A Trial To Evaluate The Efficacy And Safety Of Multiple Combination Therapies In Participants With Chronic Hepatitis B (Piranga)

Roche

Status and phase: Active, not recruiting; Phase 2

Conditions: Hepatitis B, Chronic

Treatments: Drug: PEG-IFN; Drug: CpAM (RO7049389); Drug: Nucleos(t)ide (NUC); Drug: PD-L1 LNA (RO7191863); Drug: siRNA (RO7445482); Drug: TLR7 (RO7020531)

Study type: Interventional

Funder types: Industry

Identifiers

NCT04225715

2019-002086-35 (EudraCT Number)

WV41073

Details and patient eligibility

About

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.

Enrollment: 280 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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280 participants in 9 patient groups

Nucleos(t)ide (NUC) Control Arm

Active Comparator group

Description:

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.

Treatment:

Drug: Nucleos(t)ide (NUC)

Core Protein Allosteric Modulator (CpAM; RO7049389) + Toll-like Receptor 7 (TLR7;RO7020531) + NUC

Experimental group

Description:

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.

Treatment:

Drug: TLR7 (RO7020531)

Drug: CpAM (RO7049389)

Drug: Nucleos(t)ide (NUC)

Short Interfering Ribonucleic acid (siRNA; RO7445482) (Dose1) + NUC

Experimental group

Description:

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.

Treatment:

Drug: siRNA (RO7445482)

Drug: Nucleos(t)ide (NUC)

siRNA (RO7445482) (Dose 2) + NUC

Experimental group

Description:

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.

Treatment:

Drug: siRNA (RO7445482)

Drug: Nucleos(t)ide (NUC)

siRNA (RO7445482) + Pegylated Interferon (PEG-IFN) + NUC

Experimental group

Description:

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.

Treatment:

Drug: siRNA (RO7445482)

Drug: Nucleos(t)ide (NUC)

Drug: PEG-IFN

siRNA (RO7445482) + CpAM (RO7049389) + NUC

Experimental group

Description:

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.

Treatment:

Drug: siRNA (RO7445482)

Drug: CpAM (RO7049389)

Drug: Nucleos(t)ide (NUC)

siRNA (RO7445482) + TLR7 (RO7020531) + NUC

Experimental group

Description:

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.

Treatment:

Drug: siRNA (RO7445482)

Drug: TLR7 (RO7020531)

Drug: Nucleos(t)ide (NUC)

siRNA(RO7445482)+ Programmed Death Ligand-1 Locked Nucleic Acid (PD-L1 LNA; RO7191863) + NUC [1]

Experimental group

Description:

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.

Treatment:

Drug: siRNA (RO7445482)

Drug: PD-L1 LNA (RO7191863)

Drug: Nucleos(t)ide (NUC)

siRNA (RO7445482) + PD-L1 LNA (RO7191863) + NUC [2]

Experimental group

Description:

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.

Treatment:

Drug: siRNA (RO7445482)

Drug: PD-L1 LNA (RO7191863)

Drug: Nucleos(t)ide (NUC)