Study to Assess Efficacy and Safety of Bulevirtide in Participants With Chronic Hepatitis Delta (CHD)

Phase 3

Completed

• Conditions: Chronic Hepatitis Delta
• Interventions: Drug: Bulevirtide

• Registration Number: NCT03852719
• Lead Sponsor: Gilead Sciences

Brief Summary

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. All participants will undergo a further off-treatment follow-up period of 96 weeks.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-02-21
• Study First Submitted QC: 2019-02-21
• Study First Posted: 2019-02-25
• Study Start: 2019-04-17
• Primary Completion: 2020-11-26
• Disposition First Submitted: 2021-11-12
• Disposition First Submitted QC: 2021-11-12
• Disposition First Posted: 2021-11-17
• Results First Submitted: 2022-10-03
• Results First Submitted QC: 2022-10-03
• Results First Posted: 2022-10-28
• Study Completion: 2024-08-08
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-21
• Last Update Posted: 2024-12-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 150

Inclusion Criteria

1. Provision of signed and dated informed consent form.

2. 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.

3. Positive PCR results for serum/plasma HDV RNA at screening.

4. Alanine transaminase level > 1 x upper limit of normal (ULN), but less than 10 x ULN.

5. Serum albumin > 28 g/L.

6. Negative urine pregnancy test for females of childbearing potential.

7. 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 individuals discontinued during the treatment period.

8. 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 individuals discontinued during the treatment period.

Exclusion Criteria

1. 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.
2. 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.
3. Creatinine clearance < 60 mL/min as estimated using Cockcroft-Gault formula.
4. 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.)
5. 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.
6. Systemic connective tissue disorders.
7. New York Heart Association (NYHA) class III-IV congestive heart failure.
8. Individuals with uncontrolled arterial hypertension: systolic blood pressure > 150 mm Hg and/ or diastolic blood pressure > 100 mm Hg at Screening.
9. Previous or unstable concurrent diseases or conditions that prevent individual's enrolment into the study.
10. Individuals with mental disorders or social circumstances that preclude them from following protocol requirements.
11. Current or previous (within last 2 years) decompensated liver disease, including coagulopathy, hepatic encephalopathy and esophageal varices hemorrhage.
12. 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 individuals from participation in this trial. Autoimmune hepatitis stigmata attributed to HDV infection in the opinion of the investigator are allowed.
13. White blood cells (WBC) count < 3000 cells/mm^3 (<1500 if African individuals).
14. Neutrophil count < 1500 cells/mm^3 (<1000 if African individuals).
15. Platelet count < 60,000 cells/mm^3.
16. Use of prohibited psychotropic agents at Screening.
17. Use of interferons within 6 months before Screening.
18. History of solid organ transplantation.
19. Current alcohol abuse or alcohol abuse within 6 months prior to enrolment in this study; past or current drug addict.
20. History of disease requiring regular use of systemic glucocorticosteroids (inhalative glucocorticosteroids are allowed) or other immunosuppressants.
21. Pregnant or breast-feeding females.
22. Participation in another clinical study with investigational drugs within 30 days prior to randomization.
23. Receipt of bulevirtide previously, e.g. in clinical trials.
24. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Delayed Treatment/Bulevirtide 10 mg/day	Bulevirtide	After an observational period of 48 weeks, participants will receive delayed treatment with bulevirtide 10 mg/day subcutaneously (SC) for 96 weeks and will be followed for up to 96 weeks (Up to Week 240).
Bulevirtide 2 mg/day	Bulevirtide	Participants will receive bulevirtide 2 mg/day SC for 144 weeks and will be followed for up to 96 weeks (Up to Week 240).
Bulevirtide 10 mg/day	Bulevirtide	Participants will receive bulevirtide 10 mg/day SC for 144 weeks and will be followed for up to 96 weeks (Up to Week 240).

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Combined Response at Week 48	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.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 192	Baseline, Week 192	MMRM was used for analysis.
Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 240	Baseline, Week 240
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.
Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48	Week 48	ALT normalization was defined as an ALT value within the normal range, based on the central laboratories \[Russian sites: ≤ 31 U/L for females and ≤ 41 U/L for males; all other sites: ≤ 34 U/L for females and ≤ 49 U/L for males\])
Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 48	Baseline (Baseline for Delayed Treatment/Bulevirtide 10 mg/day is reset at Week 48), Week 48	ANCOVA was used for analysis.
Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 96	Baseline (Baseline for Delayed Treatment/Bulevirtide 10 mg/day is reset at Week 48), Week 96	Mixed model for repeated measurements (MMRM) was used for analysis.
Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 144	Baseline, Week 144	MMRM was used for analysis.
Percentage of Participants With Undetectable HDV RNA 24 Weeks After Scheduled End of Treatment (Sustained Virological Response)	Week 168	Undetectable HDV RNA at Week 24 Weeks after Scheduled End of Treatment means undetectable (\< LLOQ, target not detected) HDV RNA at Week 168
Percentage of Participants With Undetectable HDV RNA 48 Weeks After Scheduled End of Treatment (Sustained Virological Response)	Week 192	Undetectable HDV RNA at Week 48 Weeks after Scheduled End of Treatment means undetectable (\< LLOQ, target not detected) HDV RNA at Week 192
Percentage of Participants Who Prematurely Discontinued Study Drug Due to an Adverse Event (AE) by Week 144	Delayed Treatment/Bulevirtide 10 mg/day arm: Week 48 up to Week 144; Bulevirtide 2mg/day and 10 mg/day arms: First dose date up to Week 144	An AE was defined as any untoward medical occurrence in a participant administered study drug and which did not necessarily have 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.

Trial Locations

Locations (19)

Universitätsklinikum Frankfurt Medizinische Klinik 1; 🇩🇪 Frankfurt am Main, Germany

Università di Modena e Reggio Emilia- Ospedale Civile S.; 🇮🇹 Modena, Italy

Cornell University Well Madical College; 🇺🇸 New York, New York, United States

Medizinische Hochschule Hannover, Klinik für Gastroenterologie, Hepatologie und Endokrinologie; 🇩🇪 Hannover, Germany

Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico; 🇮🇹 Milan, Italy

Heidelberg University Hospital, Departament of Gastroenterology, Infectious Diseases, Intoxication; 🇩🇪 Heidelberg, Germany

New York University School of Medicine, an administrative unit of New York University, an education corporation; 🇺🇸 New York, New York, United States

Universitätsklinikum Essen (AoR), Klinik für Gastroenterologie und Hepatologie; 🇩🇪 Essen, Germany

Universitätsklinikum Hamburg-Eppendorf; 🇩🇪 Hamburg, Germany

U.O. Epatologia - Azienda Ospedaliero Universitaria Pisana; 🇮🇹 Pisa, Italy

LLC"Clinic of Modern Medicine"; 🇷🇺 Moscow, Russian Federation

Karolinska University Hospital Huddinge, Dept of Infectious Diseases; 🇸🇪 Stockholm, Sweden

Stavropol Regional Hospital; 🇷🇺 Stavropol', Russian Federation

LLC Medical Company "Hepatolog"; 🇷🇺 Samara, Russian Federation

Moscow Regional Scientific and Research Clinical Institute; 🇷🇺 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

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

Specialized clinical Infectious diseases Hospital; 🇷🇺 Krasnodar, Russian Federation

Federal Budget Institution of Science "Central Research Institute of Epidemiology" of The Federal Service on Customers' Rights Protection and Human Well-being Surveillance; 🇷🇺 Moscow, Russian Federation