A Platform Study to Evaluate Investigational Therapies in Chronic Hepatitis B Infection

Study Overview
=================
Brief Summary
-----------------
This is a Phase 1b/2 platform study framework to evaluate the safety and efficacy of investigational candidate(s) and their combinations as potential treatments for adults with chronic hepatitis B virus infection.

Detailed Description
-----------------
VIR-SHB1-V201 (STRIVE) Sub-Protocol A is a Phase 2 study under the PREVAIL platform trial. This is a multi-center, open-label study designed to evaluate the safety and efficacy of regimens containing VIR-3434, VIR-2218, PEGASYS (PEG-IFNα), and nucleotide reverse transcriptase inhibitors (NRTI) in noncirrhotic adult participants with chronic HBV infection that have not received prior NRTI or PEGASYS treatment. VIR-SHB1-V202 (THRIVE) Sub-Protocol B is a Phase 2 study under the PREVAIL platform trial. This is a multi-center open-label study designed to evaluate the safety and efficacy of regimens containing VIR-3434 and NRTI with or without VIR-2218 in noncirrhotic adult participants with low viral burden of chronic HBV infection.

Official Title
-----------------
A Platform Study Evaluating the Efficacy and Safety of Investigational Therapies in Participants With Chronic Hepatitis B Infection (PREVAIL)

Conditions
-----------------
Hepatitis B, Chronic

Intervention / Treatment
-----------------
* Drug: VIR-3434
* Drug: VIR-2218
* Drug: TDF
* Drug: PEG-IFNα


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female ages 18 or older Chronic HBV infection for >/= 6 months Chronic HBV infection defined as a positive serum HBsAg, HBV DNA, or HBeAg on 2 occasions at least 6 months apart based on previous or current laboratory documentation STRIVE: HBeAg positive or negative, HBV DNA > 2,000 IU/mL, ALT > ULN and ≤ 5x ULN THRIVE: Must be/have the following, within the 1-year period prior to screening: HBeAg negative, HBV DNA ≤ 2,000 IU/mL, ALT ≤ ULN Exclusion Criteria: Any clinically significant chronic or acute medical condition that makes the participant unsuitable for participation History of clinically significant liver disease from non-HBV etiology History or current evidence of hepatic decompensation Co-infection with human immunodeficiency virus (HIV), hepatitis A virus (HAV), hepatitis C virus (HCV), hepatitis D virus (HDV) or hepatitis E virus (HEV). History or clinical evidence of alcohol or drug abuse STRIVE and THRIVE: Significant fibrosis or cirrhosis STRIVE and THRIVE: History of immune complex disease STRIVE and THRIVE: History of autoimmune disorder STRIVE and THRIVE: History of allergic reactions, hypersensitivity, or intolerance to monoclonal antibodies, antibody fragments, or any excipients of VIR-3434 STRIVE: Prior NRTI or PEG-IFN therapy STRIVE: History of known contraindication to any interferon product THRIVE: Prior NRTI therapy < 24 weeks of study or any prior PEG-IFN therapy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 66 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: STRIVE: Cohort 1a (VIR-3434 + TDF)<br>Participants will receive combination therapy with VIR-3434 + TDF for 44 weeks total | Drug: VIR-3434<br>* VIR-3434 given by subcutaneous injection<br>Drug: TDF<br>* TDF given orally<br>|
| Experimental: STRIVE: Cohort 2a (VIR-3434 + TDF)<br>Participants will receive combination therapy with VIR-3434 + TDF for 44 weeks total | Drug: VIR-3434<br>* VIR-3434 given by subcutaneous injection<br>Drug: TDF<br>* TDF given orally<br>|
| Experimental: STRIVE: Cohort 3a (VIR-3434 + TDF)<br>Participants will receive combination therapy with VIR-3434 + TDF for 36 or 40 weeks total | Drug: VIR-3434<br>* VIR-3434 given by subcutaneous injection<br>Drug: TDF<br>* TDF given orally<br>|
| Experimental: STRIVE: Cohort 4a (VIR-3434 + VIR-2218 + TDF)<br>Participants will receive combination therapy with VIR-3434 + VIR-2218 + TDF for 20 or 44 weeks total | Drug: VIR-3434<br>* VIR-3434 given by subcutaneous injection<br>Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection<br>Drug: TDF<br>* TDF given orally<br>|
| Experimental: STRIVE: Cohort 5a (VIR-3434 + VIR-2218 + TDF + PEG-IFNα)<br>Participants will receive combination therapy with VIR-3434 + VIR-2218 +TDF + PEG-IFNα for 48 weeks total | Drug: VIR-3434<br>* VIR-3434 given by subcutaneous injection<br>Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection<br>Drug: TDF<br>* TDF given orally<br>Drug: PEG-IFNα<br>* PEG-IFNα given by subcutaneous injection<br>|
| Experimental: THRIVE: Cohort 1b (VIR-3434 + TDF)<br>Participants will receive combination therapy with VIR-3434 + TDF for 44 weeks | Drug: VIR-3434<br>* VIR-3434 given by subcutaneous injection<br>Drug: TDF<br>* TDF given orally<br>|
| Experimental: THRIVE: Cohort 2b (VIR-3434 + VIR-2218 + TDF)<br>Participants will receive combination therapy with VIR-3434 + VIR-2218 + TDF for 44 weeks total | Drug: VIR-3434<br>* VIR-3434 given by subcutaneous injection<br>Drug: VIR-2218<br>* VIR-2218 given by subcutaneous injection<br>Drug: TDF<br>* TDF given orally<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| STRIVE and THRIVE: Proportion of participants achieving suppression of HBV DNA (< LLOQ) with HBsAg loss (< 0.05 IU/mL) at the end of treatment |  | Up to 72 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| STRIVE and THRIVE: Proportion of participants with treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) |  | Up to 96 weeks | 
| STRIVE and THRIVE: Proportion of participants with serum HBsAg ≤ 10 IU/mL at end of treatment |  | Up to 48 weeks | 
| STRIVE and THRIVE: Proportion of participants with serum HBsAg ≤ 10 IU/mL at 24 weeks post-end of treatment |  | Up to 72 weeks | 
| STRIVE and THRIVE: Serum HBsAg levels and change from baseline across timepoints in the study |  | Up to 96 weeks | 
| STRIVE and THRIVE: Serum HBsAg level at nadir during the study |  | Up to 96 weeks | 
| STRIVE and THRIVE: Time to achieve nadir of serum HBsAg during the study |  | Up to 96 weeks | 
| STRIVE and THRIVE: Time to achieve serum HBsAg loss (< 0.05 IU/mL) |  | Up to 96 weeks | 
| STRIVE and THRIVE: Proportion of participants with HBsAg loss with anti-HBs seroconversion at end of treatment and at 24 weeks post-end of treatment |  | Up to 76 weeks | 
| STRIVE: Proportion of participants achieving sustained suppression of HBV DNA (< LLOQ) with HBsAg loss (< 0.05 IU/mL) after discontinuation of all treatment at 24 weeks and at the F48 Follow-Up visit |  | Up to 96 weeks | 
| STRIVE: Proportion of participants with HBsAg loss (<0.05 IU/mL) at end of treatment and at 24 weeks post-end of treatment |  | Up to 72 weeks | 
| STRIVE: Proportion of participants achieving sustained suppression of HBV DNA (< LLOQ) after discontinuation of all treatment at 24 weeks and at the F48 Follow-Up visit |  | Up to 96 weeks | 
| STRIVE: For HBeAg-positive participants: proportion of participants with HBeAg loss (undetectable HBeAg) and/or anti-HBe seroconversion |  | Up to 72 weeks | 
| STRIVE: Incidence and titers of anti-drug antibodies (ADA; if applicable) to VIR-3434 |  | Up to 96 weeks | 
| STRIVE: Mean change in serum HBsAg level from baseline across timepoints in the study |  | Up to 96 weeks | 
| STRIVE: Proportion of participants achieving HBV DNA (< LLOQ) across timepoints in the study |  | Up to 96 weeks | 
| STRIVE: Proportion of participants achieving ALT ≤ ULN across timepoints in the study |  | Up to 96 weeks | 
| THRIVE: Proportion of participants achieving sustained suppression of HBV DNA (< LLOQ) with HBsAg loss (< 0.05 IU/mL) after discontinuation of all treatment at 24 weeks and at 48 weeks |  | Up to 92 weeks | 
| THRIVE: Proportion of participants achieving HBsAg loss (< 0.05 IU/mL) at end of treatment and at 24 weeks post-end of treatment |  | Up to 44 weeks | 
| THRIVE: Proportion of participants achieving sustained suppression of HBV DNA (< LLOQ) after discontinuation of all treatment at 24 weeks and at 48 weeks |  | Up to 68 weeks | 
| THRIVE: Incidence and titers of ADA (if applicable) to VIR-3434 |  | Up to 92 weeks | 
| THRIVE: Mean change in serum HBsAg level from baseline across timepoints in the study |  | Up to 92 weeks | 
| THRIVE: Proportion of participants achieving HBV DNA (< LLOQ) |  | Up to 92 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HBV, Hepatitis B Virus, Chronic Hepatitis B, Hepatitis