Study to Assess Efficacy and Safety of Bulevirtide 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 for treatment of chronic hepatitis delta (CHD) in comparison to delayed treatment.

Official Title
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A Multicenter, Open-label, Randomized Phase 3 Clinical Study to Assess Efficacy and Safety of Bulevirtide in Patients With Chronic Hepatitis Delta

Conditions
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Chronic Hepatitis Delta

Intervention / Treatment
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* Drug: Bulevirtide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated informed consent form. Positive serum anti-hepatitis delta virus (HDV) antibody results or polymerase chain reaction (PCR) results for serum/ plasma HDV ribonucleic acid (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. Negative urine pregnancy test for females of childbearing potential. Inclusion criteria for females: 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 (double barrier method or barrier contraception in combination with hormonal or intrauterine contraceptive) throughout the study and for 3 months after the last dose of the study medication for participants discontinued during the treatment period. 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 study and for 3 months after the last dose of the study medication for participants discontinued during the treatment period. Exclusion Criteria: Child-Pugh hepatic insufficiency score over 7 points. 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 uncontrolled human immunodeficiency virus (HIV) coinfection. Individuals with HCV antibodies can be enrolled, if screening HCV RNA test is negative. Individuals with HIV infection can be enrolled if cluster of differentiation (CD4+) cell counts are >500/mL and HIV RNA is below limit of detection for at least 12 months. Creatinine clearance < 60 mL/min as estimated using Cockcroft-Gault formula. Total bilirubin ≥ 34.2 µmol/L. (Participants 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 a history of malignancy, or an untreated pre-malignancy disorder 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. Participants 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. Participants with mental disorders or social circumstances that preclude them from following protocol requirements. Current or previous (within last 2 years) 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 patients 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 participants). Neutrophil count < 1500 cells/mm^3 (<1000 if African participants). Platelet count < 60,000 cells/mm^3. 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; past or current drug addict. 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: Participants with medical contraindication for liver biopsy are allowed to participate in this study. Such participants 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.

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 |
| --- | --- |
| Experimental: Delayed Treatment<br>Participants will receive delayed treatment with bulevirtide 10 mg/day subcutaneously (SC) for 96 weeks after an observational period of 48 weeks. | Drug: Bulevirtide<br>* Administered via SC injections<br>* Other names: Hepcludex®;|
| Experimental: Bulevirtide 2 mg/day<br>Participants will receive bulevirtide 2 mg/day SC for 144 weeks. | Drug: Bulevirtide<br>* Administered via SC injections<br>* Other names: Hepcludex®;|
| Experimental: Bulevirtide 10 mg/day<br>Participants will receive bulevirtide 10 mg/day SC for 144 weeks. | Drug: Bulevirtide<br>* Administered via SC 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 Combined Response at Week 48 | Combined response was defined as fulfilment of two conditions simultaneously: Undetectable (< lower limit of quantification (LLOQ, target not detected)) HDV RNA or decrease by ≥ 2 log10 IU/mL from baseline; and ALT normalization. | Week 48 | 

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 Alanine Aminotransaminase (ALT) Normalization at Week 48 | ALT normalization was defined as an ALT value within the normal range, based on the central laboratories [Russian sites: ≤ 31 U/L for females and ≤ 41 U/L for males; all other sites: ≤ 34 U/L for females and ≤ 49 U/L for males]) | Week 48 | 
| Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 48 |  | Baseline, Week 48 | 
| Percentage of Participants Who Permanently Discontinued Study Drug Due to an Adverse Event (AE) (Week 48) | An AE was defined as any untoward medical occurrence in a participant administered study drug and which did not necessarily had a causal relationship with the study drug. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not related to the study drug. | First dose date up to Week 48 | 
| Percentage of Participants Who Permanently Discontinued Study Drug Due to an Adverse Event (AE) (Week 96) | An AE was defined as any untoward medical occurrence in a participant administered study drug and which did not necessarily had a causal relationship with the study drug. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not related to the study drug. | Delayed Treatment arm: Week 48 up to Week 96; Bulevertide 2mg/day and 10 mg/day arms: First dose date up to Week 96 | 
| Percentage of Participants Who Permanently Discontinued Study Drug Due to an Adverse Event (AE) (Week 144) | An AE was defined as any untoward medical occurrence in a participant administered study drug and which did not necessarily had a causal relationship with the study drug. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not related to the study drug. | First dose date up to Week 144. | 
| Percentage of Participants With Undetectable HDV RNA 24 Weeks After Scheduled End of Treatment (Sustained Virological Response) |  | Week 168 | 
| Percentage of Participants With Undetectable HDV RNA 48 Weeks After Scheduled End of Treatment (Sustained Virological Response) |  | Week 192 | 
| Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 96 | A mixed-effects model for repeated measures (MMRM) was used to test null hypotheses of no difference compared to the control group. Change from baseline in liver stiffness was the dependent variable using data for all post-baseline analysis visits up to Week 96. The model included treatment, region, presence of cirrhosis, visit and treatment-by-visit interaction as fixed-effect factors, and baseline Liver stiffness as covariate | Baseline, Week 96 | 
| Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 144 |  | Baseline, Week 144 | 
| Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 192 |  | Baseline, Week 192 | 
| Change From Baseline in Liver Stiffness, as Measured by Elastography at Weeks 240 |  | Baseline, Week 240 |