Myrcludex B in Combination With Peginterferon Alfa-2a Versus Peginterferon Alfa-2a Alone in Patients With Chronic Viral Hepatitis B With Delta-agent

Phase 2

Completed

• Conditions: Chronic Viral Hepatitis B With Delta-agent
• Interventions: Drug: PEG IFN alfa-2a; Drug: Myrcludex B; Drug: Tenofovir

• Registration Number: NCT02888106
• Lead Sponsor: Hepatera Ltd.

Brief Summary

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

Detailed Description

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

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

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

* Arm A (n=15): PEG IFN alfa-2a 180 µg for 48 weeks

* Arm B (n=15): Myrcludex B 2 mg + PEG IFN alfa-2a 180 µg for 48 weeks

* Arm C (n=15): Myrcludex B 5 mg + PEG IFN alfa-2a 180 µg for 48 weeks

* Arm D (n=15): Myrcludex B 2 mg for 48 weeks

* Arm E (n=15): Myrcludex B 10 mg (10 mg once a day)+ PEG IFN alfa-2a 180 µg for 48 weeks

* Arm F (n=15): Myrcludex B 10 mg (5 mg twice a day)+ Tenofovir for 48 weeks

Study Timeline

• Study Start: 2016-04
• Study First Submitted: 2016-08-30
• Study First Submitted QC: 2016-08-30
• Study First Posted: 2016-09-02
• Primary Completion: 2019-11-22
• Study Completion: 2020-10-30
• Results First Submitted: 2020-12-29
• Results First Submitted QC: 2021-02-09
• Results First Posted: 2021-02-25
• Status Verified: 2021-03
• Last Update Submitted: 2021-04-07
• Last Update Posted: 2021-04-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 90

Inclusion Criteria

1. Signed Informed Consent form.
2. Males and females 18 to 65 years of age (inclusively).
3. Patients with chronic hepatitis B (HBeAg-positive or negative) and HBsAg-positive for at least 6 months prior to Screening.
4. Positive for anti-HDV antibodies for at least 6 months prior to Screening.
5. HDV RNA-positive at Screening.
6. ALT ≥ 1 x ULN and < 10 x ULN.
7. The patient agreed to use adequate method of contraception during the study, starting from the time of Informed Consent signing and until completion of the Follow-up Period.

Exclusion Criteria

1. Intolerance or hypersensitivity to the active ingredient or other components of the study drug Myrcludex B.

2. Intolerance or hypersensitivity to interferons alfa, genetically engineered E.coli medications, polyethylene glycol or other components of peginterferon alfa-2a.

3. Previous treatment with Myrcludex B (patients with previous exposure to interferon are eligible).

4. Therapy with antiviral drugs for chronic viral hepatitis B with delta-agent over the previous 6 months.

5. Therapy with anti-tumour agents (including radiotherapy) or immunomodulatory medications (including systemic glucocorticoids) over the previous 6 months.

6. The following laboratory test results at Screening:

   1. Hemoglobin < 100 g/L
   2. Leucocytes < 3000/µL
   3. Neutrophils < 1500/µL
   4. Platelets < 90000/µL
   5. Serum creatinine >1.5 x ULN.

7. Total bilirubin > 34.2 µM/L. Patients with higher total bilirubin may be enrolled upon consultation with the study Medical Monitor, if there is clear evidence that the elevated bilirubin is caused by Gilbert's syndrome.

8. Current or previous decompensated liver disease, including coagulopathy, hyperbilirubinemia, hepatic encephalopathy, hypoalbuminaemia, ascites, and oesophageal varices haemorrhage; Child-Pugh score of B/C or ≥6 points.

9. HCV or HIV coinfection (patients with anti-HCV antibodies and no HCV RNA at Screening are eligible).

10. Hepatocellular carcinoma.

11. Signs of drug- or alcohol-induced liver disease or any other medical conditions associated with chronic liver disease (e.g. autoimmune hepatitis, hemochromatosis, thalassaemia, alcoholic hepatitis, toxic liver disease).

12. Contraindications for liver biopsy.

13. Concurrent malignancy (current diagnosed or suspected malignancy; risk of a previous malignancy recurrence).

14. Severe decompensated cardiovascular diseases, including unstable and poorly controlled conditions, over 6 months before Screening.

15. History of poorly controlled thyroid conditions or clinically significant signs of thyroid dysfunction at Screening.

16. Previous or current severe renal failure or significant renal dysfunction at Screening.

17. Previous or current chronic pulmonary disease with respiratory distortion at Screening.

18. Previous or current severe retinopathy, significant ophthalmology disorders associated with diabetes mellitus or hypertension.

19. Previous or current severe psychiatric disorders at Screening (e.g. severe depressions, suicidal attempts, severe neuroses or cognitive disorders).

20. Previous or current endocrine disorders (hypoglycaemia, hyperglycaemia, diabetes mellitus) that are not adequately controlled at Screening.

21. History of visceral organ transplantation.

22. Signs of drug and/or alcohol dependence (80 g of alcohol/day for men and 40 g of alcohol/day for women) within 1 year before Screening.

23. History of immune disorders (e.g. idiopathic thrombocytopenic purpura, lupus erythematosus, sclerodermia, severe psoriasis, rheumatoid arthritis).

24. Need for concomitant use of glucocorticoids or myelotoxic agents.

25. Participation in another clinical study within 30 days prior to enrollment into this study.

26. Pregnant or breast-feeding females.

27. Any other condition that, in the opinion of Investigator, precludes the patient from taking part in this study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A	PEG IFN alfa-2a	PEG IFN alfa-2a 180 µg for 48 weeks
Arm E	PEG IFN alfa-2a	Myrcludex B 10 mg (10 mg once a day) + PEG-IFN alfa-2a 180 μg during 48 weeks
Arm B	PEG IFN alfa-2a	Myrcludex B 2 mg + PEG IFN alfa-2a 180 µg for 48 weeks
Arm C	PEG IFN alfa-2a	Myrcludex B 5 mg + PEG IFN alfa-2a 180 µg for 48 weeks
Arm F	Tenofovir	Myrcludex B 10 mg (5 mg twice a day) + Tenofovir during 48 weeks
Arm D	Myrcludex B	Myrcludex B 2 mg for 48 weeks
Arm B	Myrcludex B	Myrcludex B 2 mg + PEG IFN alfa-2a 180 µg for 48 weeks
Arm C	Myrcludex B	Myrcludex B 5 mg + PEG IFN alfa-2a 180 µg for 48 weeks
Arm E	Myrcludex B	Myrcludex B 10 mg (10 mg once a day) + PEG-IFN alfa-2a 180 μg during 48 weeks
Arm F	Myrcludex B	Myrcludex B 10 mg (5 mg twice a day) + Tenofovir during 48 weeks

Primary Outcome Measures

Name	Time	Method
Percentage of Patients With Negative HDV RNA by PCR	72 weeks	Negativation of HDV RNA by PCR (undetectable HDV RNA) at Week 72 (end of follow-up period)

Secondary Outcome Measures

Name	Time	Method
Percentage of Patients With Normalized ALT	24, 48 and 72 weeks	Percentage of patients with normalized ALT at Weeks 24, 48 and 72. ALT normalisation was defined as having an ALT value within the normal range (≤31 U/L for females and ≤41 U/L for males)
Percentage of Patients With Negative HDV RNA by PCR	24 and 48 weeks	Percentage of patients with negative HDV RNA by PCR (undetectable HDV RNA) at Weeks 24 and 48
Percentage of Patients With HВsAg Response	24, 48 and 72 weeks	HВsAg response was defined as HBsAg negativation or \> 1 log10 IU/mL decline from baseline.
Number of Participants With Change (Improvement / Worsening) in Fibrosis and Histological Activity Stage From Baseline to Post-treatment	72 weeks	Change (improvement/ worsening) in fibrosis and histological activity stage according to the liver biopsy study results from baseline to post-treatment Liver fibrosis was evaluated by histological staging systems with stage 0 corresponding to absence of fibrosis and with the highest score (the last stage in all systems) corresponding to cirrhosis.; Improvement is defined as a decrease of at least 1 point in histological staging systems; worsening is defined as an increase of at least 1 point.; Data should be interpreted with caution due to low number of paired biopsies available.
Percentage of Patients With HBsAg Negativation	48 and 72 weeks	Undetectable HВsAg with appearance of HbsAg antibodies or without it.
Percentage of Patients With Combined Response	24, 48 and 72 weeks	Combined response is defined as negative HDV RNA and ALT normalization at Weeks 24, 48, and 72. The criteria for combined response were HDV RNA value below LLoD (where LLoD=10 IU/ml) and ALT within normal range (≤31 U/L for females and ≤41 U/L for males)
Percentage of Patients With Negative HBV DNA by PCR	24, 48 and 72 weeks	Percentage of patients with undetectable HBV DNA by PCR at Weeks 24, 48 and 72
Change in Molecular Analyses of Relative HDV RNA Expression, Relative HBV Pregenomic Expression, Relative Total HBV RNA Expression (X Region), Relative HBV RNA Expression (S Region).	48 and 72 weeks	Molecular analyses of relative HDV RNA expression, relative HBV pregenomic expression, relative total HBV RNA expression (X region), relative HBV RNA expression (S region) from baseline to post-treatment.; \*Biopsy post treatment performed at Week 48 for arm D:MXB 2mg and arm F:MXB 5mg bid + Tenofovir, and performed at Week 72 for arms A:PEG-IFN, B:MXB 2mg + PEG-IFN, C:MXB 5mg + PEG-IFN and arm E:MXB 10mg + PEG-IFN.
Change in Molecular Analysis of HDAg Positive Hepatocytes (%) From Baseline to Post-treatment	48 and 72 weeks	Molecular analysis of HDAg positive Hepatocytes (percentage of HDAg positive Hepatocytes) from baseline to post-treatment.; \*Biopsy post treatment performed at Week 48 for arm D:MXB 2mg and arm F:MXB 5mg bid + Tenofovir, and performed at Week 72 for arms A:PEG-IFN, B:MXB 2mg + PEG-IFN, C:MXB 5mg + PEG-IFN and arm E:MXB 10mg + PEG-IFN.
The Intensity of Liver Fibrosis Based on Results of Transient Elastometry of Liver at Weeks 48 and 72.	48 and 72 weeks	Change in liver stiffness and intensity of liver fibrosis based on results of transient elastometry of liver at weeks 48 and 72.
Change in Molecular Analyses of Total HBV DNA (X Region) Copies/Cell, HBV DNA (S Region) Copies/Cell, cccDNA Copies/Cell From Baseline to Post-treatment.	48 and 72 weeks	Molecular analyses of total HBV DNA (X region) copies/cell, HBV DNA (S region) copies/cell, cccDNA copies/cell from baseline to post-treatment.; \*Biopsy post treatment performed at Week 48 for arm D:MXB 2mg and arm F:MXB 5mg bid + Tenofovir, and performed at Week 72 for arms A:PEG-IFN, B:MXB 2mg + PEG-IFN, C:MXB 5mg + PEG-IFN and arm E:MXB 10mg + PEG-IFN.
Change in the Gene Expression Analyses From Baseline to Post-treatment	Weeks 48 - 72	Change in the gene expression analyses of CXCL10, NTCP, CYP7A1, ISG15, MX1, OAS, HLA-E, TAP1 and USP18 from baseline to post-treatment.; Biopsy post treatment performed at Week 48 for arm D:MXB 2mg and arm F:MXB 5mg bid + Tenofovir, and performed at Week 72 for arms A:PEG-IFN, B:MXB 2mg + PEG-IFN, C:MXB 5mg + PEG-IFN and arm E:MXB 10mg + PEG-IFN.

Trial Locations

Locations (7)

LLC "Clinic of Modern Medicine"; 🇷🇺 Moscow, Russian Federation

Medical Company "Gepatolog" LLC; 🇷🇺 Samara, Russian Federation

State Budgetary Institution of healthcare 'Stavropol regional clinical hospital'; 🇷🇺 Stavropol', Russian Federation

Federal Budget Institution of Science "Central Research Institute of Epidemiology" of The Federal Service on Customers' Rights Protection and Human Well-being Surveillance; 🇷🇺 Moscow, Russian Federation

Moscow Regional Research and Clinical Institute; 🇷🇺 Moscow, Russian Federation

State Budgetary educational institution of higher professional education "South Ural State Medical University" Ministry of healthcare; 🇷🇺 Chelyabinsk, Russian Federation

State Budgetary Institution of healthcare "Specialized Clinical Infectious Diseases Hospital" Ministry of Health; 🇷🇺 Krasnodar, Russian Federation