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

Phase 2

Completed

Conditions: Chronic Hepatitis Delta

Interventions: Drug: Bulevirtide
Drug: Peginterferon Alfa-2a (PEG-IFN alfa)

Registration Number: NCT03852433

Lead Sponsor: Gilead Sciences

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

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 175

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 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.
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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Bulevirtide 2 mg/day + PEG-IFN alfa	Bulevirtide	Participants will receive bulevirtide 2 mg once a day subcutaneously incombination with PEG-IFN alfa 180 mcg once a week subcutaneously for 48 weeks followed by bulevirtide 2 mg once a day for 48 weeks and additional 48 weeks follow-up.
Bulevirtide 2 mg/day + PEG-IFN alfa	Peginterferon Alfa-2a (PEG-IFN alfa)	Participants will receive bulevirtide 2 mg once a day subcutaneously incombination with PEG-IFN alfa 180 mcg once a week subcutaneously for 48 weeks followed by bulevirtide 2 mg once a day for 48 weeks and additional 48 weeks follow-up.
Bulevirtide 10 mg/day + PEG-IFN alfa	Peginterferon Alfa-2a (PEG-IFN alfa)	Participants will receive bulevirtide 10 mg once a day subcutaneously in combination with PEG-IFN alfa 180 mcg once a week subcutaneously for 48 weeks followed by bulevirtide 10 mg once a day for 48 weeks and additional 48 weeks follow-up.
Pegylated Interferon alfa-2a (PEG-IFN alfa)	Peginterferon Alfa-2a (PEG-IFN alfa)	Participants will receive PEG-IFN alfa 180 microgram (mcg) once a week subcutaneously for 48 weeks with additional 48 weeks follow-up.
Bulevirtide 10 mg/day + PEG-IFN alfa	Bulevirtide	Participants will receive bulevirtide 10 mg once a day subcutaneously in combination with PEG-IFN alfa 180 mcg once a week subcutaneously for 48 weeks followed by bulevirtide 10 mg once a day for 48 weeks and additional 48 weeks follow-up.
Bulevirtide 10 mg once a day	Bulevirtide	Participants will receive bulevirtide 10 mg once a day subcutaneously for 96 weeks with additional 48 weeks follow-up

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Sustained Virological Response at Week 24 After the Scheduled End of Treatment (SVR24)	24 weeks after EOT (Week 72 for Arm A and study Week 120 for Arms B, C, and D)	SVR24 was defined as undetectable hepatitis delta virus (HDV) RNA (HDV RNA value \< lower limit of quantitation \[LLOQ\] with target not detected) at 24 weeks after the scheduled end of treatment (EOT).

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Undetectable HDV RNA at Week 48	Week 48	Undetectable HDV RNA at Week 48 means undetectable (\< LLOQ, target not detected) HDV RNA at Week 48.
Change From Baseline in Liver Stiffness as Measured by Elastography at Week 144	Baseline, 48 weeks after EOT (Week 96 for Arm A and study Week 144 for Arms B, C, and D)	The MMRM model was used for analysis.
Percentage of Participants With Sustained Virological Response 48 After the Scheduled End of Treatment (SVR 48)	48 weeks after EOT (Week 96 for Arm A; Week 144 for Arms B, C, and D)	SVR 48 is defined as undetectable hepatitis delta virus (HDV) RNA (HDV RNA value \< lower limit of quantitation \[LLOQ\] with target not detected) at 48 weeks after the scheduled end of treatment.
Percentage of Participants With Undetectable HDV RNA at Week 96 (Arms B, C, and D Only)	Week 96	Undetectable HDV RNA at Week 96 means undetectable (\< LLOQ, target not detected) HDV RNA at Week 96.
Change From Baseline in Liver Stiffness as Measured by Elastography at Week 96	Baseline, Week 96	The MMRM model was used for analysis.
Percentage of Participants With Combined Response at Week 24 After the Scheduled End of Treatment	24 weeks after EOT (Week 72 for Arm A and Week 120 for Arms B, C, and D)	Combined response was defined as fulfilment of 2 conditions simultaneously: 1) undetectable HDV RNA or decrease by ≥ 2 log10 IU/mL from baseline, alanine aminotransferase (ALT) normalization, defined as an ALT value within the normal range, based on the central laboratories \[Russian sites: ≤ 31 U/L for females and ≤ 41 U/L for males; all other sites: ≤ 34 U/L for females and ≤ 49 U/L for males\]).
Percentage of Participants With Combined Response at Week 48 After the Scheduled End of Treatment	48 weeks after EOT (Week 96 for Arm A and Week 144 for Arm B, C, and D)	Combined response is defined as fulfilment of 2 conditions simultaneously: 1) undetectable HDV RNA or decrease by ≥ 2 log10 IU/mL from baseline, ALT normalization, defined as an ALT value within the normal range, based on the central laboratories \[Russian sites: ≤ 31 U/L for females and ≤ 41 U/L for males; all other sites: ≤ 34 U/L for females and ≤ 49 U/L for males\]).
Change From Baseline in Liver Stiffness as Measured by Elastography at Week 48	Baseline, Week 48	The mixed-effects models for repeated measurements (MMRM) model was used for analysis.

Trial Locations

Locations (20): LLC Medical Company "Hepatolog"
🇷🇺
Samara, Russian Federation
Federal Budget Institute of Science "Central Research Institute for Epidemiology" of Federal Service on Consumers Rights Protection and Human Well-Being Surveillance
🇷🇺
Moscow, Russian Federation
State Budgetary Educational Institution of Higher Professional Education "South Ural State Medical University" of the Ministry of Healthcare of the Russian Federation
🇷🇺
Chelyabinsk, Russian Federation
Moscow Regional Scientific and Research Clinical Institute
🇷🇺
Moscow, Russian Federation
Centre Hospitalier Universitaire Grenoble Alpes
🇫🇷
Grenoble, France
Hospital Croix Rousee
🇫🇷
Lione, France
"Matei Bals" National Institute of Infectious Diseases, Hospital department
🇷🇴
Bucharest, Romania
Dr. V. Babes Clinical Hospital of Infectious and Tropical Diseases
🇷🇴
Bucharest, Romania
"Victor Babes" Centre of Diagnostic and Treatment
🇷🇴
Bucharest, Romania
N.V.Sklifosovsky Scientific Research Institute of Emergency care of the Moscow Healthcare Department
🇷🇺
Moscow, Russian Federation
Hôpital Beaujon-Pavillon Abrami -Sce Hépatologie
🇫🇷
Clichy, France
Federal State Budgetary Institution National Research Medical Center for Phthisiopulmonology and Infectious Diseases of the Ministry of Health of the Russian Federation
🇷🇺
Moscow, Russian Federation
Hôpital Saint Joseph Hépato-Gastroentérologie
🇫🇷
Marseille, France
Specialized clinical Infectious diseases Hospital
🇷🇺
Krasnodar, Russian Federation
LLC"Clinic of Modern Medicine"
🇷🇺
Moscow, Russian Federation
Hôpital Cochin - Unité d'Hépatologie Pavillon Achard
🇫🇷
Paris, France
CH Pitié-Salpétrière - Hépato-Gastroentérologie
🇫🇷
Paris, France
"Matei Bals" National Institute of Infectious Diseases,Clinical Trials department
🇷🇴
Bucharest, Romania
Infectious Clinical Hospital "T. Ciorba", Department 5 / Medical University Department of Infectious Diseases
🇲🇩
Chisinau, Moldova, Republic of
Infectious Clinical Hospital "T. Ciorba", Department 4 / Medical University Department of Infectious Diseases
🇲🇩
Chisinau, Moldova, Republic of