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

Chronic Hepatitis Delta Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03852719
• Other study ID #: MYR301
• Secondary ID: 2019-001213-17
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: April 17, 2019
• Est. completion date: July 2024

Study information

• Verified date: September 2023
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 150
• Est. completion date: July 2024
• Est. primary completion date: November 26, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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 participants 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 participants 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. (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.)

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. Participants 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. Participants 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 patients 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 participants).

14. Neutrophil count < 1500 cells/mm^3 (<1000 if African participants).

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:

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.

Related Conditions & MeSH terms

• Chronic Hepatitis Delta
• Hepatitis
• Hepatitis A
• Hepatitis D
• Hepatitis, Chronic

Intervention

Drug:
• Bulevirtide
Administered via SC injections

Locations

Country	Name	City	State
Germany	Universitätsklinikum Essen (AoR), Klinik für Gastroenterologie und Hepatologie	Essen
Germany	Universitätsklinikum Frankfurt Medizinische Klinik 1	Frankfurt am Main
Germany	Universitätsklinikum Hamburg-Eppendorf	Hamburg
Germany	Medizinische Hochschule Hannover, Klinik für Gastroenterologie, Hepatologie und Endokrinologie	Hannover
Germany	Heidelberg University Hospital, Departament of Gastroenterology, Infectious Diseases, Intoxication	Heidelberg
Italy	Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico	Milan
Italy	Università di Modena e Reggio Emilia- Ospedale Civile S.	Modena
Italy	U.O. Epatologia - Azienda Ospedaliero Universitaria Pisana	Pisa
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	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	LLC Medical Company "Hepatolog"	Samara
Russian Federation	Stavropol Regional Hospital	Stavropol'
Sweden	Karolinska University Hospital Huddinge, Dept of Infectious Diseases	Stockholm
United States	Cornell University Well Madical College	New York	New York
United States	New York University School of Medicine, an administrative unit of New York University, an education corporation	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Germany,  Italy,  Russian Federation,  Sweden, 

References & Publications (5)

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. — View 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.

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.

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.

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Percentage of Participants With Undetectable HDV RNA at Week 48		Week 48
Secondary	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
Secondary	Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 48		Baseline, Week 48
Secondary	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
Secondary	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
Secondary	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.
Secondary	Percentage of Participants With Undetectable HDV RNA 24 Weeks After Scheduled End of Treatment (Sustained Virological Response)		Week 168
Secondary	Percentage of Participants With Undetectable HDV RNA 48 Weeks After Scheduled End of Treatment (Sustained Virological Response)		Week 192
Secondary	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
Secondary	Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 144		Baseline, Week 144
Secondary	Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 192		Baseline, Week 192
Secondary	Change From Baseline in Liver Stiffness, as Measured by Elastography at Weeks 240		Baseline, Week 240

External Links

•   Gilead Clinical Trials Website