Study to Assess Efficacy and Safety of Bulevirtide in Combination With Pegylated Interferon Alfa-2a in Participants With Chronic Hepatitis Delta (CHD)

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the efficacy of bulevirtide combination with pegylated interferon in participants with chronic hepatitis delta (CHD).

Official Title
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A Multicenter, Open-label, Randomized Phase 2b Clinical Study to Assess Efficacy and Safety of Bulevirtide in Combination With Pegylated Interferon Alfa-2a in Patients With Chronic Hepatitis Delta

Conditions
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Chronic Hepatitis Delta

Intervention / Treatment
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* Drug: Bulevirtide
* Drug: Peginterferon Alfa-2a (PEG-IFN alfa)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated informed consent form. Positive serum hepatitis delta virus (HDV) antibody results or polymerase chain reaction (PCR) results for serum/ plasma HDV RNA for at least 6 months before screening. Positive PCR results for serum/ plasma HDV RNA at screening. Alanine transaminase level >1 x upper limit of normal (ULN), but less than 10 x ULN. Serum albumin >28 g/L. Thyroid stimulating hormone (TSH) within normal ranges (including on medication for control of thyroid function) Negative urine pregnancy test for females of childbearing potential. Inclusion criteria for female individuals: 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 treatment period, or Willingness to use highly effective contraception (double barrier method or barrier contraception in combination with hormonal or intrauterine contraceptive) throughout the treatment period and for 6 months after the last dose of the study medication. Male individuals must agree to use a highly effective contraception (double barrier method or barrier contraception in combination with hormonal or intrauterine contraceptive used by female partners) and not to donate sperm throughout the treatment period and for 6 months after the last dose of the study medication. Exclusion Criteria: Child-Pugh hepatic insufficiency score of B-C or over 6 points. Note: Child-Pugh hepatic insufficiency score of 6 points is allowed. Only individuals with compensated cirrhosis are allowed. Uncomplicated oesophageal varices allowed; individuals with current bleeding or ligation, or history of bleeding or ligation within the last 2 years are excluded. Hepatitis C virus (HCV) or human immunodeficiency virus (HIV) coinfection. Individuals with HCV antibodies can be enrolled, if screening HCV RNA test is negative. Creatinine clearance < 60 mL/min as estimated using Cockcroft-Gault formula. Total bilirubin ≥ 34.2 µmol/L. (Individuals with higher total bilirubin values may be included after the consultation with the Study Medical Monitor, if such elevation can be clearly attributed to Gilbert's syndrome associated with low-grade hyperbilirubinemia.) Evidence of an active or suspected malignancy, or an untreated pre-malignancy disorder, or a history of malignancy within the last 5 years (with the exception of successfully treated carcinoma of the cervix in situ and successfully treated basal cell carcinoma and squamous cell carcinoma not less than 1 year prior to screening [and no more than 3 excised skin cancer within the last 5 years prior to screening]) or history of hepatic carcinoma. Systemic connective tissue disorders. New York Heart Association (NYHA) class III-IV congestive heart failure. Individuals with uncontrolled arterial hypertension: systolic blood pressure > 150 mm Hg and/ or diastolic blood pressure > 100 mm Hg at Screening. Previous or unstable concurrent diseases or conditions that prevent individual's enrolment into the study. Individuals with mental disorders or social circumstances that preclude them from following protocol requirements. Current or previous decompensated liver disease, including coagulopathy, hepatic encephalopathy and esophageal varices hemorrhage. One or more additional known primary or secondary causes of liver disease, other than hepatitis B (e.g., alcoholism, autoimmune hepatitis, malignancy with hepatic involvement, hemochromatosis, alpha-1 antitrypsin deficiency, Wilson's Disease, other congenital or metabolic conditions affecting the liver, congestive heart failure or other severe cardiopulmonary disease, etc.). Gilbert's syndrome, a benign disorder associated with low-grade hyperbilirubinemia, will not exclude individauls from participation in this trial. Autoimmune hepatitis stigmata attributed to HDV infection in the opinion of the investigator are allowed. White blood cells (WBC) count < 3000 cells/mm^3 (<1500 if African individuals). Absolute neutrophil count < 1500 cells/mm^3 (<1000 if African individuals). Platelet count < 90,000 cells/mm^3. Haemoglobin < 12 g/dL. Use of prohibited psychotropic agents at Screening. Use of interferons within 6 months before Screening. History of solid organ transplantation. Current alcohol abuse or alcohol abuse within 6 months prior to enrolment in this study; current drug addict or history of drug use within 2 years prior to Screening. History of disease requiring regular use of systemic glucocorticosteroids (inhalative glucocorticosteroids are allowed) or other immunosuppressants. Pregnant or breast-feeding females. Participation in another clinical study with investigational drugs within 30 days prior to randomization. Receipt of bulevirtide previously, e.g. in clinical trials. Inability to follow protocol requirements and undergo all protocol procedures. Note: Individuals with medical contraindication for liver biopsy are allowed to participate in this study. Such individuals will exempt from liver biopsy requirements in this study. Individuals receiving prohibited treatment at screening cannot be included into the study unless this treatment is withdrawn prior to randomization. Contraindications, intolerance or hypersensitivity to interferons alfa, genetically engineered E.coli medications, polyethylene glycol or other components of peginterferon alfa-2а. Presence or history of severe retinopathy, significant diabetic or hypertensive retinopathy. Uncontrolled diabetes mellitus. Uncontrolled cardiovascular disorders within 6 months before screening. History of autoimmune disorder (e.g. myositis, hepatitis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, severe psoriasis, rheumatoid arthritis, interstitial nephritis, thyroiditis, and systemic lupus erythematosus) Presence or history of significant psychiatric disorder (e.g. severe depression, suicide attempt, severe neurosis or cognitive disorder). Presence or history of chronic lung disease with respiratory malfunction.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pegylated Interferon alfa-2a (PEG-IFN alfa) (Arm A)<br>Participants will receive PEG-IFN alfa 180 microgram (mcg) once a week for 48 weeks | Drug: Peginterferon Alfa-2a (PEG-IFN alfa)<br>* Administered via subcutaneous injections<br>|
| Experimental: Bulevirtide 2 mg/day + PEG-IFN alfa (Arm B)<br>Participants will receive bulevirtide 2 mg/day in combination with PEG-IFN alfa 180 mcg once a week for 48 weeks followed by bulevirtide 2 mg/day for 48 weeks | Drug: Bulevirtide<br>* Administered via subcutaneous injections<br>* Other names: Hepcludex®;Drug: Peginterferon Alfa-2a (PEG-IFN alfa)<br>* Administered via subcutaneous injections<br>|
| Experimental: Bulevirtide 10 mg/day + PEG-IFN alfa (Arm C)<br>Participants will receive bulevirtide 10 mg/day in combination with PEG-IFN alfa 180 mcg once a week for 48 weeks followed by bulevirtide 10 mg/day for 48 weeks | Drug: Bulevirtide<br>* Administered via subcutaneous injections<br>* Other names: Hepcludex®;Drug: Peginterferon Alfa-2a (PEG-IFN alfa)<br>* Administered via subcutaneous injections<br>|
| Experimental: Bulevirtide 10 mg/day (Arm D)<br>Participants will receive bulevirtide 10 mg/day for 96 weeks | Drug: Bulevirtide<br>* Administered via subcutaneous injections<br>* Other names: Hepcludex®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Sustained Virological Response 24 (SVR 24) Defined as Undetectable (< limit of detection (LoD)) Hepatitis Delta Virus (HDV) Ribonucleic acid (RNA) at Week 24 after the Scheduled End of Treatment (Arms B, C and D Only) |  | Posttreatment Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Undetectable HDV RNA at Week 48 |  | Week 48 | 
| Percentage of Participants With Undetectable HDV RNA at Week 96 (Arms B, C, and D Only) |  | Week 96 | 
| Combined Sustained Response at Week 24 After the Scheduled End of Treatment: Percentage of Participants With Undetectable HDV RNA or Decrease by ≥ 2 log10 IU/ml From Baseline and Alanine Transaminase (ALT) Normalization |  | Posttreatment Week 24 | 
| Combined Sustained Response at Week 48 After the Scheduled End of Treatment: Percentage of Participants With Undetectable HDV RNA or Decrease by ≥ 2 log10 IU/ml From Baseline and Alanine Transaminase (ALT) Normalization |  | Posttreatment Week 48 | 
| Percentage of Participants With Sustained Virological Response 48 (SVR 48) Defined as Undetectable HDV RNA at Week 48 after the Scheduled End of Treatment |  | Posttreatment Week 48 | 
| Change From Baseline in Liver Stiffness as Measured by Elastography at Week 48 |  | Baseline, Week 48 | 
| Change From Baseline in Liver Stiffness as Measured by Elastography at Week 96 |  | Baseline, Week 96 | 
| Change From Baseline in Liver Stiffness as Measured by Elastography at Week 144 |  | Baseline, Week 144 | 
| Percentage of Participants who Permanently Discontinue Study Drug due to an Adverse Event |  | Up to 144 Weeks |