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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase II, Randomised, Adaptive, Open-Label Platform Trial To Evaluate Efficacy And Safety Of Multiple Combination Therapies In Participants With Chronic Hepatitis B

Conditions
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Hepatitis B, Chronic

Intervention / Treatment
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* Drug: Nucleos(t)ide (NUC)
* Drug: CpAM (RO7049389)
* Drug: TLR7 (RO7020531)
* Drug: siRNA (RO7445482)
* Drug: PEG-IFN
* Drug: PD-L1 LNA (RO7191863)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Nucleos(t)ide (NUC) Control Arm<br>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. | Drug: Nucleos(t)ide (NUC)<br>* Nucleos(t)ide (NUC) will be administered orally<br>|
| Experimental: Core Protein Allosteric Modulator (CpAM; RO7049389) + Toll-like Receptor 7 (TLR7;RO7020531) + NUC<br>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. | Drug: Nucleos(t)ide (NUC)<br>* Nucleos(t)ide (NUC) will be administered orally<br>Drug: CpAM (RO7049389)<br>* CpAM (RO7049389) will be administered orally<br>Drug: TLR7 (RO7020531)<br>* TLR7 (RO7020531) will be administered orally<br>|
| Experimental: Short Interfering Ribonucleic acid (siRNA; RO7445482) (Dose1) + NUC<br>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. | Drug: Nucleos(t)ide (NUC)<br>* Nucleos(t)ide (NUC) will be administered orally<br>Drug: siRNA (RO7445482)<br>* siRNA (RO7445482) will be administered subcutaneously<br>|
| Experimental: siRNA (RO7445482) (Dose 2) + NUC<br>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. | Drug: Nucleos(t)ide (NUC)<br>* Nucleos(t)ide (NUC) will be administered orally<br>Drug: siRNA (RO7445482)<br>* siRNA (RO7445482) will be administered subcutaneously<br>|
| Experimental: siRNA (RO7445482) + Pegylated Interferon (PEG-IFN) + NUC<br>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. | Drug: Nucleos(t)ide (NUC)<br>* Nucleos(t)ide (NUC) will be administered orally<br>Drug: siRNA (RO7445482)<br>* siRNA (RO7445482) will be administered subcutaneously<br>Drug: PEG-IFN<br>* PEG-IFN will be administered subcutaneously<br>* Other names: Pegasys®;|
| Experimental: siRNA (RO7445482) + CpAM (RO7049389) + NUC<br>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. | Drug: Nucleos(t)ide (NUC)<br>* Nucleos(t)ide (NUC) will be administered orally<br>Drug: CpAM (RO7049389)<br>* CpAM (RO7049389) will be administered orally<br>Drug: siRNA (RO7445482)<br>* siRNA (RO7445482) will be administered subcutaneously<br>|
| Experimental: siRNA (RO7445482) + TLR7 (RO7020531) + NUC<br>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. | Drug: Nucleos(t)ide (NUC)<br>* Nucleos(t)ide (NUC) will be administered orally<br>Drug: TLR7 (RO7020531)<br>* TLR7 (RO7020531) will be administered orally<br>Drug: siRNA (RO7445482)<br>* siRNA (RO7445482) will be administered subcutaneously<br>|
| Experimental: siRNA(RO7445482)+ Programmed Death Ligand-1 Locked Nucleic Acid (PD-L1 LNA; RO7191863) + NUC [1]<br>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. | Drug: Nucleos(t)ide (NUC)<br>* Nucleos(t)ide (NUC) will be administered orally<br>Drug: siRNA (RO7445482)<br>* siRNA (RO7445482) will be administered subcutaneously<br>Drug: PD-L1 LNA (RO7191863)<br>* PD-L1 LNA (RO7191863) will be administered subcutaneously<br>|
| Experimental: siRNA (RO7445482) + PD-L1 LNA (RO7191863) + NUC [2]<br>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. | Drug: Nucleos(t)ide (NUC)<br>* Nucleos(t)ide (NUC) will be administered orally<br>Drug: siRNA (RO7445482)<br>* siRNA (RO7445482) will be administered subcutaneously<br>Drug: PD-L1 LNA (RO7191863)<br>* PD-L1 LNA (RO7191863) will be administered subcutaneously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with HBsAg loss |  | Up to 96 weeks | 
| Percentage of Participants with HBsAg seroconversion |  | 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 | 
| 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 | 
| Plasma Pharmacokinetics (PK) (TLR7) (IU/mL) |  | Up to 48 weeks | 
| Plasma PK (CpAM) (IU/mL) |  | Up to 48 weeks | 
| Plasma PK (NUC) (IU/mL) |  | Up to 48 weeks | 
| Plasma PK (siRNA) (IU/mL) |  | Up to 48 weeks | 
| Serum PK (PEG-IFN) (IU/mL) |  | Up to 48 weeks | 
| Percentage of Participants with Adverse Events (AEs) |  | Up to 96 weeks | 
| Percentage of Participants with Anti-siRNA Antibodies |  | Up to 96 weeks | 
| Percentage of Participants with Anti-PEG-IFN Antibodies |  | Up to 96 weeks | 
| Plasma PK PD-L1 LNA |  | Up to 37 weeks | 
| Percentage of Participants with Anti PD-L1 LNA Antibodies |  | Up to 85 weeks |