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

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

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

Study Overview

• Status: Completed
• Conditions: Chronic Hepatitis Delta
• Intervention / Treatment: Drug: Peginterferon Alfa-2a (PEG-IFN alfa); Drug: Bulevirtide

• Study Type: Interventional
• Enrollment (Actual): 175
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Clichy, France
    • Hôpital Beaujon-Pavillon Abrami -Sce Hépatologie
  • Grenoble, France
    • Centre Hospitalier Universitaire Grenoble Alpes
  • Lione, France
    • Hospital Croix Rousee
  • Marseille, France
    • Hôpital Saint Joseph Hépato-Gastroentérologie
  • Paris, France
    • CH Pitié-Salpétrière - Hépato-Gastroentérologie
  • Paris, France
    • Hôpital Cochin - Unité d'Hépatologie Pavillon Achard
• Moldova, Republic of
  • Chisinau, Moldova, Republic of
    • Infectious Clinical Hospital "T. Ciorba", Department 4 / Medical University Department of Infectious Diseases
  • Chisinau, Moldova, Republic of
    • Infectious Clinical Hospital "T. Ciorba", Department 5 / Medical University Department of Infectious Diseases
• Romania
  • Bucharest, Romania
    • "Matei Bals" National Institute of Infectious Diseases, Hospital department
  • Bucharest, Romania
    • "Matei Bals" National Institute of Infectious Diseases,Clinical Trials department
  • Bucharest, Romania
    • "Victor Babes" Centre of Diagnostic and Treatment
  • Bucharest, Romania
    • Dr. V. Babes Clinical Hospital of Infectious and Tropical Diseases
• Russian Federation
  • Chelyabinsk, Russian Federation
    • State Budgetary Educational Institution of Higher Professional Education "South Ural State Medical University" of the Ministry of Healthcare of the Russian Federation
  • Krasnodar, Russian Federation
    • Specialized clinical Infectious diseases Hospital
  • Moscow, 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
    • 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
    • LLC"Clinic of Modern Medicine"
  • Moscow, Russian Federation
    • Moscow Regional Scientific and Research Clinical Institute
  • Moscow, Russian Federation
    • N.V.Sklifosovsky Scientific Research Institute of Emergency care of the Moscow Healthcare Department
  • Samara, Russian Federation
    • LLC Medical Company "Hepatolog"

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Gilead Sciences
• Investigators: Study Chair: Gilead Medical Monitor, Gilead Sciences

Publications and helpful links

Helpful Links

• Gilead Clinical Trials Website

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2019
• Primary Completion (Actual): April 5, 2022
• Study Completion (Actual): September 23, 2022

Study Registration Dates

• First Submitted: February 21, 2019
• First Submitted That Met QC Criteria: February 21, 2019
• First Posted (Actual): February 25, 2019

Study Record Updates

• Last Update Posted (Actual): March 30, 2023
• Last Update Submitted That Met QC Criteria: March 24, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Liver Diseases; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis; Hepatitis A; Hepatitis D; Hepatitis, Chronic; Anti-Infective Agents; Antiviral Agents; Peginterferon alfa-2a
• Other Study ID Numbers: MYR204; 2019-001485-15 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes