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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Chronic Hepatitis D Infection With Hepatitis B

Intervention / Treatment
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* Drug: Myrcludex B
* Drug: Myrcludex-B
* Drug: Myrcludex-B
* Drug: Tenofovir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age from 18 to 65 years inclusively at the time of signing Informed Consent Form. Positive serum HBsAg for at least 6 months before Screening. Positive serum anti-HDV antibody for at least 6 months before screening. Positive PCR results for serum HDV RNA at Screening. Patients with liver cirrhosis, irrespective of previous interferon treatment . 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) . Alanine aminotransferase level >1 x ULN, but less than 10 x ULN. 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. Negative urine pregnancy test for females of childbearing potential. 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. Male and female subjects must agree to use a highly effective contraception throughout the study and for 3 months after the last dose of the study medication. 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: Child-Pugh score of B-C or over 6 points. HCV or HIV coinfection. Subjects with anti-HCV antibodies can be enrolled, if screening HCV RNA test is negative. Creatinine clearance <60 mL/min. 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. Any previous or current malignant neoplasms, including hepatic carcinoma.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicenter, Open-label, Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>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. | Drug: Myrcludex B<br>* 2 mg, once daily, subcutaneously<br>Drug: Tenofovir<br>* tenofovir disoproxil 245 mg, equivalent to tenofovir disoproxil fumarate 300 mg<br>* Other names: Viread;|
| Experimental: Arm B<br>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. | Drug: Myrcludex-B<br>* 5 mg, once daily, subcutaneously<br>Drug: Tenofovir<br>* tenofovir disoproxil 245 mg, equivalent to tenofovir disoproxil fumarate 300 mg<br>* Other names: Viread;|
| Experimental: Arm C<br>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. | Drug: Myrcludex-B<br>* 10 mg, once daily, subcutaneously<br>Drug: Tenofovir<br>* tenofovir disoproxil 245 mg, equivalent to tenofovir disoproxil fumarate 300 mg<br>* Other names: Viread;|
| Active Comparator: Arm D<br>tenofovir treatment for 48 weeks | Drug: Tenofovir<br>* tenofovir disoproxil 245 mg, equivalent to tenofovir disoproxil fumarate 300 mg<br>* Other names: Viread;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HDV RNA Response at Week 24 | HDV RNA negativation or decrease by ≥2 log10 from baseline to Week 24 | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Durability of HDV RNA Response | Durability of HDV RNA response to 24 weeks post treatment | 48 weeks | 
| Combined Response: HDV RNA Response and Normal ALT at Treatment Week 24 | Combined response: HDV RNA negativation or ≥2 log decline and normal ALT at treatment week 24 | 24 weeks | 
| Changes in ALT Values | Changes in ALT values at Week 24 and Week 48 compared to baseline. | 24 and 48 weeks | 
| Change (Absence of Increase) in Fibrosis Marker | Change (absence of increase) in fibrosis marker: serum alpha-2-macroglobulin at Week 24 and Week 48 compared to baseline | 24 and 48 weeks | 
| Change in Hepatitis B Surface Antigen | Changes in hepatitis B surface antigen (HBsAg) (defined as decline in HBsAg levels, disappearance of HBsAg and HBsAg seroconversion to anti-HBsAg) at week 24 and week 48 compared to baseline | 24 and 48 weeks | 
| Change in HBV DNA Levels at Week 24 and Week 48 Compared to Baseline | Change in hepatitis B virus (HBV) DNA levels at Week 24 and Week 48 compared to baseline. | 24 and 48 weeks | 
| Absence of a Fibrosis Progression According to the Findings of Transient Elastometry | Decrease in liver stiffness and absence of a fibrosis progression according to the findings of transient elastometry (fibroscan) at week 24 compared to baseline | 24 weeks | 
| Number of Participants With Improvement of Histological Findings According to the Liver Biopsy Results | Change (improvement/ worsening) in fibrosis and histological activity stage according to the liver biopsy study results at week 24 compared to baseline. 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. | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis D