What side effects are associated with this type of intervention?

Common treatments for Chronic Hepatitis B, such as nucleos(t)ide analogs (e.g., lamivudine, adefovir, entecavir) and pegylated interferon, have various side effects. Nucleos(t)ide analogs are generally well-tolerated but can cause mild to moderate side effects like headache, nausea, and fatigue. Rarely, they may lead to more severe issues such as lactic acidosis and hepatomegaly with steatosis. Pegylated interferon can cause flu-like symptoms, including fever, chills, and muscle aches, as well as more serious side effects like depression, cytopenias, and thyroid dysfunction. Monitoring and managing these side effects are crucial for patient safety and treatment efficacy.

What prior FDA approvals exist?

The FDA has approved several nucleos(t)ide analogs for the treatment of Chronic Hepatitis B, including tenofovir and entecavir, which are recommended for their potent antiviral activity and low risk of drug resistance. Tenofovir is available in two forms: tenofovir alafenamide, preferred for its reduced renal and bone toxicity, and tenofovir disoproxil fumarate. Entecavir is another first-line treatment, particularly effective in nucleos(t)ide-naïve patients. Pegylated interferon (PegIFN) is also used, either alone or in combination with nucleos(t)ide analogs, to enhance treatment efficacy. These treatments are similar to the NME combination therapies being studied, which aim to improve safety, tolerability, and efficacy in CHB patients.

What other types of research exist?

Promising novel alternatives to NME combination therapies for Chronic Hepatitis B patients include Pegylated Interferon (PegIFN) alfa-2a and PegIFN alfa-2b. These therapies have shown efficacy in achieving HBeAg seroconversion, ALT normalization, and sustained suppression of HBV DNA levels. PegIFN monotherapy or in combination with lamivudine has demonstrated higher rates of virological response compared to lamivudine monotherapy. Extending PegIFN treatment duration to 96 weeks may also enhance virological response.

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Nucleos(t)ide

Combination Hepatitis B Therapies for Chronic Hepatitis B (Piranga Trial)

Phase 2

Waitlist Available

Research Sponsored by Hoffmann-La Roche

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Be older than 18 years old

Must not have

History of or suspicion of Hepatocellular Carcinoma (HCC)

Thyroid disease poorly controlled on prescribed medications or clinically relevant abnormal thyroid function tests

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 5 years

Awards & highlights

No Placebo-Only Group

Summary

This trial tests new drug combinations for Chronic Hepatitis B in patients with stable liver conditions. It aims to see if these drugs can safely and effectively treat the disease. Adefovir dipivoxil is an approved treatment for chronic hepatitis B, often used in combination with other drugs to improve efficacy.

Who is the study for?

This trial is for adults with Chronic Hepatitis B who've been on NUC therapy for at least a year, have low HBV DNA levels, and normal liver enzyme ALT levels. They must not be pregnant or breastfeeding and agree to use contraception. Excluded are those with heart disease, drug abuse history, significant liver fibrosis/cirrhosis, recent cancer treatments or immunosuppressants.

What is being tested?

The study tests the safety and effectiveness of new combination therapies (including PD-L1 LNA, PEG-IFN, TLR7 agents) in treating Chronic Hepatitis B compared to a control group. It includes screening up to 8 weeks, treatment up to 48 weeks and follow-up for another 48 weeks.

What are the potential side effects?

Potential side effects may include reactions related to immune system activation such as flu-like symptoms from PEG-IFN; gastrointestinal issues; fatigue; possible changes in blood counts or liver enzymes due to the various drugs being tested.

Eligibility Criteria

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have or might have liver cancer.

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My thyroid condition is not well-managed with medication.

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I have a history of severe liver problems.

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I do not have infections like Hepatitis or HIV.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 5 years for reporting.

Treatment Details

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

9Treatment groups

Experimental Treatment

Active Control

Group I: siRNA(RO7445482)+ Programmed Death Ligand-1 Locked Nucleic Acid (PD-L1 LNA; RO7191863) + NUC [1]Experimental Treatment3 Interventions

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.

Group II: siRNA (RO7445482) + TLR7 (RO7020531) + NUCExperimental Treatment3 Interventions

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.

Group III: siRNA (RO7445482) + Pegylated Interferon (PEG-IFN) + NUCExperimental Treatment3 Interventions

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.

Group IV: siRNA (RO7445482) + PD-L1 LNA (RO7191863) + NUC [2]Experimental Treatment3 Interventions

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.

Group V: siRNA (RO7445482) + CpAM (RO7049389) + NUCExperimental Treatment3 Interventions

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.

Group VI: siRNA (RO7445482) (Dose 2) + NUCExperimental Treatment2 Interventions

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.

Group VII: Short Interfering Ribonucleic acid (siRNA; RO7445482) (Dose1) + NUCExperimental Treatment2 Interventions

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.

Group VIII: Core Protein Allosteric Modulator (CpAM; RO7049389) + Toll-like Receptor 7 (TLR7;RO7020531) + NUCExperimental Treatment3 Interventions

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.

Group IX: Nucleos(t)ide (NUC) Control ArmActive Control1 Intervention

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

First Studied

Drug Approval Stage

How many patients have taken this drug

CpAM (RO7049389)

2020

Completed Phase 2

~290

siRNA (RO7445482)

2020

Completed Phase 2

~290

Nucleos(t)ide (NUC)

2020

Completed Phase 2

~290

TLR7 (RO7020531)

2020

Completed Phase 2

~290

PEG-IFN

2020

Completed Phase 2

~290

PD-L1 LNA (RO7191863)

2020

Completed Phase 2

~290

0 / 4Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for Chronic Hepatitis B (CHB) include nucleos(t)ide analogues such as entecavir and tenofovir, which inhibit viral replication by targeting the viral polymerase enzyme. Pegylated interferon works by enhancing the immune response to the virus. Novel combination therapies, including NMEs, aim to achieve a functional cure by targeting various stages of the HBV life cycle and the host immune response. These treatments are crucial for CHB patients as they can reduce viral load, improve liver function, and potentially lead to long-term remission or cure, thereby preventing complications like cirrhosis and liver cancer.

Direct-acting antivirals and viral RNA targeting for hepatitis B cure.Hepatitis B virus: promising drug targets and therapeutic implications.