Clinical trial NCT03852433: Study to Assess Efficacy and Safety of Bulevirtide in Combination With Pegylated Interferon Alfa-2a in Participants With Chronic Hepatitis Delta (CHD)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Hepatitis Delta
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2019-02-25
Enrollment: 175
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 in combination with pegylated interferon in participants with chronic hepatitis delta (CHD).


Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants With Sustained Virological Response at Week 24 After the Scheduled End of Treatment (SVR24)
timeFrame: 24 weeks after EOT (Week 72 for Arm A and study Week 120 for Arms B, C, and D)
Secondary outcomes:
measure: Percentage of Participants With Undetectable HDV RNA at Week 48
timeFrame: Week 48
measure: Percentage of Participants With Undetectable HDV RNA at Week 96 (Arms B, C, and D Only)
timeFrame: Week 96
measure: Percentage of Participants With Combined Response at Week 24 After the Scheduled End of Treatment
timeFrame: 24 weeks after EOT (Week 72 for Arm A and Week 120 for Arms B, C, and D)
measure: Percentage of Participants With Combined Response at Week 48 After the Scheduled End of Treatment
timeFrame: 48 weeks after EOT (Week 96 for Arm A and Week 144 for Arm B, C, and D)
measure: Percentage of Participants With Sustained Virological Response 48 After the Scheduled End of Treatment (SVR 48)
timeFrame: 48 weeks after EOT (Week 96 for Arm A; Week 144 for Arms B, C, and D)
measure: Change From Baseline in Liver Stiffness as Measured by Elastography at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in Liver Stiffness as Measured by Elastography at Week 96
timeFrame: Baseline, Week 96
measure: Change From Baseline in Liver Stiffness as Measured by Elastography at Week 144
timeFrame: Baseline, 48 weeks after EOT (Week 96 for Arm A and study Week 144 for Arms B, C, and D)
Other outcomes:
Locations:
city: Clichy
country: France
facility: Hôpital Beaujon-Pavillon Abrami -Sce Hépatologie
city: Grenoble
country: France
facility: Centre Hospitalier Universitaire Grenoble Alpes
city: Lione
country: France
facility: Hospital Croix Rousee
city: Marseille
country: France
facility: Hôpital Saint Joseph Hépato-Gastroentérologie
city: Paris
country: France
facility: CH Pitié-Salpétrière - Hépato-Gastroentérologie
city: Paris
country: France
facility: Hôpital Cochin - Unité d'Hépatologie Pavillon Achard
city: Chisinau
country: Moldova, Republic of
facility: Infectious Clinical Hospital "T. Ciorba", Department 4 / Medical University Department of Infectious Diseases
city: Chisinau
country: Moldova, Republic of
facility: Infectious Clinical Hospital "T. Ciorba", Department 5 / Medical University Department of Infectious Diseases
city: Bucharest
country: Romania
facility: "Matei Bals" National Institute of Infectious Diseases, Hospital department
city: Bucharest
country: Romania
facility: "Matei Bals" National Institute of Infectious Diseases,Clinical Trials department
city: Bucharest
country: Romania
facility: "Victor Babes" Centre of Diagnostic and Treatment
city: Bucharest
country: Romania
facility: Dr. V. Babes Clinical Hospital of Infectious and Tropical Diseases
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 Institute of Science "Central Research Institute for Epidemiology" of Federal Service on Consumers 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: Moscow
country: Russian Federation
facility: N.V.Sklifosovsky Scientific Research Institute of Emergency care of the Moscow Healthcare Department
city: Samara
country: Russian Federation
facility: LLC Medical Company "Hepatolog"
Study officials:
affiliation: Gilead Sciences
name: Gilead Medical Monitor
role: STUDY_CHAIR
References:
citation: Asselah T, Arama SS, Bogomolov P, Bourliere M, Fontaine H, Gherlan GS, et al. Safety and Efficacy of Bulevirtide Monotherapy and in Combination with Peginterferon Alfa-2a in Patients with Chronic Hepatitis Delta: 24 Weeks Interim Data of MYR204 Phase 2b Study [Presentation]. European Association for the Study of the Liver (EASL): The Digital International Liver Congress; 2021 23-26 June.
citation: Asif B, Koh C. Hepatitis D virus (HDV): investigational therapeutic agents in clinical trials. Expert Opin Investig Drugs. 2022 Sep;31(9):905-920. doi: 10.1080/13543784.2021.1977795. Epub 2021 Oct 1.
citation: Soriano V, Moreno-Torres V, Trevino A, Corral O, de Mendoza C. Bulevirtide in the Treatment of Hepatitis Delta: Drug Discovery, Clinical Development and Place in Therapy. Drug Des Devel Ther. 2023 Jan 21;17:155-166. doi: 10.2147/DDDT.S379964. eCollection 2023.
citation: Asselah T, Lampertico P, Wedemeyer H, Streinu-Cercel A, Pantea V, Lazar S, et al. Efficacy and Safety of Bulevirtide in Combination with Pegylated Interferon alfa-2a in Patients with Chronic Hepatitis Delta: Primary Endpoint Results from a Phase 2b Open-Label, Randomized, Multicenter Study MYR204. [Poster #5009]. AASLD - The Liver Meeting; 2023 November 10-24; Boston, MA.