. 
7.13 Changes to planned analysis 
7.13.1 HDV RNA levels 
Change from baseline in HDV RNA levels at Week 24 and Week 48 was added as a secondary efficacy 
endpoint. 
7.13.2 Combined response 
In addition to the analysis at Week 24, as stated in the protocol, it was decided to perform analysis of 
this secondary endpoint at Week 48 as well. 
7.13.3 Development of antibodies to HBsAg 
There were no subjects with HBsAg loss, and thus it will not be necessary to analyse anti-HBsAg. 
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 cor-
responding 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. 


 
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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. 
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) or a decrease by at least 
2 (i.e., change from baseline is less than or equal to -2) in log-10 transformed HDV RNA level. 
8.4.2 Durability of HDV RNA response 
Durability of HDV RNA response is defined as sustained meeting of the response criterion. A categorical 
variable indicating 'No response', 'Response at Week 24 only' or 'Response at weeks 24 and 48' will be 
derived. 
8.4.3 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 ALAT (i.e., ALAT value is within the normal range). 
8.4.4 Histological findings 
The change from baseline will be categorised as improvement (decrease of at least 1 point), no change 
or worsening (increase of at least 1 point) for each of the following parameters: HAI, Knodell fibrosis 
score, Ishak fibrosis score, METAVIR fibrosis stage and METAVIR activity grade. 
8.5 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. 


 
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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 an at least twofold increase 
in the concentration of antibodies compared to baseline (i.e., if the ratio to baseline was at least 2). 
8.6 Pharmacokinetic variables 
8.6.1 Accumulation ratio 
The AUC accumulation ratio will be computed as 𝐴𝑈𝐶0–24 value for subperiod II divided by the 𝐴𝑈𝐶0–24 
value for subperiod I. 
The 𝐶max accumulation ratio will be computed analogously. 
8.6.2 AUC ratio 
The 𝐴𝑈𝐶0–∞ ratio of 1-hydroxymidazolam/midazolam will be computed as the 𝐴𝑈𝐶0–∞ value for 
1-OHMDL divided by the 𝐴𝑈𝐶0–∞ value for MDZ. 
8.6.3 Dose-normalisation 
A dose-normalised parameter is defined as a parameter divided by the daily dose. 
9 
References 
1. ICH Harmonised Tripartite Guideline for Statistical Principles for Clinical Trials E9. February 1998. 
2. ICH Harmonised Tripartite Guideline for Structure and Content of Clinical Trial Reports E3. 
November 1995. 
3. Clinical Study Protocol MYR 202, country-specific version 3.0 (Germany), 2017-12-25.  
4. Clinical Study Protocol MYR 202, version 7.0, 2017-09-28.  
 
 


 
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10 Signoff 
We have read this SAP for the MYR 202 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 
PCG Clinical Services SAP Author: Fredrik Thunarf, Senior Biostatistician 
SIGNATURE AND DATE 


 
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Appendix A: Schedule of assessments 
Table 1. Schedule of assessments (excluding the pre-treatment period) 
 
Screen. 
Rand. 
Treatment period 
Follow-up period 
Visit  
01 
1 
2 
3 
4 
5 
6 
7 
8 
9 
FU1 
FU2 
FU3 
FU4 
FU5 
Week 
 
 
W1 
W2 
W4 
W8 
W12 
W16 
W20 
W24 
W25 
W26 
W28 
W36 
W48 
Study day1 
– -1 
1 
8 
15 
28 
56 
84 
112 
140 
168 
175 
182 
196 
252 
336 
Efficacy assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HDV RNA 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBsAg 
 
X 
 
 
Х 
Х 
X 
Х 
Х 
X 
 
 
Х 
X 
X 
HBV DNA 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
Serum marker for fibrosis 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Liver biopsy2 
Х 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Transient elastometry 
Х 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
HBV/HDV genotyping 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Resistance testing 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK sampling, main study3 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
PK sampling, sub-study4 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Safety assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haematology, coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry5 
X 
X 
(X) 
(X) 
(X) 
(X) 
X 
(X) 
(X) 
X 
(X) 
(X) 
(X) 
(X) 
X 
Serum total bile acids 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Serum bile acids 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
                                                     
1 Visit windows of ±2 days apply for the treatment period. For Germany, the window is ±2 days for follow-up visits 1, 2 and 5, and ±5 days for follow-up visits 3–4, whereas windows of ±3 days apply to all follow-up 
visits for Russia. 
2 Can be replaced with transient elastometry, by investigator's decision. 
3 Sampling will be done at 1 hour post-dose. 
4 PK sampling is done at Day 1 and 14, pre-dose and at timepoints 0:05, 0:15, 0:30, 1:00, 1:30, 2:00, 2:30, 4:00, 6:00, 10:00, 14:00, 24:00 after dosing 
5 At visits indicated by '(X)', only the abbreviated blood chemistry panel (albumin, total bilirubin, creatinine, GGT, ALAT, ASAT, phosphate, lipase and pancreatic amylase) is analysed. 


 
MYR202 Statistical Analysis Plan 2.0 final 2018-11-13.docx 
 
Template used: BISTemp07-07 
31 (32) 
 
Screen. 
Rand. 
Treatment period 
Follow-up period 
Visit  
01 
1 
2 
3 
4 
5 
6 
7 
8 
9 
FU1 
FU2 
FU3 
FU4 
FU5 
Week 
 
 
W1 
W2 
W4 
W8 
W12 
W16 
W20 
W24 
W25 
W26 
W28 
W36 
W48 
Study day1 
– -1 
1 
8 
15 
28 
56 
84 
112 
140 
168 
175 
182 
196 
252 
336 
Urine analysis 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
Urine pregnancy test6 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and body weight7 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
12-lead ECG  
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
Immunogenicity 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
Other assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBeAg, anti-HBeAg antibodies8 
X 
 
 
 
 
 
 
 
 
(X) 
 
 
 
 
(X) 
Table 2. Schedule of assessments (pre-treatment period) 
Visit  
02 
03 
04 
Study day 
-84 
-28 
-14– -1 
Efficacy assessments 
 
 
 
HDV RNA, HBsAg, HBV DNA 
X 
 
 
HBV/HDV genotyping 
X 
 
 
Resistance testing 
X 
 
 
Pharmacokinetics 
 
 
 
PK sampling, sub-study9 
 
 
X 
Safety assessments 
 
 
 
Haematology, coagulation 
X 
 
X 
Blood chemistry10 
X 
 
X 
                                                     
6 Only for women of child-bearing potential. 
7 Height is collected at screening only. 
8 Assessments at Week 24 and Follow-up visit 5 only for subjects who were HBeAg-positive at screening. 
9 PK sampling is done at Day -13, pre-dose and at timepoints 0:05, 0:15, 0:30, 1:00, 1:30, 2:00, 2:30, 4:00, 6:00, 10:00, 14:00, 24:00 after dosing. 
10 Only the abbreviated blood chemistry panel (albumin, total bilirubin, creatinine, GGT, ALAT, ASAT, phosphate, lipase and pancreatic amylase) is analysed during the pre-treatment phase. 


 
MYR202 Statistical Analysis Plan 2.0 final 2018-11-13.docx 
 
Template used: BISTemp07-07 
32 (32) 
Visit  
02 
03 
04 
Study day 
-84 
-28 
-14– -1 
Urine pregnancy test 
 
 
X 
Physical examination 
X 
 
X 
Vital signs and body weight 
X 
 
X 
 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 1 of 26 
 
 
 
PATIENT INFORMATION SHEET 
AND INFORMED CONSENT FORM 
 
Study title: 
Multicenter, Open-Labeled, Randomized Clinical Study to Assess 
Efficacy and Safety of 3 Doses of Myrcludex B for the Treatment of 
Patients with Chronic Hepatitis B with delta agent for 24 weeks in 
Combination with Tenofovir to Suppress Hepatitis B Virus Replication 
Vs. the Administration of Tenofovir to Suppress Hepatitis B Virus 
Replication” 
 
 
Protocol No. 
MYR 202 
 
 
Version and date of this Patient 
Information Sheet  
Version 8.0 dated September 28, 2017 
 
 
Study sponsor: 
Hepatera LLC, Russia 
 
Study doctor: 
 
Full name: 
 
 
 
 
 
 
Study site: 
 
Name: 
 
 
 
 
 
 
 
Address: 
 
 
 
 
 
Telephone: 
 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 2 of 26 
 
 
 
PATIENT INFORMATION 
 
Dear Patient, 
 
You are invited to volunteer for participation in a clinical study of a new drug for the treatment of chronic 
hepatitis B with delta agent. 
Before you agree to participate in this study, it is important that you read and understand the following 
explanation of the objectives, procedures, benefits, risks, inconveniences and cautions for this study. This 
document also describes the alternative treatments that are available to you and your right to stop 
participating in the study at any time. 
Please read the information below and discuss it with the study doctor. Take your time and ask your study 
doctor as many questions on the study as you like. If it is difficult for you to make a decision, you can take 
this information sheet and informed consent form with you home for the time you need to discuss it with 
family members, relatives, close people and friends. If you see any words or information that you do not 
understand, your study doctor will explain them to you. Reading this form and talking to the study doctor can 
help you make a decision on the participation in this study. 
If you are not completely honest with your study doctor when discussing your health, you may harm yourself 
by participating in this study. 
If you decide to participate in the study, you need to personally write your full name and data on page 25, the 
name and initials of the study doctor who discussed with you the participation in the study on page 26, and 
your signature and date on page 26. You also need to write your initials and the number provided by the 
study doctor on each page of two copies of this document. You will receive one signed and dated copy. This 
will serve as confirmation that you have been informed about the purpose of the study and its procedures, 
and that you agree to the terms and conditions of the study, but this does not deprive you of any legal rights. 
You need to sign this form prior to the performance of any study procedures. 
 
DO I HAVE TO TAKE PART IN THIS STUDY? 
Only you can decide whether to participate or not. You can stop participating in the study at any time. Your 
decision will in no way affect any medical care provided to you in the future. If you refuse to continue to 
participate in the study, the sponsor company or its partners will still have access to the data obtained prior to 
your withdrawal. 
 
SUMMARY OF THE CLINICAL STUDY 
You are invited to take part in a Phase II / III clinical study of a new drug, Myrcludex B, a lyophilisate for 
preparation of solution for injections. This study is of a research and experimental nature. You are asked to 
participate in this study because you have been diagnosed with chronic hepatitis B with delta agent. This 
disease affects your health and causes you inconvenience in everyday life. Lack of treatment may lead to the 
progression of the disease, which may result in death. 
This clinical study combines two phases (phase II and phase III): 
Phase II is a research study to evaluate the efficacy and safety of Myrcludex B in patients with chronic 
hepatitis B with delta agent and to compare the results of treatment with Myrcludex B in three doses with the 
control group receiving therapy with Tenofovir against the hepatitis B virus. 
Phase III is a research study to evaluate the efficacy and safety of the most effective and safe dose of 
Myrcludex B in patients with chronic hepatitis B with delta agent selected on the basis of analysis of the 
results of treatment of patients in Phase II, and to compare the results of treatment with Myrcludex B in the 
optimal dose to the control group receiving therapy with Tenofovir. 
This means that the clinical study will start from Phase II and then move to Phase III after the completion of 
the therapeutic and diagnostic measures provided for in Phase II. 
The study drug will be administered along with Tenofovir. 
This study is open, that is, after the allocation to groups both you and the investigator will know at which 
dose you will receive the drug. Thus, the information about the treatment you receive will be available to 
your investigator. 
The study drug will be administered for 24 weeks, every day, preferably at the same time. For 48 weeks, you 
will receive Tenofovir no matter which group you are assigned to. 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 3 of 26 
 
In phase II of the study, it is planned to obtain data from 120 patients aged from 18 years to 65 years 
inclusive, who will be randomly assigned to one of the 4 treatment groups in the ratio of 1:1:1:1. 
Group A (30 patients): Myrcludex B 2 mg/day subcutaneously for 24 weeks + Tenofovir, followed by 24 
weeks follow-up against the background of therapy with Tenofovir. 
Group B (30 patients): Myrcludex B 5 mg/day subcutaneously for 24 weeks + Tenofovir, followed by 24 
weeks follow-up against the background of therapy with Tenofovir. 
Group C (30 patients): Myrcludex B 10 mg/day subcutaneously for 24 weeks + Tenofovir, followed by 24 
weeks follow-up against the background of therapy with Tenofovir. 
Group D (30 patients): therapy with Tenofovir for 48 weeks. 
The number of patients to participate in phase III will be calculated on the basis of the data of the Interim 
Report prepared in phase II. Randomization (random allocation of patients to one of the treatment groups) 
will be made in 2 groups in the ratio of 1:1. 
Group I: Myrcludex B in optimal dosage subcutaneously for 24 weeks + Tenofovir, followed by 24 weeks 
follow-up against the background of therapy with Tenofovir. 
Group II: Therapy with Tenofovir for 48 weeks. 
The study will be conducted in several study sites in Russia. Your participation in the study (monitoring of 
your condition) will last no more than 64 weeks (including the screening period). 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 4 of 26 
 
 
SUMMARY OF THE STUDY DRUG CHARACTERISTICS 
 
Myrcludex B is an antiviral drug and is planned to be used for the treatment of chronic hepatitis B with delta 
agent. 
In earlier clinical studies, Myrcludex B showed good tolerability and efficacy in the treatment of hepatitis B 
with delta agent. 
Myrcludex B will be used in the form of a lyophilized powder for injections, which will be diluted with 1 ml 
of water for injections before use. 
 
Composition: 
Active ingredient: Myrcludex-B acetate, 2.0 mg/vial, 5.0 mg/vial. 
Excipients: water for injection, sodium carbonate, sodium bicarbonate, mannitol, hydrochloric acid and 
sodium hydroxide used to dissolve the drug before aseptic filling and lyophilization. The excipients used are 
of pharmaceutical grade. 
In phase II of this clinical study, Myrcludex B will be administered at doses of 2, 5 and 10 mg/day 
subcutaneously for 24 weeks along with the administration of Tenofovir, followed by 24 weeks follow-up 
against the background of therapy with Tenofovir. 
In phase III of this clinical study, Myrcludex B will be administered at an optimal dose subcutaneously (the 
optimal dose will be determined according to the results of phase II) for 24 weeks along with the 
administration of Tenofovir, followed by 24 weeks follow-up against the background of therapy with 
Tenofovir. 
 
OBJECTIVES OF THE STUDY 
The primary objective of Phase II of this clinical study is to evaluate the efficacy of Myrcludex B (Hepatera 
LLC, Russia) against the background of therapy for chronic hepatitis B with delta agent and to compare the 
results of Myrcludex B therapy in three doses with the control group receiving Tenofovir therapy. 
The secondary objectives of Phase II of the study are to assess the side effects of Myrcludex B, to assess the 
pharmacokinetics (drug concentration in the blood, including studying the effect of Myrcludex B on the 
activity of the liver enzyme system) and immunogenicity (production of antibodies to the drug). 
The primary objective of Phase III of this clinical study is to evaluate the efficacy of Myrcludex B (Hepatera 
LLC, Russia) against the background of therapy for treating chronic hepatitis B with a delta agent and to 
compare the results of Myrcludex B therapy in the most optimal dose with the comparison group receiving 
Tenofovir. 
The secondary objectives of the III phase of the study are to assess the safety and tolerability of the drug 
Myrcludex B when administered in the optimal dose, to assess the pharmacokinetics (drug concentration in 
the blood) and immunogenicity (production of antibodies to the drug). 
In addition, we want to learn more about your disease and the response of your body to the study drug by 
identifying some “biomarkers”. “Biomarkers” are various types of substances/indicators in the blood that are 
associated with the disease and/or your response to the administration of the study drug. 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 5 of 26 
 
 
WHAT DO I HAVE TO DO IF I AGREE TO PARTICIPATE IN THE STUDY? 
If you agree to participate, and the study doctor confirms your eligibility for the study, you will be randomly 
assigned to one of the following groups (depending on the phase of the study in which you will be invited to 
participate): 
 
 Phase II: 
Group A (30 patients): Myrcludex B 2 mg/day subcutaneously (s.c.) for 24 weeks + Tenofovir; 24 weeks 
follow-up against the background of therapy with Tenofovir; 
Group B (30 patients): Myrcludex B 5 mg/day subcutaneously (s.c.) for 24 weeks + Tenofovir; 24 weeks 
follow-up against the background of therapy with Tenofovir; 
Group C (30 patients): Myrcludex B 10 mg/day subcutaneously (s.c.) for 24 weeks + Tenofovir; 24 weeks 
follow-up against the background of therapy with Tenofovir; 
Group D (30 patients): Tenofovir for 48 weeks; 
 
 Phase III: 
Group I: Myrcludex B in optimal dosage subcutaneously for 24 weeks + Tenofovir, with 24 weeks follow-up 
against the background of therapy with Tenofovir. 
Group II: Tenofovir for 48 weeks. 
 
You are invited to participate in: 
[__] Phase II of this clinical study; 
[__] Phase III of this clinical study. 
 
Regardless of whether you are assigned to one of the Myrcludex B treatment groups, you will be prescribed 
treatment with Tenofovir to suppress the hepatitis B virus. 
Participation in this study involves periods of hospitalization (if you agree to participate in an additional 
pharmacokinetic study) and outpatient clinic visits. 
If you have not taken any nucleoside/nucleotide analogues before or have taken these drugs for less than 12 
weeks up to this point, you will need to undergo a 12-week course of pre-therapy with Tenofovir. The 
respective drugs will be provided by the sponsor for free. 
You will need to inform your study doctor if your health condition changes and you need to take other 
medications. 
 
Moreover, during the study and for 3 months after taking the last dose of the study drug, you will need to 
follow effective methods of contraception, which are described below. In the event of a pregnancy (in a 
female patient or female partner of a study participant) during the study period or within 30 days after taking 
the last dose of the study drug, you will need to inform the study doctor about it. 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 6 of 26 
 
 
 
STUDY DESIGN AND PROCEDURES 
 
The schedule of your visits is very important, and you should try to comply the pre-arranged schedule. 
In case of your participation in both Phase II and Phase III of this study, in addition to taking the drug, you 
will need to visit your doctor 15 times if you do not need a 12-week course of pre-therapy, or 17 times if you 
are prescribed the pre-therapy, as well as a series of examinations that will help us make the correct 
diagnosis, as well as monitor the course of your treatment. The procedures at each visit will take you 1 to 3 
hours. 
 
You will undergo the following examinations: 
1. Physical examination involves examination of all organ systems and body parts by your study doctor to 
obtain complete information about your health. 
 
2. Evaluation of anthropometric data (measuring body height and weight). 
 
3. Evaluation of vital functions includes the measurement of body temperature, heart rate, and arterial 
pressure. 
 
4. Collecting anamnesis and demographic data. The doctor will write down your personal data (date of 
birth, gender, race), ask you about your earlier health condition and ask some other questions of a medical 
nature. 
 
5. Electrocardiography (ECG) is a painless procedure to record the electrical activity of the heart, which 
will be performed to monitor the safety of your health. You will be asked to lie down in order to fix the 
electrodes with a sticky coating on the clean surface of the skin with no hair. Twelve electrodes will be 
placed on various parts of your body: chest, arms and legs. You will have to lie still for 10-15 minutes. Since 
the ECG is performed without penetration into the body and without the use of dyes or X-rays, the procedure 
is safe. 
 
6. Blood sampling is necessary for the following laboratory tests: general blood analysis, biochemical blood 
analysis, assessment of the blood coagulation system, determination of biomarkers and determination of the 
drug concentration in the blood. The total amount of blood taken throughout the study will be at least 648 ml. 
With the appointment of a 12-week preliminary course of treatment with Tenofovir, the volume of blood 
collected will increase by approximately 30 ml. With the participation in an additional pharmacokinetic 
study of Myrcludex B and systemic (total) metabolic activity of CYP3A (within phase II), the volume of 
blood collected will increase by approximately 280 ml. 
In the case of clinically significant abnormality of the laboratory test results or if it is not possible to analyze 
the sample taken (for example, in the case of hemolysis, damage during transportation, etc.), additional blood 
volume may be required for repeated tests. 
If it is necessary to conduct repeated blood tests or control the safety of the study therapy, you may be 
invited to the study site for additional tests. After an unplanned visit, the next visit will be held according to 
the previously approved schedule in accordance with the protocol. 
 
7. Clinical and biochemical blood tests, evaluation of the blood coagulation system (coagulogram) will 
be conducted to assess the safety of your participation in the study. 
 
8. The blood test for alpha-fetoprotein (AFP) will be conducted for all patients at the screening stage. The 
analysis is performed in a central laboratory to exclude hepatocellular carcinoma. 
 
9. The content of bile acids in the blood. The bile acid test is used to control the effects of the study drug. 
 
10. HDV RNA. Determination of RNA of hepatitis D virus in blood serum by the method of polymerase 
chain reaction (PCR) in the “real time” mode. 
 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 7 of 26 
 
11. HBV DNA. Determination of DNA of hepatitis B virus in blood serum by the method of polymerase 
chain reaction (PCR) in the “real time” mode. 
 
12. HBV and HDV genotyping. It is carried out to determine the genotype of hepatitis B and D viruses by 
the method of sequencing (determination of the amino acid or nucleotide sequences of viral RNA or DNA). 
 
13. HBsAg, HBeAg - Markers of infection with hepatitis B virus. 
 
14. Analysis of immunogenicity. The enzyme immunoassay for the determination of antibodies to 
Myrcludex B will be carried out only in groups of patients who received the therapy with Myrcludex B. 
 
15. NTCP polymorphism. Determination of the type of receptors on the liver cell. 
 
16. Analysis for fibrosis serum marker. Conducted to assess the progression of fibrosis. 
 
17. Additional pharmacokinetic study. In this study included in Phase II, 30 patients will take part (10 
patients from each of the groups А, В and С). The pharmacokinetic (PK) study will be performed for the 
following purposes: 
 
1) Evaluation of the concentration of Myrcludex B in the blood 
Blood sampling to determine the concentration of the study drug in the blood (within Phase II of the 
study) is necessary for the secondary research objective of Phase II of the study. During the first day of 
treatment before the first injection of Myrcludex B and at certain time intervals (14 days after the first 
injection of the drug) after the administration of the drug, you will be taken 14 blood samples of 4 ml each. 
Over the entire study period, to determine the concentration of the study drug in the blood, you will have 112 
ml of blood collected (if applicable). 
 
2) Evaluation of the systemic (general) metabolic activity of the liver enzyme system prior to 
prescribing the study drug and during therapy with Myrcludex B. To study the metabolic activity of the 
liver enzyme system, you will be injected with a microdose (low dose that does not result in any therapeutic 
effect and has no negative effect on the body) of Midazolam (MDZ) and a study of its concentration in the 
blood will be conducted. Thus, the activity of the liver enzyme system will be evaluated by the concentration 
of Midazolam in the blood. 
In clinical practice, in therapeutic doses, Midazolam is used in patients with sleep disorders, for 
premedication and sedation, as well as induction of anesthesia. 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 8 of 26 
 
 
A 10 µg microdose of Midazolam will be administered with 20 ml of physiological sodium chloride solution 
intravenously before the administration of Myrcludex B. The duration of the solution administration is 5 
minutes. 
Blood sampling to study the concentration of Midazolam in the blood will be carried out in 3 stages: 
– Day (-13) – Day (-12) [Visit 04] separately from the administration and PK study of Myrcludex B; 
– Day 1 – Day 2 [Visit 1] together with the administration and PK study of Myrcludex B; 
– Day 14 – Day 15 [Visit 3] together with the administration and PK study of Myrcludex B. 
On Day (-13-12), the pharmacokinetics of Midazolam will be studied prior to the beginning of therapy with 
Myrcludex B at the following time points: before the administration of MDZ and 00:05; 00:15; 00:30; 1:00, 
1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 10:00, 14:00, 24:00 (h:min) after the administration of MDZ. 
To study the pharmacokinetics of MDZ on Day 1 and Day 14, Midazolam is administered before the 
administration of Myrcludex B study drug and blood is taken (except for the zero time point) after 
Myrcludex B has been administered. The time for taking blood samples for the MDZ PK analysis: prior to 
the administration of MDZ and Myrcludex B and 00:05; 00:15; 00:30; 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 
6:00, 10:00, 14:00, 24:00 (h:min) after the administration of Myrcludex B. The total volume of blood to be 
collected from you during the entire period of your participation in the additional pharmacokinetic study to 
evaluate the concentration of Myrcludex B and Midazolam in the blood will be 280 ml. 
 
18. The main pharmacokinetic study. Blood sampling to determine the concentration of the study drug 
in the blood (as part of Phase II of the study) is necessary for a more accurate study of the possible 
cumulation of the drug (i.e. accumulation of Myrcludex B in the human body). During the entire period of 
the study, blood samples will be taken from all patients receiving Myrcludex B 7 times in a total volume of 
28 ml. Blood sampling will be carried out 1 hour +/- 15 min after the drug administration. 
 
19. Taking urine samples. Urine samples for general analysis will be collected to control the safety of your 
condition. 
For women of childbearing age, a urine pregnancy test is provided. 
 
20. Liver biopsy and fibroelastometry. Biopsy is performed to determine the extent of the inflammatory 
process and the stage of liver fibrosis. An immunohistochemical analysis of HDV-positive cells will also be 
carried out. Part of the biopsy sample will be frozen for analysis of intrahepatic parameters. A liver biopsy is 
performed as follows: 1 - The patient lies down on his/her back and puts his/her right arm over his/her head. 
During the biopsy sampling you may not move; 2 - To ensure your psychological comfort you may be 
offered to take a mild sedative; 3 - Before the procedure, the puncture site is disinfected and anesthetized, 
after which a small incision is made and a biopsy needle is inserted through it, and a small piece of liver 
tissue is taken. The procedure itself occurs very quickly, usually in tenths of a second. After the liver biopsy, 
you will be under the supervision of the medical staff for four hours, because you may experience discomfort 
and pain, and you may need to take pain medication. For eight hours after the procedure, you are not 
recommended to drive or resume activities related to the operation of complex machinery. During the day 
after the biopsy, you should not play sports. 
By decision of your study doctor, instead of a liver biopsy, you may have to undergo fibroelastometry – an 
examination of the liver that is not accompanied by body punctures and performed with the help of special 
equipment (fibroscan). The procedure for this examination resembles ultrasonography: the condition of the 
liver will be assessed using a special sensor. 
Fibroelastometry and biopsy procedures can be performed directly at the study site, or, if this is not possible, 
at an authorized medical institution that has the proper equipment and qualified personnel. 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 9 of 26 
 
 
21. Evaluation of recent and concomitant therapy will be carried out throughout the study. Your study 
doctor will regularly inquire in and keep a record of what medicines you are taking and what other types of 
treatment you are receiving. This information will help assess the relationship of adverse events detected in 
you with the use of the study drug. In addition, information will be collected on whether you have ever been 
administered interferon for the treatment of hepatitis, regardless of the duration of treatment, and if so, with 
what drugs and when. 
 
22. Records of adverse events will be kept throughout the study in order to monitor the safety of your health 
and assess the safety of the use of the study drug. Adverse events are any adverse symptoms, complaints or 
illnesses that you may experience during this study. 
 
23. Inclusion/exclusion criteria will be evaluated prior to randomization. The study doctor may ask you 
additional questions to clarify these criteria. 
For more information about the research procedures, you can ask your doctor. You can ask him/her any 
questions concerning this study. 
 
DURATION OF YOUR PARTICIPATION IN THE STUDY 
Your participation in the Phase II study (monitoring your condition after the administration of the first dose 
of the study drug - Myrcludex B or Tenofovir) will last 48 weeks. Within 24 weeks, you will receive 
Myrcludex B (in the case of randomization into groups A, B or C) or therapy of hepatitis B with Tenofovir 
(in the case of randomization into group D). After that, patients of all groups will receive therapy with 
Tenofovir for another 24 weeks. The total participation in the study will take you no more than 52 ± 3 weeks 
(including the screening period) if you do not need a 12-week course of pre-therapy with Tenofovir, and no 
more than 64 ± 3 weeks (including a screening period of up to 28 days) if you will be prescribed such course. 
If you participate in Phase III of this clinical study, then monitoring of your condition after the 
administration of the first dose of the study drug - Myrcludex B or Tenofovir will last 48 weeks. Within 24 
weeks, you will receive Myrcludex B (in case of randomization into group I) or Tenofovir (in case of 
randomization into group II). After that, patients of all groups will receive therapy with Tenofovir for 
another 24 weeks. The total participation in the study will take you no more than 52 ± 3 weeks (including the 
screening period of up to 28 days) if you do not need a 12-week course of pre-therapy with Tenofovir and no 
more than 64 ± 3 weeks (including the screening period) if you are prescribed such course. 
You can withdraw from the study at any time without explaining the reasons for refusing to further 
participate in it. However, in the event that you decide to withdraw from the study, we recommend that you 
first talk with the study doctor. 
The doctor conducting the study may exclude you from it at any time, if he considers that the best option for 
you is to stop taking the study drug. The reasons for this decision may be the following: 
 This is in your interests (for example, for safety reasons); 
 You are female and expecting a baby (the pregnancy occurred during the study); 
 The clinic staff found out that, along with the study drug, you received any other treatment prohibited by 
the study protocol. 
You may also be excluded from the study for administrative reasons: 
 If you violate the visit schedule, or 
 If you take Myrcludex B or drug therapy for hepatitis B in larger or smaller quantities than is provided for 
by the protocol. 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 10 of 26 
 
 
SCHEDULE OF VISITS 
The schedule of visits is the same for Phases II and III 
Screening (Visit 01): 
In order to determine whether you are eligible the study, after you have agreed to participate in the study, 
you need to undergo the following tests and procedures. The procedures of this visit can take you about 1-3 
hours. In some cases, the study doctor may ask you to come on an empty stomach. Screening procedures are 
the same for Phases II and III and include: 
 Collection of baseline information (demographic data, data on participation in other studies, etc.); 
 Collection of medical history; 
 Physical examination; 
 Measurement of vital functions: blood pressure (in the sitting position after 5 minutes of rest on the non-
dominant hand), and heart rate; 
 Collection of anthropometric data (measurement of body height and weight); 
 The following laboratory and instrumental tests: 
o Complete Blood Count; 
o Blood clotting test; 
o Blood chemistry; 
o Clinical urine analysis; 
o 12-lead ECG; 
o Serological blood test (HIV, hepatitis B, C and B with delta agent); 
o Urine drug screen; 
o Breath test for alcohol; 
o Test for AFP (alpha-fetoprotein, analysis necessary to exclude a liver tumor); 
o HDV RNA; 
o HBeAg and antibodies to HBeAg; 
o HBsAg (nonquantitative determination) 
o For female patients – urine pregnancy test; 
 Abdominal ultrasound; 
 Liver biopsy (or fibroelastometry, depending on the decision of the study doctor); 
 Evaluation of inclusion and exclusion criteria; 
 Registration of Serious Adverse Events; 
 Collection of data on concomitant therapy, as well as on previous therapy for hepatitis with interferon 
preparations, regardless of the remoteness of treatment. 
 
The period of pre-therapy with Tenofovir (Visits 02-04): 
If you were prescribed a 12-week course of pre-therapy with Tenofovir, you will need to come to the study 
site twice: for the first time - no later than 84 days before the expected date of the randomization visit, for the 
second - no later than 14 days before the expected date of the randomization visit. In addition, 4 weeks 
before the randomization visit, you will need to answer a number of doctor’s questions by phone. The doctor 
will agree with you on the date and time of the call. 
The procedures of the first visit within the period of pre-therapy with Tenofovir (Visit 02) are performed on 
an outpatient basis. These procedures may take you about 1 to 3 hours. In some cases, the study doctor may 
ask you to come on an empty stomach. The procedures of Visit 02 include: 
 Physical examination; 
 Body weight measurement; 
 Measurement of vital functions: blood pressure (in the sitting position after 5 minutes of rest on the non-
dominant hand), and heart rate; 
 The following laboratory and instrumental tests: 
o Complete blood count and blood clotting test - if more than 14 days have passed since the previous blood 
sampling; 
o Blood chemistry; 
o HDV RNA; 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 11 of 26 
 
o HBV DNA and HBsAg; 
o HBV/HDV genotyping (frozen specimens) is performed in patients who have been pre-treated with 
Tenofovir; 
o Resistance test (frozen specimens) is performed in patients who have been prescribed pre-therapy with 
Tenofovir; 
 Registration of Serious Adverse Events; 
 Collection of data on concomitant therapy; 
 Issuance of Tenofovir in the amount necessary for a 12-weeks therapy course; 
In addition, you will agree with the doctor on the date and time of the phone call, which must be made no 
later than 8 weeks from the date of Visit 02. 
During the phone call (remote Visit 03), you will need to answer several questions of the doctor regarding 
your health condition, as well as calculate the amount of used and unused drug and pass this information to 
the doctor. During the phone call, the doctor will remind you to come to Visit 04 at the study site and set a 
date for this visit. 
The procedures of Visit 04 (a visit at the study site, in outpatient mode, 14 days prior to the scheduled 
randomization visit) These procedures may take you about 1 to 3 hours. In some cases, the study doctor may 
ask you to undergo the tests on an empty stomach. The procedures of this visit include: 
 Physical examination; 
 Body weight measurement; 
 Measurement of vital functions: blood pressure (in the sitting position after 5 minutes of rest on the non-
dominant hand), and heart rate; 
 The following laboratory and instrumental tests: 
o Complete blood count; 
o Blood clotting test; 
o Blood chemistry; 
o For female patients – urine pregnancy test; 
 Re-evaluation of inclusion and exclusion criteria; 
 Only for patients participating in the additional pharmacokinetic study in Phase II: hospitalization in the 
evening before blood sampling (Day (-14)). Taking blood samples before the administration of Midazolam 
and 00:05; 00:15; 00:30; 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 10:00, 14:00, 24:00 on the next day 
(h:min) after the administration of Midazolam (Days (-13) and (-12)). 
 Registration of Serious Adverse Events; 
 Calculation by the doctor of used and unused Tenofovir; 
 Evaluation by the doctor of compliance with the prescribed therapy; 
 Collection of data on concomitant therapy. 
 
Visit 1: Randomization and Beginning of Therapy: this visit is conducted after the end of the screening 
procedures or the period of pre-therapy with Tenofovir and confirmation of your eligibility for the study. The 
visit procedures will take about 1-3 hours. 
During this visit, after completing the planned procedures, you will be randomly assigned to one of the four 
therapy groups (in Phase II) or to one of the 2 therapy groups (in Phase III). 
The treatment and the visits will take place on an outpatient basis, in the same way for Phases II and III. 
Only patients participating in the additional pharmacokinetic study (in Phase II) will be hospitalized three 
times at the study site. For the first time, they will be hospitalized in the evening 2 weeks prior to 
randomization and leave the center the next morning after the administration of Myrcludex B (approximately 
24 hours after the administration of Myrcludex B). For the second time, the patients will be hospitalized 
before the beginning of therapy with the study drug (after randomization) and will be discharged the next day 
after the daily blood sampling. Then (for the third time) the patients will be hospitalized on the evening 
before the 14th day of the study and will be discharged the next day after daily blood sampling. 
The following procedures and measurements will be carried out during this visit: 
 Physical examination; 
 Body weight measurement; 
 Final evaluation of inclusion/exclusion criteria; 
 Measurement of vital functions: blood pressure (in the sitting position after 5 minutes of rest on the non-


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 12 of 26 
 
dominant hand), and heart rate; 
 The following laboratory and instrumental tests: 
o Complete blood count; 
o Blood clotting test; 
o Blood chemistry; 
o Test for total bile acids in the blood; 
o The content of bile acids in the blood; 
o Clinical urine analysis; 
o HDV RNA; 
o HBV DNA and HBsAg; 
o HBV/HDV genotyping (frozen specimens) is performed in patients who were NOT prescribed pre-
therapy with Tenofovir; 
o Resistance analysis (frozen samples) is performed in patients who were NOT prescribed pre-therapy with 
Tenofovir; 
o Immunogenicity; 
o Serum fibrosis marker; 
o NTCP polymorphism; 
o Breath test for alcohol; 
o For female patients – urine pregnancy test; 
 Registration of Adverse Events 
 Collection of data on concomitant therapy 
 Randomization; 
 Issuance of the study drug for 28 days; 
 Issuance of Tenofovir; 
 Issuance of patient diaries; 
 For patients participating in the additional PK sub-study (sub-study of pharmacokinetics of Myrcludex B) 
in Phase II: hospitalization in the evening before blood sampling. Taking blood samples immediately before 
the administration of Myrcludex B and Midazolam and 00:05; 00:15; 00:30; 1:00, 1:30, 2:00, 2:30, 3:00, 
4:00, 6:00, 10:00, 14:00, 24:00 on the next day (h:min) after the administration of Myrcludex B. 
 
 For patients participating in the additional PK study (study of the systemic metabolic activity of CYP3A) 
in Phase II: hospitalization in the evening before blood sampling (Day (-1)). Taking blood samples before 
Midazolam administration and 00:05; 00:15; 00:30; 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 10:00, 14:00, 
24:00 on the next day (h:min) after the administration of Myrcludex B (Days 1-2). 
 
 Blood sampling for the main pharmacokinetic study. For patients who are not participating in the PK 
study, a blood sampling time point is scheduled at the randomization visit (1 hour +/- 15 min after the 
administration of Myrcludex B). 
Your treatment will begin at this visit. The study doctor will teach you the technique of subcutaneous 
administration of the drug, as well as filling-in the patient's diary. Separately, you will be provided with 
training documents. At this visit, in the presence of the doctor, you will make a subcutaneous injection of the 
study drug and take Tenofovir. Later on, the injection of the study drug and taking of Tenofovir should be 
carried out every 24 hours ± 1 hour. At that, you can adjust the administration of the second and subsequent 
doses of the study drug to the schedule convenient for you, which should be reflected in the patient's diary. 
The administration of subsequent doses of the drug should be carried out every 24 ± 1 hours from the 
scheduled time. 
The doctor will also instruct you that if you miss a dose of the study drug, you should follow the following 
algorithm: if you remembered about the missed dose no later than 4 hours after the time scheduled at the 
randomization visit, the dose should be administered. On the next day, the dose should be administered at the 
scheduled time. If more than 4 hours have passed after the scheduled time, the dose should not be 
administered, it should be considered as missed, and on the next day, you should self-administer the next 
dose at the scheduled time. The fact of missing a dose should be recorded in the patient’s diary, and you will 
also need to inform the investigator about the missed dose by phone. 
The procedures and evaluations in the treatment period will be the same for Phases II and III. 
 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 13 of 26 
 
Visit 2: Treatment week 1 /Day 8 ± 2: The procedures of this visit will take about 1 to 2 hours. 
The following procedures will be performed at Visit 2: 
 Measurement of vital functions: blood pressure (in the sitting position after 5 minutes of rest on the non-
dominant hand), and heart rate; 
 Complete blood count, coagulogram; 
 Blood chemistry; 
 Total bile acids in the blood; 
 The content of bile acids in the blood; 
 HDV RNA; 
 Collection of data on concomitant therapy; 
 Assessment of the correctness of filling-in of patients’ diaries; 
 Registration of AE; 
 Accounting of study drugs and assessment of compliance with the prescribed therapy. 
 
At this visit, you will have to provide the filled-in diary so that the doctor can check the patient's diary entries 
and enter the data on compliance with the therapy. Copies of the filled-in patient diary pages will be stored at 
the study site. 
 
Visit 3: Treatment Week 2 / Day 15 ± 2: 
The following procedures will be performed at Visit 3: 
 Measurement of vital functions: blood pressure (in the sitting position after 5 minutes of rest on the non-
dominant hand), and heart rate; 
 Complete blood count, coagulogram; 
 Blood chemistry; 
 Total bile acids in the blood; 
 The content of bile acids in the blood; 
 HDV RNA; 
 Collection of data on concomitant therapy; 
 Assessment of the correctness of filling-in of patients’ diaries; 
 Accounting of study drugs and assessment of compliance with the prescribed therapy; 
 Registration of AE; 
 For patients participating in the additional PK sub-study (sub-study of pharmacokinetics of Myrcludex B) 
in Phase II: hospitalization in the evening before blood sampling. Taking blood samples immediately before 
the administration of Myrcludex B and Midazolam and 00:05; 00:15; 00:30; 1:00, 1:30, 2:00, 2:30, 3:00, 
4:00, 6:00, 10:00, 14:00, 24:00 on the next day (h:min) after the administration of Myrcludex B. 
 For patients participating in the additional PK study in Phase II: hospitalization in the evening before 
blood sampling (Day 13). Taking blood samples before Midazolam administration and 00:05; 00:15; 00:30; 
1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 10:00, 14:00, 24:00 on the next day (h:min) after the administration 
of Myrcludex B (Days 14-15). 
At this visit, you will have to provide the filled-in diary so that the doctor can check the patient's diary entries 
and enter the data on compliance with the therapy. Copies of the filled-in patient diary pages will be stored at 
the study site. 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 14 of 26 
 
 
 
Visit 4: Treatment week 4 / Day 28 ± 2: 
The following procedures will be performed at this visit: 
 Measurement of vital functions: blood pressure (in the sitting position after 5 minutes of rest on the non-
dominant hand), and heart rate; 
 Complete blood count, coagulogram; 
 Blood chemistry; 
 Urine analysis; 
 For female patients – urine pregnancy test; 
 Total bile acids in the blood; 
 The content of bile acids in the blood; 
 HDV RNA; 
 HBsAg; 
 Blood sampling for the main pharmacokinetic study (1 h ± 15 min after administration of Myrcludex B); 
 Collection of data on concomitant therapy; 
 Assessment of the correctness of filling-in of patients’ diaries; 
 Registration of AE; 
 Accounting of study drugs and assessment of compliance with the prescribed therapy; 
 Issuance of the study drug for 28 days; 
 Issuance of Tenofovir. 
If you receive the study drug, then at this visit you will need to return unused vials of the drug in order for 
the doctor to verify the patient's diary entries and enter the data on compliance with the therapy. Copies of 
the filled-in patient diary pages will be stored at the study site. 
Also, at this visit you will have to return the unused drug for the treatment of hepatitis B. 
 
Visit 5: Treatment week 8 ± 2 days: 
The following procedures will be performed at this visit: 
 Measurement of vital functions: blood pressure (in the sitting position after 5 minutes of rest on the non-
dominant hand), and heart rate; 
 Complete blood count, coagulogram; 
 Blood chemistry; 
 For female patients – pregnancy test; 
 Total bile acids in the blood; 
 The content of bile acids in the blood; 
 HDV RNA; 
 HBsAg; 
 Blood sampling for the main pharmacokinetic study (1 h ± 15 min after administration of Myrcludex B); 
 Registration of AE; 
 Collection of data on concomitant therapy; 
 Assessment of the correctness of filling-in of patients’ diaries; 
 Accounting of study drugs and assessment of compliance with the prescribed therapy; 
 Issuance of the study drug for 28 days; 
 Issuance of Tenofovir. 
At this visit, you will have to return all unused drugs, as well as the used and unused vials with Tenofovir so 
that the doctor can verify the patient's diary entries and enter the data on compliance with the therapy. Copies 
of the filled-in patient diary pages will be stored at the study site. 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 15 of 26 
 
 
 
Visit 6: Treatment week 12 ± 2 days: 
The following procedures will be performed at Visit 6: 
 Physical examination; 
 Body weight measurement; 
 Measurement of vital functions: blood pressure (in the sitting position after 5 minutes of rest on the non-
dominant hand), and heart rate; 
 12-lead ECG; 
 Complete blood count, coagulogram; 
 Blood chemistry; 
 Urine analysis; 
 For female patients – pregnancy test; 
 Total bile acids in the blood; 
 The content of bile acids in the blood; 
 HDV RNA; 
 HBV DNA; 
 HBsAg; 
 Blood sampling for the main pharmacokinetic study (1 h ± 15 min after administration of Myrcludex B); 
 Immunogenicity; 
 Registration of AE; 
 Collection of data on concomitant therapy; 
 Assessment of the correctness of filling-in of patients’ diaries; 
 Accounting of study drugs and assessment of compliance with the prescribed therapy; 
 Issuance of the study drug for 28 days; 
 Issuance of Tenofovir. 
At this visit, you will have to return all unused drugs, as well as the used and unused vials with Tenofovir so 
that the doctor can verify the patient's diary entries and enter the data on compliance with the therapy. Copies 
of the filled-in patient diary pages will be stored at the study site. 
 
Visit 7: Treatment week 16 ± 2 days: 
The following procedures will be performed at this visit: 
 Measurement of vital functions: blood pressure (in the sitting position after 5 minutes of rest on the non-
dominant hand), and heart rate; 
 Complete blood count, coagulogram; 
 Blood chemistry; 
 For female patients – pregnancy test; 
 Total bile acids in the blood; 
 The content of bile acids in the blood; 
 HDV RNA; 
 HBsAg; 
 Blood sampling for the main pharmacokinetic study (1 h ± 15 min after administration of Myrcludex B); 
 Registration of AE; 
 Collection of data on concomitant therapy; 
 Assessment of the correctness of filling-in of patients’ diaries; 
 Accounting of study drugs and assessment of compliance with the prescribed therapy; 
 Issuance of the study drug for 28 days; 
 Issuance of Tenofovir. 
At this visit, you will have to return all unused drugs, as well as the used and unused vials with Tenofovir so 
that the doctor can verify the patient's diary entries and enter the data on compliance with the therapy. Copies 
of the filled-in patient diary pages will be stored at the study site. 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 16 of 26 
 
 
 
Visit 8: Treatment week 20 ± 2 days: 
The following procedures will be performed at Visit 8: 
 Measurement of vital functions: blood pressure (in the sitting position after 5 minutes of rest on the non-
dominant hand), and heart rate; 
 Complete blood count, coagulogram; 
 Blood chemistry; 
 For female patients – pregnancy test; 
 Total bile acids in the blood; 
 The content of bile acids in the blood; 
 HDV RNA; 
 HBsAg; 
 Blood sampling for the main pharmacokinetic study (1 h ± 15 min after administration of Myrcludex B); 
 Registration of AE; 
 Collection of data on concomitant therapy; 
 Assessment of the correctness of filling-in of patients’ diaries; 
 Accounting of study drugs and assessment of compliance with the prescribed therapy; 
 Issuance of the study drug for 28 days; 
 Issuance of Tenofovir. 
At this visit, you will have to return all unused drugs, as well as the used and unused vials with Tenofovir so 
that the doctor can verify the patient's diary entries and enter the data on compliance with the therapy. Copies 
of the filled-in patient diary pages will be stored at the study site. 
 
Visit 9: Treatment week 24 ± 2 days: End of therapy with the study drug 
The following procedures will be performed at this visit: 
 Physical examination; 
 Body weight measurement; 
 Measurement of vital functions: blood pressure (in the sitting position after 5 minutes of rest on the non-
dominant hand), and heart rate; 
 12-lead ECG; 
 The following laboratory and instrumental tests: 
o Complete blood count; 
o Blood clotting test; 
o Blood chemistry; 
o Total bile acids in the blood; 
o The content of bile acids in the blood; 
o General urine analysis; 
o HDV RNA; 
o HBV DNA and HBsAg; 
o Blood sampling for the main pharmacokinetic study (1 h ± 15 min after administration of Myrcludex B); 
o HBeAg and antibodies to HBeAg (only in patients with a positive HBeAg result at screening); 
o Resistance test; 
o Immunogenicity; 
o Serum fibrosis marker; 
o For female patients – urine pregnancy test; 
 Liver biopsy (or fibroelastometry, depending on the decision of the study doctor); 
 Registration of AE; 
 Evaluation of compliance with the prescribed therapy; 
 Collection of data on concomitant therapy; 
 Issuance of Tenofovir for 56 days; 
 Assessment of the correctness of filling-in of patients’ diaries. 
At this visit, you will need to return all the unused drug, as well as the used and unused vials with Tenofovir 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 17 of 26 
 
so that the doctor can verify the patient's diary entries and enter the data on compliance with the therapy. 
 
Follow-up period (FUV – follow up visits) 
Upon completion of the treatment period begins the 24-weeks follow-up period, the procedures of which are 
the same for Phases II and III. During the follow-up period you will continue to take Tenofovir. 
FUV-1: FU Week 1 – Study Week 25 ± 3 days: 
FUV-2: FU Week 2 – Study Week 26 ± 3 days: 
The following examinations will be performed at visits FUV-1 and FUV-2: 
 Measurement of vital functions: blood pressure (in the sitting position after 5 minutes of rest on the non-
dominant hand), and heart rate; 
 Complete blood count, coagulogram; 
 Blood chemistry; 
 Total bile acids in the blood; 
 The content of bile acids in the blood; 
 HDV RNA; 
 Registration of Adverse Events; 
 Collection of data on concomitant therapy. 
 
FUV-3: FU Week 4 – Study Week 28 ± 3 days: 
The following procedures will be performed at this visit: 
 Measurement of vital functions: blood pressure (in the sitting position after 5 minutes of rest on the non-
dominant hand), and heart rate; 
 Complete blood count, coagulogram; 
 Blood chemistry; 
 HDV RNA; 
 HBsAg (frozen samples); 
 Collection of data on concomitant therapy; 
 Registration of Adverse Events; 
 Issuance of Tenofovir for 56 days. 
At this visit, you will have to return the packages of the used drug so that the doctor can record the data on 
compliance with the therapy. 
 
FUV-4: FU Week 12 – Study Week 36 ± 3 dais: 
 Measurement of vital functions: blood pressure (in the sitting position after 5 minutes of rest on the non-
dominant hand), and heart rate; 
 Complete blood count, coagulogram; 
 Blood chemistry; 
 Urine analysis; 
 HDV RNA; 
 HBV DNA, HBsAg; 
 Immunogenicity; 
 Collection of data on concomitant therapy; 
 Registration of Adverse Events; 
 Issuance of Tenofovir for 56 days. 
At this visit, you will have to return the packages of the used drug so that the doctor can record the data on 
compliance with the therapy. 
 
FUV-5: FU Week 24 – Study Week 48 ± 3 days: Final visit of the study 
At this visit, you will have to return the packages of the used and unused Tenofovir so that the doctor can 
record the data on compliance with the therapy. 
The following final procedures will be performed at this visit: 
 Physical examination; 
 Body weight measurement; 
 Measurement of vital functions: blood pressure (in the sitting position after 5 minutes of rest on the non-


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 18 of 26 
 
dominant hand), and heart rate; 
 12-lead ECG; 
 Complete blood count, coagulogram; 
 Blood chemistry; 
 Urine analysis; 
 Total bile acids in the blood; 
 The content of bile acids in the blood; 
 HDV RNA; 
 HBV DNA; 
 HBsAg; 
 HBeAg and antibodies to HBeAg (only in patients with a positive HBeAg result at screening); 
 Immunogenicity; 
 Serum fibrosis marker; 
 Collection of data on concomitant therapy; 
 Registration of Adverse Events; 
 Accounting of the drug. 
 
Unscheduled visit / Early withdrawal visit 
At the discretion of your study doctor, you can be invited to an unscheduled visit to the study site at any time 
during the study. If your study doctor decides that your further participation in the study is not appropriate, 
you can be excluded from the study, and you will be prescribed another necessary therapy, according to the 
doctor's professional judgment. However, you will be required to undergo the following procedures to assess 
the safety of the therapy: 
 Registration of adverse events; 
 Physical examination; 
 Body weight measurement; 
 Assessment of vital functions; 
 Complete Blood Count, coagulogram; 
 Blood chemistry (complete set); 
 Total bile acids in the blood; 
 The content of bile acids in the blood; 
 HDV RNA; 
 HBV DNA; 
 HBsAg; 
 Urine analysis; 
 Collection of data on concomitant therapy. 
You will be asked to inform the study personnel during the study about any changes in your condition that 
you experienced during the study, and to inform the study personnel about any drugs you take. 
 
PATIENT RESPONSIBILITIES 
In order to participate in this study, you must give your consent to all procedures and study visits. 
Only you may use the study drug, and you should keep the study drug out of the reach of children, as 
well as other persons other than the personnel of the study site. 
Your responsibilities as a patient in the study include the following: 
 You will come to study visits, follow the instructions of the doctors and take the study drug according to 
the instructions. Inform the study site if you cannot come to a scheduled visit. 
 Provide true information about your medical history and current health status. 
 Inform your attending physician about whether you participated in any study within the previous 30 days 
or whether you are participating in any other study now. 
 It is important that you tell your attending physician about any changes in your health status, regardless of 
whether you think that they are related or not to the administration of the study drug. 
 Contact your attending physician immediately if you experience any undesirable sign or symptom. 
 You must also inform your attending physician about any drugs you are currently taking. This applies to 
both drugs prescribed by your doctor and medicines sold over-the-counter (for example, at a pharmacy or 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 19 of 26 
 
health food store, including herbal medicines and vitamin supplements). Your study doctor will tell you if 
you can keep taking these drugs. 
 You must to inform your attending physician in advance about any planned changes in the administration 
of your current drugs or starting new ones, even if they are prescribed by another doctor. Always follow the 
instructions of your attending physician during the study. 
 You will be given a study patient card with all the necessary information about this study, which you can 
use for emergency contact with your attending physician. You will need to carry this card with you 
throughout your participation in the study. It will also contain information about the experimental drug 
Myrcludex B you receive as part of your participation in this study. If you have questions or you need any 
additional information, contact your study doctor. 
 You will be given a patient diary in which you will need to enter information about the administration of 
the drugs; you will be required to bring the completed diary to the visits at the study site. 
 Follow the instructions of the attending physician, including recommendations on diet and physical 
activity. 
 Female patients of childbearing age, as well as male patients, must consent to use effective contraception 
defined as a double barrier method, a single barrier method in combination with a spermicide, intrauterine 
device or female oral contraceptives. Effective contraception should be applied during 30 days before the 
start of the study, throughout the study and for 3 months after its completion. If you are female and become 
pregnant or suspect pregnancy, or if you are male and your partner becomes pregnant during your 
participation in the study, you should immediately inform your doctor. If you are a woman of childbearing 
age, your study doctor will tell you whether the drugs you are taking can affect the efficacy of your 
contraceptives, and whether you should use another method. 
 
HANDLING OF BIO SAMPLES 
Samples and, if applicable, data obtained may be re-analyzed in the future by the sponsor company or its 
affiliates, subsidiaries and authorized companies, employees, partners or third parties potentially using the 
new technology. Based on the permission of the Ministry of Health of the Russian Federation, the samples 
will be exported to Germany for study. This process is not limited by time frame. You agree that we are 
entitled to re-examine the samples and any other data. 
In addition, samples and such data may be used in future studies of Myrcludex B, your health or other 
medical issues. This process is not limited by time frame. You consent to the use of your samples and all 
data obtained in such future studies. 
Blood samples taken for routine laboratory tests and disease assessments will be used only as part of this 
study, and upon completion of the study all unused samples will be destroyed. These samples will not be 
stored for possible future use outside the scope of this study. If these provisions change, it will first be 
necessary to obtain your consent before conducting any research. You have the right to refuse this. 
Bio samples can be stored by Hepatera LLC for up to 5 years after completion of the study. After this period, 
the samples will either be destroyed, or a new approval of additional sample storage period will be requested 
from the Council of Ethics / Ministry of Health (CE/MOH) of the Russian Federation. It is possible that the 
samples will be re-analyzed during this period. This may include analysis of newly identified markers and/or 
repeating the initial analysis using new improved technologies. 
If you revoke your consent to the storage of your samples, the results of all analyzes performed up to this 
time can be saved in accordance with legal and regulatory requirements. You can request the destruction of 
all remaining samples that can be identified as belonging to you. 
 
HAS THIS STUDY RECEIVED ETHICAL APPROVAL? 
The protocol of this clinical study was submitted to the Council of Ethics of the Ministry of Health and the 
Local Ethics Committee (LEC), who both gave their written approval to conduct this study. Also, the 
permission of the Ministry of Health of the Russian Federation to conduct this study. The structure of the 
study complies with the regulatory documents of the Ministry of Health and other regulatory bodies of the 
Russian Federation on clinical studies, as well as the World Medical Association's Declaration of Helsinki, 
which contain recommendations for doctors on biomedical research involving human subjects. You can get a 
copy of these documents from your study if you want to read them. 
 
POSSIBLE RISKS, SIDE EFFECTS AND INCONVENIENCES 
In studies like this, it is impossible to foresee all possible risks or side effects. The response of each patient to 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 20 of 26 
 
the study drug, device, or procedure may vary. You may experience a side effect, or you may have an 
increased risk of developing symptoms, diseases, and/or complications that your study doctor or study 
sponsor cannot predict. If such a side effect occurs, you should immediately inform your study doctor. 
In order to ensure your safety, you must also inform your study doctor about all the drugs you are taking. 
The results of clinical studies have shown that Myrcludex B is well tolerated. 
Based on the data collected during the conduct of clinical studies to date, the predicted side effects are local 
skin reactions, such as redness, itching, or inflammation. 
The drug for the treatment of chronic hepatitis B used in the study, Tenofovir, has been used in clinical 
practice for many years and is well tolerated. 
The most frequent adverse reactions are a decrease in the level of phosphates in the blood, dizziness, 
abnormalities in the gastrointestinal tract, headache, and fatigue. 
If you are not completely honest with your study doctor and study personnel in matters relating to the side 
effects that you may have, you may harm yourself by participating in this study. 
 
Other risks and inconveniences 
In addition, the procedures performed during the clinical study may also pose a risk or cause discomfort. 
The puncture and/or catheterization of veins for blood sampling may be painful; at the puncture site, may 
occur bleeding and formation of a hematoma (bruising), which in rare cases leads to thrombosis (vein 
clogging by thrombus) or thrombophlebitis (thrombosis combined with vein inflammation) and/or peripheral 
nerve damage (numbness). In the event of adverse events, the catheter will be immediately removed, and 
further blood collection will be carried out through single punctures. 
Measurement of blood pressure may cause a feeling of pressure and mild soreness at the site of the cuff when 
it is pumped up, as well as the formation of small subcutaneous bruises in case of repeated measurements of 
blood pressure during the day. 
During electrocardiography (ECG), you may experience skin rash or irritation where the sticky gel is applied 
and where ECG electrodes are placed. Some male volunteers may need to have small areas of chest hair 
shaven to properly attach the electrodes. 
Women of childbearing age and men need to use effective methods of contraception throughout their 
participation in the study. An effective contraceptive method is a method the failure rate of which is no 
higher than 1%. In this study, acceptable methods of contraception are the methods listed in the Patient 
Responsibilities section above. 
It is you, and not your partner, who are responsible for preventing pregnancy. If necessary, consult your 
study doctor on the method of contraception most appropriate for you among those listed above. 
Before the beginning of the study, women of childbearing age will be tested for pregnancy (urine test using 
test strips). Women who suspect that they may be pregnant should report this to the study doctor. 
Women should not take part in the study during pregnancy or breastfeeding. 
Sexually active men need to use reliable methods to prevent pregnancy in their partners. 
Throughout the study, your doctor will notify you of any new information that may be available and may 
affect your decision to continue your participation in the study. 
 
Unknown risks 
You may experience side effects or inconveniences that are not listed in this form or may not yet be known. 
You may experience new side effects. If you have any problems, immediately inform your study doctor or 
study personnel. 
 
The influence of the study drug on driving vehicles and operating machinery requiring increased 
concentration of attention 
Care should be taken when driving vehicles and operating machinery during therapy with the study drug, 
since the drug may cause dizziness. 
 
OTHER DRUGS 
There are certain drugs that you should not take while participating in this study. Your study doctor will tell 
you about them and provide you with a list of prohibited drugs. If another doctor prescribes you any of these 
drugs, please notify your study doctor before taking any of these drugs during your participation in the study. 
 
ALTERNATIVES TO PARTICIPATION IN THIS STUDY 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 21 of 26 
 
You are not obliged to participate in this study to receive treatment for chronic hepatitis B with delta agent. 
You may be prescribed other available drugs. A study doctor can discuss with you the risks and benefits of 
alternative treatment options. 
 
POSSIBLE BENEFITS FROM PARTICIPATION IN THIS STUDY 
During the study, you will be under close supervision of a qualified doctor as well as other medical 
personnel. Your condition will be regularly evaluated. You may or may not directly benefit from 
participation in this study. It is possible that your condition will improve, remain the same or worsen. 
Your participation in the study may be beneficial for other patients with chronic hepatitis B with a delta 
agent. 
 
COST OF PARTICIPATION AND REIMBURSEMENT OF EXPENSES 
All procedures associated with the study, the issuance of the study drug, medical examinations, laboratory 
tests, and pregnancy tests will be completely free for you. The drugs used in this study - Myrcludex B and 
Tenofovir - will be provided to you for free. Thus, participation in the study will be free for you. 
 
PAYMENT FOR PARTICIPATION 
Remuneration for participation in this study is not provided. 
During the study, patients of Group D may be individually reimbursed for the reasonable costs of public 
transport related to attending scheduled visits at study sites, provided that there are no deviations from the 
visits schedule. 
After the completion of the study according to the protocol, the Sponsor of the study will donate Myrcludex 
B for this group of patients in the prescribed maximum effective and safe dosage, in an amount sufficient for 
a 24-weeks course of treatment. 
 
IMPORTANT! The drug will be provided after registration of the drug in the Russian Federation. 
 
INSURANCE AGAINST POSSIBLE HARM TO HEALTH 
Your safety during this study is the responsibility of the principal investigator of this study site. In the event 
that an adverse reaction develops in you, the principal investigator and his staff will provide you with free 
qualified medical assistance and will do everything possible for your treatment. 
If you agree to participate in this study, your participation in this study will be insured in accordance with the 
Federal Law dated April 12, 2010 No. 61-FZ “On Drug Circulation”, Resolution of the Government of the 
Russian Federation No. 714 “On Approval of the Standard Rules for Mandatory Insurance of Life and Health 
of Patients Participating in Clinical Studies of Drugs” dated September 13, 2010 and Resolution of the 
Government of the Russian Federation No. 393 “On Amendments to the Standard Rules for Mandatory 
Insurance of Life and Health of Patients Participating in Clinical Studies of Drugs” dated May 18, 2011. 
Attached to this document is an original certificate of insurance and a leaflet describing the insurance 
conditions stipulated by the certificate as well as your actions in case of harm to health. You will receive the 
original certificate of insurance along with the leaflet, and a copy of the certificate will be kept in the 
insurance company. In order to ensure anonymity, your personal data in the certificate will be replaced with 
the Individual Patient Identification Code, which will be assigned to you in the study in the form established 
in the Russian Federation, and which is indicated at the end of this document. In the event of harm to your 
health associated with this clinical study, INGOSSTRAKH Open Insurance Company undertakes to 
reimburse all costs for the necessary medical examinations and treatment, the need for which will arise as a 
result of direct exposure to the study drug and the comparison drugs and/or medical procedures performed 
according to the study protocol. 
This study does not provide for any additional types of voluntary insurance or other options for treatment 
and/or compensation in the event of a patient’s death or harm to the patient’s health caused in this study. 
Please note that if you have a valid voluntary health insurance (VHI) policy, participation in a clinical study 
may violate the terms of this policy and deprive you of the rights to receive medical assistance under VHI. If 
you have a valid VHI certificate, please read the insurance terms and conditions set out in it. 
 
For more information, please contact: INGOSSTRAKH Open Insurance Company, 41 Lesnaya Street, 
127994 Moscow, Russia 
Department for loss adjustment, insurance of property and liability. 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 22 of 26 
 
Tel/fax: 8 (495) 641-41-01, 725-73-25, 234-36-00. 
 
If you believe that you were treated unethically during the study, or that your rights as a patient were 
violated, please contact the Council of Ethics, whose contacts are given below. 
The sponsor bears no responsibility for any losses, harm and/or damage that may be caused to you, if such 
losses are caused by: 
 Taking a prohibited drug during the study; 
 Deviation, on your part, from the study protocol, this patient information sheet (informed consent form), 
the requirements of the study and/or any instructions given to you by your study doctor; 
 Action or inaction of a third party in response to an adverse event or reaction to the study drug. 
During your participation in a clinical study, you may not participate in another study. If you need to receive 
any medical assistant that is not related to this study, you should inform your study doctor. 
 
CONFIDENTIALITY OF PERSONAL INFORMATION 
Records made during the study are called study records. Records that will be collected, used and transferred 
to other persons in this study may include a study record about you, your data from medical records, results 
of laboratory, diagnostic and other tests, results of analyzes of stored bio samples (blood, urine, biopsy), and 
clinical and research observational data obtained during your participation in the study. Primary records will 
be kept at the study site. 
As part of this study, your study doctor and personnel will make records about your health, which will 
include your name and other personal information. Authorized representatives of Hepatera LLC, the Council 
of Ethics and the Federal Service for Supervision of Health and Social Development of the Russian 
Federation may have access to this data. Copies of research records that will not contain your name can be 
provided to Hepatera LLC, Councils of Ethics and laboratories that can be involved in conducting this study. 
The sponsor may send a copy of the impersonated records to the Federal Service for Supervision of Health 
and Social Development of the Russian Federation or other regulatory authorities, for example, state 
regulatory authorities of other countries. 
Information on the study and the results of this study can be presented at conferences or published in 
scientific magazines. Presentations and publications will not include your name or information which allows 
to establish your identity. 
For your safety, the study doctor should inform the health care provider, who usually provides you with 
medical assistance, about your participation in this study, if your study doctor is not this health care provider. 
Please discuss any questions about this with your study doctor. 
You have the right to receive information on the results of all laboratory tests of biological samples that you 
have submitted, and on your health condition. 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 23 of 26 
 
 
GETTING ANSWERS TO YOUR QUESTIONS ON THE STUDY 
You can ask questions on this form or on the study at any time. You may have questions about the study, 
about the harm associated with the study, or about payment during the study. You may have other questions. 
You should contact your study doctor or the personnel participating in the study to discuss any questions or 
concerns. To ask questions related to this study, as well as to report on the harm associated with the study, or 
to obtain information on research procedures, please contact your study doctor: 
 
Last name, First name, Patronymic of the doctor _______________ 
__________________________________________________________ 
 
Telephone: _______________________________________________ 
 
If you feel that your rights as a study participant have been violated, or if you have questions related to the 
ethical aspects of this study, then you should contact the representative of the Local Ethics Committee 
__________________________________________________________ 
__________________________________________________________ 
 
Tel._______________________________________________________ 
 
Address: ___________________________________________________ 
___________________________________________________________ 
 
This committee is a group of people from scientific and other fields who carry out initial and further 
supervision of the study from the point of view of ethical principles in order to ensure the safety and well-
being of patients. 
If you have questions about this study, you should first discuss them with your study doctor or representative 
of the Local Ethics Committee. After you have discussed them with your study doctor or the local ethics 
committee, and have not received a satisfactory answer, you can contact the Council of Ethics of the 
Ministry of Health: 
Council of Ethics of the Ministry of Health: 
Rakhmanovsky Lane 3, GSP 4, 127994 Moscow, 
Telephone: (495) 625-44-21. 
If you have any questions to the company sponsoring the study, you can contact the representative office of 
the company: 
Verkhnyaya Radischevskaya Street 12/19, bldg. 1, 1109240 Moscow. Tel. +7 (495) 726-52-53. 
 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 24 of 26 
 
 
VOLUNTARY PARTICIPATION 
Participation in this study is voluntary. Anyone who is invited to participate in the study may refuse it. No 
one is obliged to participate in the study. If you agree to participate in the study, you can withdraw from it at 
any time. You are not required to explain the reason. No doctor may discriminate you or treat you differently 
if you decide not to participate in the study or decide later to discontinue your participation. If you withdraw 
from the study, it is in your interest to inform the study personnel and to follow their instructions. 
 
NEW INFORMATION ABOUT THE STUDY 
The information provided in this form reflects available knowledge about the study at the time of its signing. 
If during the study we become aware of any new information that may affect your decision to continue to 
participate in the study, you will be informed by your study doctor. 
 
DATA PROTECTION 
By signing this form, you give express permission to inspect, transfer and process medical information about 
you, as described in the Confidentiality of Personal Information section and as described below: 
 Representatives of the sponsor (monitors, study managers, auditors, other authorized persons) and 
representatives of the abovementioned regulatory authorities can study medical information about you with 
direct access to medical records. 
 Study data, including anonymous medical information about you, can be processed, i.e. they will be 
collected, entered into a computer database, verified, analyzed, printed and will be reported in due course for 
legitimate scientific purposes, including use in future medical or pharmaceutical research. 
 Study data may be transferred for processing to other countries, including countries not covered by the 
European Privacy Directive. 
 You can access medical information about you in accordance with the laws of the Russian Federation. 
 The sponsor will not disclose information about your health status to insurance companies, unless 
required by law. In this case, you will be asked to provide a separate written consent to this. If you decide to 
revoke your consent to use your health information after it is provided to the Sponsor, from then on no such 
data will be transmitted by the Sponsor to any third party, including the insurance company. Data transmitted 
prior to revocation of consent, are not subject to return. 
If you do not want your data to be used for the study as described above, you should refuse to participate in 
the study. 
In case of your early withdrawal from the study, including because of your refusal to further participate in 
the study, the data collected in the study before you leave it, however, can be processed along with other data 
obtained as part of this clinical study. 
For more information about the procedures for transmission of medical data from the study, please contact 
your study doctor. You can ask him/her any questions on this study. 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 25 of 26 
 
 
PATIENT INFORMED CONSENT 
to participation in clinical study 
I, _____________________________________________________________________________, 
born on _____________________________, tel.: ________________________________, 
have been informed by the study doctor about the nature of the planned study on the efficacy and safety of 
Myrcludex B (Hepatera LLC, Russia) in combination with Tenofovir. 
By signing this document, I confirm the following: 
 
 I have read and understood the contents of the patient information sheet of the above study 
and confirm that I had enough time to make a decision on participation in this study 
Patient's 
signature 
 I have received satisfactory answers to all the questions I asked 
Patient's 
signature 
 I voluntarily agree to take part in this scientific study, follow the study procedures and 
provide the information needed to the study doctor, nurses or other personnel upon request 
Patient's 
signature 
 I understand that I can withdraw from this study at any time without explaining the reason, 
and that this decision will not affect my medical care or my legal rights. 
Patient's 
signature 
 I have received one original copy of this Patient Information Sheet 
Patient's 
signature 
 If the study doctor is not my attending physician, I consent that my attending physician is 
informed about my participation in this study and asked for medical information about my health 
status 
Patient's 
signature 
 I consent to taking samples from me and use samples as described in this information sheet 
Patient's 
signature 
 I consent to use and transfer of my personal and medical data, as described in this Patient 
Information Sheet, and to: 
 identification of information only with the help of my study participant identification 
number; 
 analysis, processing and disclosure of the data to the sponsor, its branches and authorized 
representatives, auditors and monitors of the study for the purposes described in the study 
protocol; 
 analysis or verification of the data by properly authorized organizations; 
 publication and transmission of the data to regulatory authorities or health insurance 
organizations located in my country or in other countries; and to transmission of the data, if 
necessary, to any country where the laws on the protection of my personal data may be less 
strict. 
Patient's 
signature 
 I understand that I may also be asked for permission to contact me later to obtain my consent 
in connection with this study or any sub-study within it. 
Patient's 
signature 
 
I have signed and dated this information sheet, including patient information and informed consent form, on 
26 pages in 2 copies; I have received 1 copy signed and dated by me personally and by the study doctor. 
 
Investigator (full name) ___________________________________________________________, who 
discussed with me the question of my participation in the study, gave me a thorough explanation of the 
nature, objectives and duration of the study. I had the opportunity to ask him/her questions regarding all 
aspects of the study. 
 
I voluntarily agree to take part in the clinical study according to protocol No. MYR 202 “A multicenter, 
open-label, randomized clinical study of the efficacy and safety of 3 doses of Myrcludex B for treating 
patients with chronic hepatitis B with delta agent for 24 weeks in combination with the use of Tenofovir to 
suppress replication of hepatitis B virus compared to using Tenofovir to suppress the replication of hepatitis 
B virus.” I have been informed that I can refuse to participate or withdraw from this study at any time. 
 
Patient's signature: ___________________________________ Date _______________________ 
 


Protocol No. MYR 202 
 
Patient Information Sheet and Informed Consent Form 
                                                        Version 8.0 dated 28.09.2017 
 
Sponsor: Hepatera LLC, Russia 
Patient No.: __________________ 
Patient’s initials: ______________ 
                                   Page 26 of 26 
 
I confirm that I explained in detail the purpose and possible risks of this study to the patient 
_____________________________________________________________________, and the patient had 
the opportunity to ask any questions about the nature, risks and benefits of his/her participation in the study. 
Signature of the study doctor: ________________________ Date _____________________ 
* Full name of independent witness and/or legal representative (in block letters): 
_______________________________________________________________________________ 
Signature of the witness and/or legal representative: ______________ Date ________________ 
* If applicable 
(If the participant is illiterate, verbal consent must be obtained in the presence of an independent witness, 
confirmed by the signature of the witness) 
 
The patient has been assigned an individual patient identification code: 
 
|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__|__| 
 
 
 
 
 
Permission 
No. issued by 
the Ministry 
of Health of 
the Russian 
Federation 
Issue date of 
the 
permission 
issued by the 
Ministry of 
Health of the 
Russian 
Federation 
Study site number  
Patient’s full 
name 
Patient’s birth 
date
Patient’s unique number in 
the study