Clinical trial NCT03852719: Study to Assess Efficacy and Safety of Bulevirtide in Participants With Chronic Hepatitis Delta (CHD)
Official title: A Multicenter, Open-label, Randomized Phase 3 Clinical Study to Assess Efficacy and Safety of Bulevirtide in Patients With Chronic Hepatitis Delta
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Hepatitis Delta
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2019-02-25
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants With Combined Response at Week 48
timeFrame: Week 48
Secondary outcomes:
measure: Percentage of Participants With Undetectable HDV RNA at Week 48
timeFrame: Week 48
measure: Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48
timeFrame: Week 48
measure: Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 48
timeFrame: Baseline (Baseline for Delayed Treatment/Bulevirtide 10 mg/day is reset at Week 48), Week 48
measure: Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 96
timeFrame: Baseline (Baseline for Delayed Treatment/Bulevirtide 10 mg/day is reset at Week 48), Week 96
measure: Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 144
timeFrame: Baseline, Week 144
measure: Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 192
timeFrame: Baseline, Week 192
measure: Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 240
timeFrame: Baseline, Week 240
measure: Percentage of Participants With Undetectable HDV RNA 24 Weeks After Scheduled End of Treatment (Sustained Virological Response)
timeFrame: Week 168
measure: Percentage of Participants With Undetectable HDV RNA 48 Weeks After Scheduled End of Treatment (Sustained Virological Response)
timeFrame: Week 192
measure: Percentage of Participants Who Prematurely Discontinued Study Drug Due to an Adverse Event (AE) by Week 144
timeFrame: 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
Other outcomes:
Locations:
city: New York
country: United States
facility: New York University School of Medicine, an administrative unit of New York University, an education corporation
state: New York
city: New York
country: United States
facility: Cornell University Well Madical College
state: New York
city: Essen
country: Germany
facility: Universitätsklinikum Essen (AoR), Klinik für Gastroenterologie und Hepatologie
city: Frankfurt am Main
country: Germany
facility: Universitätsklinikum Frankfurt Medizinische Klinik 1
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover, Klinik für Gastroenterologie, Hepatologie und Endokrinologie
city: Heidelberg
country: Germany
facility: Heidelberg University Hospital, Departament of Gastroenterology, Infectious Diseases, Intoxication
city: Milan
country: Italy
facility: Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
city: Modena
country: Italy
facility: Università di Modena e Reggio Emilia- Ospedale Civile S.
city: Pisa
country: Italy
facility: U.O. Epatologia - Azienda Ospedaliero Universitaria Pisana
city: Chelyabinsk
country: Russian Federation
facility: State Budgetary Educational Institution of Higher Professional Education "South Ural State Medical University" of the Ministry of Healthcare of the Russian Federation
city: Krasnodar
country: Russian Federation
facility: Specialized clinical Infectious diseases Hospital
city: Moscow
country: Russian Federation
facility: Federal Budget Institution of Science "Central Research Institute of Epidemiology" of The Federal Service on Customers' Rights Protection and Human Well-being Surveillance
city: Moscow
country: Russian Federation
facility: Federal State Budgetary Institution National Research Medical Center for Phthisiopulmonology and Infectious Diseases of the Ministry of Health of the Russian Federation
city: Moscow
country: Russian Federation
facility: LLC"Clinic of Modern Medicine"
city: Moscow
country: Russian Federation
facility: Moscow Regional Scientific and Research Clinical Institute
city: Samara
country: Russian Federation
facility: LLC Medical Company "Hepatolog"
city: Stavropol'
country: Russian Federation
facility: Stavropol Regional Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital Huddinge, Dept of Infectious Diseases
Study officials:
affiliation: Gilead Sciences
name: Gilead Medical Monitor
role: STUDY_CHAIR
References:
citation: Wedemeyer H, Aleman S, Andreone P, Blank A, Brunetto M, Bogomolov P, et al. Bulevirtide Monotherapy at Low and High Doses in Patients With Chronic Hepatitis Delta: 24 Weeks Interim Data of the Phase 3 MYR301 Study [Poster 2730]. European Association for the Study of the Liver (EASL): The Digital International Liver Congress; 2021 23-26 June.
citation: Wedemeyer H, Aleman S, Brunetto M, Blank A, Andreone P, Bogomolov P, et al. Efficacy and Safety of Bulevirtide Monotherapy Given at 2 mg or 10 mg Dose Level Once Daily for Treatment of Chronic Hepatitis Delta: Week 48 Primary Endpoint Results From a Phase 3 Randomized, Multicenter, Parallel Design Study [Oral Presentation 509]. EASL The International Liver Congress; 2022 22-26 June; London, UK.
citation: Lampertico P, Roulot D, Wedemeyer H. Bulevirtide with or without pegIFNalpha for patients with compensated chronic hepatitis delta: From clinical trials to real-world studies. J Hepatol. 2022 Nov;77(5):1422-1430. doi: 10.1016/j.jhep.2022.06.010. Epub 2022 Jun 22.
citation: Wedemeyer H, Aleman S, Brunetto M, Blank A, Andreone P, Bogomolov P, et al. Efficacy and Safety at 96 weeks of Bulevirtide 2 mg or 10 mg Monotherapy for Chronic Hepatitis D: Results From an Interim Analysis of a Phase 3 Randomized Study. [Oral Presentation OS-068]. EASL The International Liver Congress; 2023 21-24 June; Vienna, AUS.
citation: Wedemeyer H, Aleman S, Brunetto MR, Blank A, Andreone P, Bogomolov P, Chulanov V, Mamonova N, Geyvandova N, Morozov V, Sagalova O, Stepanova T, Berger A, Manuilov D, Suri V, An Q, Da B, Flaherty J, Osinusi A, Liu Y, Merle U, Schulze Zur Wiesch J, Zeuzem S, Ciesek S, Cornberg M, Lampertico P; MYR 301 Study Group. A Phase 3, Randomized Trial of Bulevirtide in Chronic Hepatitis D. N Engl J Med. 2023 Jul 6;389(1):22-32. doi: 10.1056/NEJMoa2213429. Epub 2023 Jun 22.
citation: Wedemeyer H, Aleman S, Brunetto M, Blank A, Andreone P, Bogomolov P, Chulanov V, Mamonova N, Geyvandova N, Morozov V, Sagalova O, Stepanova T, Berger A, Ciesek S, Manuilov D, Mercier RC, Da BL, Chee GM, Li M, Flaherty JF, Lau AH, Osinusi A, Schulze Zur Wiesch J, Cornberg M, Zeuzem S, Lampertico P. Bulevirtide monotherapy in patients with chronic HDV: Efficacy and safety results through week 96 from a phase III randomized trial. J Hepatol. 2024 Oct;81(4):621-629. doi: 10.1016/j.jhep.2024.05.001. Epub 2024 May 9.