| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis B Virus (HBV) Infection |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Hepatitis B Virus (HBV) Infection |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008910 |
| E.1.2 | Term | Chronic hepatitis B |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To evaluate the efficacy of the investigational regimen(s) |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of the investigational regimens
• To assess the effect of the investigational regimens on serum hepatitis B surface antigen (HBsAg)
• To assess the effect of the investigational regimens on anti-HBs |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. VIR-SHB1-V201 - A Phase 2 Study Evaluating the Efficacy and Safety of VIR-3434 and/or VIR-2218 Containing Regimens in Participants with Chronic Hepatitis B Infection (STRIVE) - Protocol Amendment 3, Version 1.0 dated 14 December 2023
Primary Objectives:
-To evaluate the efficacy of VIR-3434 and tenofovir disoproxil fumarate (TDF) with or without VIR-2218, or VIR-2218 and PEGIFNα
Secondary Objectives:
In addition to the Master Protocol:
-To assess the effect of VIR-3434 and TDF with or without VIR-2218, or VIR-2218 and PEG-IFNα on HBsAg
-To assess the effect of VIR-3434 and TDF with or without VIR-2218, or VIR-2218 and PEG-IFNα on HBV DNA
-To assess the effect of VIR-3434 and TDF with or without VIR-2218, or VIR-2218 and PEG-IFNα on HBeAg and anti-HBe
-To assess the immunogenicity of VIR-3434
-To assess the effect of VIR-3434 and TDF with or without VIR-2218, or VIR-2218 and PEG-IFNα on ALT levels
2. VIR-SHB1-V202 - A Phase 2 Study Evaluating the Efficacy and Safety of VIR-3434 and/or VIR-2218 Containing Regimens in HBeAg-negative Participants with Low Viral Burden of Chronic Hepatitis B Infection (THRIVE) - Protocol Amendment 3, version 1.0 dated 26January 2024.
Primary Objectives:
-To evaluate the efficacy of VIR-3434 and tenofovir disoproxil fumarate (TDF) with or without VIR-2218
Secondary Objectives:
In addition to the Master Protocol:
-To assess the effect of VIR-3434 and TDF with or without VIR-2218 on HBV DNA
-To assess the effect of VIR-3434 and TDF with or without VIR-2218 on HBsAg
-To assess the immunogenicity of VIR-3434 |
|
| E.3 | Principal inclusion criteria |
Participants must meet the following inclusion criteria to be eligible for this Master Protocol. Additional clarifications and sub-protocol-specific criteria as described in respective sub-protocol(s) will be applicable:
1. Adult ≥ 18 years of age (or age of legal consent, whichever is older)
2. 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 (any combination of these tests performed 6 months apart is acceptable)
Additional characteristics of the chronic HBV infection (eg: HBeAg status, HBV DNA level, ALT level) will be required based on the patient population (Table 3) included in respective sub-protocols
3. Besides chronic infection with HBV, must be in good health, determined from medical history, and no clinically significant findings from physical examination other than those expected in persons with cirrhosis, vital signs, and laboratory values
4. Female participants must have a negative pregnancy test or confirmation of postmenopausal status. Post-menopausal status is defined as 12 months with no menses without an alternative medical cause (see Section 10.5 for additional details). Women of child-bearing potential (WOCBP) must have a negative blood pregnancy test at screening and a negative urine pregnancy test on Day 1, cannot be breast feeding, and must be willing to use highly effective methods of contraception (Section 10.5) 14 days before study intervention administration through period defined in sub-protocol.
Female participants must also agree to refrain from egg donation and in vitro fertilization from the time of study intervention administration through period defined in sub-protocol
5. Male participants with female partners of child-bearing potential must agree to meet 1 of the following contraception requirements from the time of study intervention administration through period defined in sub-protocol: documentation of vasectomy or azoospermia, or male condom use plus partner use of 1 of the contraceptive options listed for contraception for WOCBP (Section 10.5). Male participants must also agree to not donate sperm from the time of first study intervention administration through period defined in sub-protocol
6. Able to understand and comply with the study requirements and able to provide written informed consent |
|
| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply. Additional exclusion criteria may be described in respective sub-protocol(s):
1. History of clinically significant liver disease from non-HBV etiology
2. History or current evidence of hepatic decompensation, including ascites, hepatic encephalopathy, and/or esophageal or gastric varices
3. History or current suspicion of malignancy diagnosed or treated within 5 years (localized treatment of squamous or non-invasive basal cell skin cancers is permitted; cervical carcinoma in situ is allowed if appropriately treated prior to screening); participants under evaluation for malignancy are not eligible.
4. History of bone marrow or solid organ transplant
5. Known active infection other than chronic HBV infection or any clinically significant acute condition such as fever (> 38° C) or acute respiratory or GI illness within 7 days prior to Day 1
6. Co-infection with human immunodeficiency virus (HIV), hepatitis A virus (HAV), hepatitis C virus (HCV), hepatitis D virus (HDV) or hepatitis E virus (HEV). Participants who are HCV antibody or HDV antibody positive, but have a documented negative HCV RNA or HDV RNA, respectively, are eligible. Participants with positive HAV immunoglobulin M (IgM) or HEV IgM but asymptomatic and with a positive HAV IgG or HEV immunoglobulin G (IgG) are eligible.
7. History or clinical evidence of alcohol or drug abuse within the 12 months before screening or a positive drug screen at screening unless it can be explained by a prescribed medication (the diagnosis and prescription must be approved by the investigator). Note: cannabis use is permitted
8. Received an investigational agent within 90 days or 5 half-lives (if known), whichever is longer, before study intervention administration or are active in the follow-up phase of another clinical study involving interventional treatment. Participants must also agree not to take part in any other interventional study at any time during their participation in this study, inclusive of the Follow-Up Period.
9. Any clinically significant medical or psychiatric condition that may interfere with study intervention, assessment, or compliance with the protocol or otherwise makes the participant unsuitable for participation in the study, as determined by the investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Proportion of participants achieving sustained suppression of HBV DNA (< LLOQ) with HBsAg loss (< 0.05 IU/mL) at 24 weeks after discontinuation of all treatment
• Proportion of participants achieving sustained suppression of HBV DNA (< LLOQ) at 24 weeks after discontinuation of all treatment
• Proportion of participants with HBsAg loss (< 0.05 IU/mL) at 24 weeks post-end of treatment
• Proportion of participants achieving suppression of HBV DNA (< LLOQ [lower limit of quantitation]) with HBsAg loss (< 0.05 IU/mL) at the end of treatment
• Proportion of participants with HBsAg loss (< 0.05 IU/mL) at the end of treatment
• Mean change in serum HBsAg from baseline across timepoints in the study |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Depending on the development phase, the primary endpoint(s) associated analysis methods and power calculations will be from those listed above. The time point at which it will be assessed will be specified within the sub-protocol. |
|
| E.5.2 | Secondary end point(s) |
1. Proportion of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)
2. Proportion of participants with serum HBsAg < 10 IU/mL at the end of treatment
3. Proportion of participants with serum HBsAg < 10 IU/mL at 24 weeks post-end of treatment
4. Serum HBsAg levels and change from baseline across timepoints in the study
5. Serum HBsAg level at nadir during the study
6. Time to achieve nadir of serum HBsAg during the study
7. Time to achieve serum HBsAg loss (< 0.05 IU/mL)
8. Proportion of participants with HBsAg loss and anti-HBs seroconversion at end of treatment and at 24 weeks post-end of treatment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints of each end point detailed in previous section (E.5.2). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 7 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Moldova, Republic of |
| Hong Kong |
| Korea, Republic of |
| United Kingdom |
| France |
| Romania |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of study for this Master Protocol is defined as the date of the last scheduled visit (or scheduled contact) of the last participant in the last open sub-protocol. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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