A Trial To Evaluate The Efficacy And Safety Of Multiple Combination Therapies In Participants With Chronic Hepatitis B
Phase 2
Completed
- Conditions
- Hepatitis B, Chronic
- Interventions
- Drug: Nucleos(t)ide (NUC)Drug: CpAM (RO7049389)Drug: TLR7 (RO7020531)Drug: siRNA (RO7445482)Drug: PD-L1 LNA (RO7191863)Drug: PEG-IFN
- Registration Number
- NCT04225715
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
This is a study designed to evaluate the safety, tolerability and efficacy of New Molecular Entity (NME) combination therapies in Chronic Hepatitis B (CHB) participants with preserved liver function and without significant fibrosis/cirrhosis. The platform design allows comparison of multiple NME combination therapies against a common control, and introduction of additional treatment arms at later study time points. Each arm will consist of a screening phase (up to 8 weeks), treatment phase (up to 48 weeks) and post-treatment follow-up phase (48 weeks). The safety and efficacy will be monitored throughout the study.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 281
Inclusion Criteria
- Body mass index between 18 and 32 kg/m2 inclusive.
- Participants with Chronic Hepatitis B (CHB) infection (HBsAg positive for >=6 months) who are on established NUC (entecavir or tenofovir alafenamide/disoproxil fumarate) monotherapy for >=12 months, having received the same NUC therapy for >=3 months prior to screening.
- HBV DNA below the lower LLOQ or < 20 IU/mL for > 6 months prior to screening and confirmed at screening.
- Alanine transaminase (ALT) <=1.5 x upper limit of normal (ULN) for > 6 months prior to screening and confirmed at screening.
- Female Participants: Eligible to participate if she is not pregnant, not breastfeeding and agrees to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive methods.
- Male Participants: During the treatment period and for at least 6 months after the final dose of study treatment, agrees to remain abstinent (refrain from heterosexual intercourse), use contraceptive measures and refrain from donating sperm.
Exclusion Criteria
- Pregnant or lactating women.
- Co-infection with other pathogens such as Hepatitis A, C, D and E or Human Immunodeficiency Virus (HIV).
- History of cirrhosis or current evidence of significant liver fibrosis or cirrhosis or decompensated liver disease.
- History of or suspicion of Hepatocellular Carcinoma (HCC).
- Thyroid disease poorly controlled on prescribed medications or clinically relevant abnormal thyroid function tests.
- Clinically significant disease other than CHB that, in the opinion of the Investigator, makes the participant unsuitable for the study.
- Pre-existing cardiac disease that in the opinion of the investigator would increase the risk for the participant to take part in the study.
- History of alcohol abuse and/or drug abuse within one year of randomization.
- History of having received (in the last 6 months) or currently receiving any systemic antineoplastic (including radiation) or immunosuppressive (including biologic immunosuppressors) or immune modulating treatment.
- Currently taking, or have received within 3 months of Day 1, systemic corticosteroids.
- Electrocardiogram (ECG) with clinically significant abnormalities.
- Previous treatment with an investigational agent for Hepatitis B (HBV) within 6 months prior to screening.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Core Protein Allosteric Modulator (CpAM; RO7049389) + Toll-like Receptor 7 (TLR7;RO7020531) + NUC TLR7 (RO7020531) Participants will receive RO7049389 (600 mg once daily \[QD\]) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg once every other day \[QOD\]) will be administered during Weeks 1-12 and Weeks 25-36. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. Nucleos(t)ide (NUC) Control Arm Nucleos(t)ide (NUC) Participants will continue their background NUC therapy for the 48-week treatment period. At the end of the treatment period, in line with current CHB treatment guidelines, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. siRNA (RO7445482) + TLR7 (RO7020531) + NUC Nucleos(t)ide (NUC) Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg QOD) will be administered during Weeks 13-24 and Weeks 37-48 (i.e., 2 treatment cycles of 12 weeks' duration each and 42 doses of RO7020531 for each cycle). At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. siRNA (RO7445482) + TLR7 (RO7020531) + NUC TLR7 (RO7020531) Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg QOD) will be administered during Weeks 13-24 and Weeks 37-48 (i.e., 2 treatment cycles of 12 weeks' duration each and 42 doses of RO7020531 for each cycle). At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. siRNA (RO7445482) + TLR7 (RO7020531) + NUC siRNA (RO7445482) Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg QOD) will be administered during Weeks 13-24 and Weeks 37-48 (i.e., 2 treatment cycles of 12 weeks' duration each and 42 doses of RO7020531 for each cycle). At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. Short Interfering Ribonucleic acid (siRNA; RO7445482) (Dose1) + NUC Nucleos(t)ide (NUC) Participants will receive RO7445482 (Dose 1) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. Core Protein Allosteric Modulator (CpAM; RO7049389) + Toll-like Receptor 7 (TLR7;RO7020531) + NUC CpAM (RO7049389) Participants will receive RO7049389 (600 mg once daily \[QD\]) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg once every other day \[QOD\]) will be administered during Weeks 1-12 and Weeks 25-36. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. siRNA(RO7445482)+ Programmed Death Ligand-1 Locked Nucleic Acid (PD-L1 LNA; RO7191863) + NUC [1] PD-L1 LNA (RO7191863) Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 13-24, in addition to their background NUC therapy for the 24-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. siRNA (RO7445482) + PD-L1 LNA (RO7191863) + NUC [2] siRNA (RO7445482) Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 25-36, in addition to their background NUC therapy for the 36-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. Core Protein Allosteric Modulator (CpAM; RO7049389) + Toll-like Receptor 7 (TLR7;RO7020531) + NUC Nucleos(t)ide (NUC) Participants will receive RO7049389 (600 mg once daily \[QD\]) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg once every other day \[QOD\]) will be administered during Weeks 1-12 and Weeks 25-36. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. siRNA (RO7445482) (Dose 2) + NUC Nucleos(t)ide (NUC) Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. siRNA (RO7445482) (Dose 2) + NUC siRNA (RO7445482) Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. siRNA (RO7445482) + Pegylated Interferon (PEG-IFN) + NUC Nucleos(t)ide (NUC) Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. PEG-IFN will be administered at a dose of 180 μg once weekly (QW) for 48 weeks. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. Short Interfering Ribonucleic acid (siRNA; RO7445482) (Dose1) + NUC siRNA (RO7445482) Participants will receive RO7445482 (Dose 1) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. siRNA (RO7445482) + Pegylated Interferon (PEG-IFN) + NUC PEG-IFN Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. PEG-IFN will be administered at a dose of 180 μg once weekly (QW) for 48 weeks. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. siRNA (RO7445482) + PD-L1 LNA (RO7191863) + NUC [2] Nucleos(t)ide (NUC) Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 25-36, in addition to their background NUC therapy for the 36-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. siRNA (RO7445482) + PD-L1 LNA (RO7191863) + NUC [2] PD-L1 LNA (RO7191863) Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 25-36, in addition to their background NUC therapy for the 36-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. siRNA (RO7445482) + Pegylated Interferon (PEG-IFN) + NUC siRNA (RO7445482) Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. PEG-IFN will be administered at a dose of 180 μg once weekly (QW) for 48 weeks. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. siRNA (RO7445482) + CpAM (RO7049389) + NUC siRNA (RO7445482) Participants will receive RO7445482 (Dose 2) and RO7049389 (600 mg QD) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. siRNA (RO7445482) + CpAM (RO7049389) + NUC Nucleos(t)ide (NUC) Participants will receive RO7445482 (Dose 2) and RO7049389 (600 mg QD) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. siRNA (RO7445482) + CpAM (RO7049389) + NUC CpAM (RO7049389) Participants will receive RO7445482 (Dose 2) and RO7049389 (600 mg QD) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. siRNA(RO7445482)+ Programmed Death Ligand-1 Locked Nucleic Acid (PD-L1 LNA; RO7191863) + NUC [1] Nucleos(t)ide (NUC) Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 13-24, in addition to their background NUC therapy for the 24-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met. siRNA(RO7445482)+ Programmed Death Ligand-1 Locked Nucleic Acid (PD-L1 LNA; RO7191863) + NUC [1] siRNA (RO7445482) Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 13-24, in addition to their background NUC therapy for the 24-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
- Primary Outcome Measures
Name Time Method Percentage of Participants with Hepatitis B Surface Antigen (HBsAg) loss at 24 weeks post-EOT (End Of Treatment) Up to 72 weeks
- Secondary Outcome Measures
Name Time Method Plasma PK (CpAM) (IU/mL) Up to 48 weeks Plasma PK PD-L1 LNA Up to 37 weeks Change from baseline in quantitative HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc, HBcrAg, HBV RNA, and HBV DNA levels over time (IU/mL) Up to 96 weeks Percentage of Participants with Anti PD-L1 LNA Antibodies Up to 85 weeks Plasma Pharmacokinetics (PK) (TLR7) (IU/mL) Up to 48 weeks Plasma PK (NUC) (IU/mL) Up to 48 weeks Percentage of Participants with Adverse Events (AEs) Up to 96 weeks Percentage of Participants with Hepatitis B Early Antigen (HBeAg) loss (baseline HBeAg-positive participants). Up to 96 weeks Percentage of Participants with HBeAg seroconversion (baseline HBeAgpositive participants) Up to 96 weeks Percentage of Participants with HBV DNA < lower limit of quantification (LLOQ), <200 IU/mL and <2,000 IU/mL Up to 96 weeks Plasma PK (siRNA) (IU/mL) Up to 48 weeks Percentage of Participants with Anti-siRNA Antibodies Up to 96 weeks Percentage of Participants with Anti-PEG-IFN Antibodies Up to 96 weeks Serum PK (PEG-IFN) (IU/mL) Up to 48 weeks Percentage of Participants with HBsAg loss Up to 96 weeks Percentage of Participants with HBsAg seroconversion Up to 96 weeks
Trial Locations
- Locations (51)
Inland Empire Liver Foundation
🇺🇸Rialto, California, United States
Quest Clinical Research
🇺🇸San Francisco, California, United States
Tokuda Hospital Sofia; Hematology department
🇧🇬Sofia, Bulgaria
University Multiprofile Hospital For Active Treatment "Sveti Ivan Rilski" EAD; clinical hematology
🇧🇬Sofia, Bulgaria
Medical Center "Nov Rehabilitatsionen Tsentar", EOOD
🇧🇬Stara Zagora, Bulgaria
University of Calgary; HSC- Faculty of Medicine
🇨🇦Calgary, Alberta, Canada
Uni of Alberta Hospital
🇨🇦Edmonton, Alberta, Canada
Ottawa Hospital
🇨🇦Ottawa, Ontario, Canada
Toronto General Hospital
🇨🇦Toronto, Ontario, Canada
Toronto Liver Centre
🇨🇦Toronto, Ontario, Canada
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