| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis D Virus (HDV) Infection |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Hepatitis D Virus (HDV) 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 | 10019762 |
| E.1.2 | Term | Hepatitis D |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10047455 |
| E.1.2 | Term | Viral hepatitis B without mention of hepatic coma, with hepatitis delta |
| 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 VIR-2218 and VIR-3434 in participants with chronic HDV infection in Cohorts 2 and 3 only.
-To evaluate the safety of VIR-2218 and VIR-3434 in participants with chronic HDV infection in each cohort. |
|
| E.2.2 | Secondary objectives of the trial |
-To evaluate the efficacy of VIR-2218 and VIR-3434 in participants with chronic HDV infection on HDV RNA and ALT normalization in each cohort.
-To assess the immunogenicity of VIR-3434 (for cohorts with VIR-3434)
-To assess the effects of VIR-2218 and VIR-3434 on liver fibrosis and hepatic function in each cohort. |
|
| 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. Optional Liver Biopsy
-To assess changes in liver fibrosis during treatment with the study drug
-To assess HBV and HDV replication in hepatocytes as well as for exploratory studies
2. Optional VIR-3434 PK Sub-study
-To better characterize the PK properties of VIR-3434 in participants with baseline HBsAg > 3000 IU/mL |
|
| E.3 | Principal inclusion criteria |
Age
1. Age ≥ 18 (or age of legal consent, whichever is older) to < 70 years at the time of screening
Type of Participant and Disease Characteristics
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 (within the past 12 months) or current laboratory documentation (any combination of these tests performed 6 months apart is acceptable)
3. On locally approved NRTI therapy for at least 12 weeks prior to Day 1
4. HBsAg > 0.05 IU/mL at screening
5. Positive HDV antibody for at least 6 months prior to screening and HDV RNA ≥ 500 IU/mL at screening
6. Serum alanine aminotransferase (ALT) > ULN and < 5 x ULN
Weight
7. Body Mass Index (BMI) ≥ 18 kg/m2 to ≤ 40 kg/m2
Sex and Contraceptive/Barrier Requirements
8. Female participants must have a negative pregnancy test or confirmation of postmenopausal status. Postmenopausal status is defined as 12 months with no menses without an alternative medical cause (see Section 10.7 for additional details). Women of childbearing 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 10.7) 14 days before study intervention administration through 48 weeks after the last dose of VIR-2218 or VIR-3434. Female participants must also agree to refrain from egg donation and in vitro fertilization from the time of study intervention administration through 48 weeks after the last dose of VIR-2218 or VIR-3434.
9. Male participants with female partners of childbearing potential must agree to meet 1 of the following contraception requirements from the time of study intervention administration through 48 weeks after the last dose of VIR-2218 or VIR-3434: documentation of vasectomy or azoospermia, or male condom use plus partner use of 1 of the contraceptive options listed for contraception for WOCBP (Section 10.7). Male participants must also agree to not donate sperm from the time of first study intervention administration through 48 weeks after the last dose of VIR-2218 or VIR-3434.
Informed Consent
10. Capable of giving signed informed consent as described in Section 10.1.3, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
Other Inclusion Criteria
11. 12-lead electrocardiogram (ECG) within normal limits; or, with no clinically significant abnormalities at screening, as determined by the investigator.
12. Agrees not to donate blood during the duration of the study and for an additional 3 months after the last dose of study intervention.
Cohort Specific Inclusion Criteria
13. Cohort 1 specific inclusion criteria
• Noncirrhotic
− Liver biopsy with METAVIR F0-F3 or Liver elastography (eg, Fibroscan®)
< 12 kilopascal (kPa) within the 12 months prior to screening
− Creatinine clearance (CLcr) ≥ 30 mL/min as calculated by the Cockcroft-Gault formula at screening
− Platelet count > 150,000 cells/mm3 (/μL)
14. Cohorts 2a, 2b1, 2b2, 2c, 3 & 4 specific inclusion criteria
• Noncirrhotic
-Liver biopsy with METAVIR F0-F3 or Liver elastography (eg, Fibroscan®) < 12 kPa within the 12 months prior to screening
-CLcr ≥ 30 mL/min as calculated by the Cockcroft-Gault formula at screening
-Platelet count > 150,000 cells/mm3 (/μL)
• CPT-A Cirrhotic
-Liver biopsy with METAVIR F4 or Liver elastography (eg, Fibroscan®) ≥ 12 kPa within the 12 months prior to screening
-CLcr ≥ 60 mL/min as calculated by the Cockcroft-Gault formula at screening
-Platelet count > 90,000 cells/mm3 (/μL)
-CPT score of 5 or 6, inclusive at screening and at start of study
*Alternatives to Fibroscan, eg, 2D-Shear Wave Elastography, can be allowed following approval of the sponsor
15. Cohort 5 specific inclusion criteria
• Noncirrhotic
− Liver biopsy with METAVIR F0-F3 or Liver elastography (eg,
Fibroscan®)
< 8 kilopascal (kPa) within the 12 months prior to screening
− Creatinine clearance (CLcr) ≥ 30 mL/min as calculated by the
Cockcroft-Gault formula at screening
− Platelet count > 150,000 cells/mm3 (/μL)
− HBsAg < 10,000 IU/mL |
|
| E.4 | Principal exclusion criteria |
Medical Conditions
1. History of clinically significant liver disease from non-HBV and non-HDV etiology as determined by the investigator
2. History of clinically significant immune complex disease as determined by the investigator
3. History of clinically significant autoimmune disorder as determined by the investigator
4. History of HBV-related extrahepatic disease, including but not limited to HBV-related rash, arthritis, or glomerulonephritis
5. History of allergic reactions, hypersensitivity, or intolerance to study intervention, its metabolites or excipients
6. Anti-HBs >10 mIU/L at screening
7. Corrected QT interval (QTc) > 450 milliseconds
8. ALT or AST ≥ 5x ULN
9. Total bilirubin > 2.0 mg/dL
10. Serum albumin < 30 g/L
11. Absolute neutrophil count < 1,000/mm3 (/μL)
12. International normalized ratio (INR) > 1.5
13. Hemoglobin < 8 g/dL
14. History of anaphylaxis
15. History of malignancy diagnosed or treated within 5 years (localized treatment of squamous or noninvasive 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
16. History of or listed for bone marrow or solid organ transplant
17. Known active infection other than chronic HBV and HDV infection or any clinically significant acute condition such as fever (> 38° C) or acute respiratory illness within 7 days prior to Day 1
18. Coinfection with human immunodeficiency virus (HIV), hepatitis A virus (HAV), hepatitis C virus (HCV) or hepatitis E virus (HEV). Participants who are HCV antibody positive and HCV RNA negative are eligible. Participants who are HAV or HEV immunoglobulin M antibody (IgM) positive are not eligible. Participants who are asymptomatic and HAV or HEV immunoglobulin G antibody (IgG) positive are eligible.
19. 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. Participants with controlled Diabetes Mellitus are eligible.
20. Acute or worsening chronic hepatitis, fluctuating or rapidly deteriorating hepatic function or use of any therapy known to exacerbate hepatic dysfunction in the opinion
of the investigator.
Prior/Concomitant Therapy
21. Therapy with an immunomodulatory agent, IFN-α (eg, IFN-alfa-2a or IFN-alfa-2b, or pegylated IFN-alfa-2a or alfa 2b), immunosuppressants (eg, disease-modifying antirheumatic drugs), cytotoxic or chemotherapeutic agent, or chronic systemic corticosteroids within 6 months of screening.
22. Received an HDV active agent (including lonafarnib and bulevirtide) within 90 days or 5 half-lives (if known), whichever is longer, before study intervention administration or are active in the Follow-Up period 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.
23. Receipt of an oligonucleotide (eg, siRNA, antisense oligonucleotide) with activity against HBV within 48 weeks before study intervention administration
24. Receipt of VIR-3434 or any antibody targeting HBV or HDV within 24 weeks of first study intervention administration
Additional Exclusions
25. 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). Cannabis use is permitted.
Additional Exclusions Criteria for Hepatically Impaired Participants
26. Participants requiring paracentesis > 1 time per month.
27. Participants with refractory encephalopathy or significant Central Nervous System disease as judged by the investigator.
28. History of gastric or esophageal variceal bleeding within the past 6 months.
29. Participants with Transjugular Intrahepatic Portosystemic Shunt (TIPS) placement.
30. Presence of hepatopulmonary or hepatorenal syndrome.
31. Presence of primary cholestatic liver diseases.
32. Inability or unwillingness to comply with dietary recommendations for liver cirrhosis and hepatic impairment as advised by the investigator and lifestyle considerations outlined in this protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Proportion of participants with undetectable HDV RNA (< LOD) or ≥ 2 log10 decrease in HDV RNA from baseline and alanine aminotransferase (ALT) normalization (ALT<upper limit of normal [ULN]) at Week 24 (Cohort 2 and 3 only)
• Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Week 24
• Total study duration (up to 214 weeks) |
|
| E.5.2 | Secondary end point(s) |
• Proportion of participants with undetectable HDV RNA (< LOD) or ≥ 2 log10 decrease in HDV RNA from baseline and ALT normalization at
Week 12, Week 48, Week 72, Week 96, Week 144 and Week 192
• Proportion of participants with undetectable HDV RNA (< LOD) or ≥ 2 log10 decrease in HDV RNA from baseline at Week 12, Week 24,
Week 48, Week 72, Week 96, Week 144 and Week 192
• Proportion of participants with undetectable HDV RNA (< LOD) at Week 12, Week 24, Week 48, Week 72, Week 96, Week 144 and Week 192
• Proportion of participants with HDV RNA < lower limit of quantitation (LLOQ) at Week 12, Week 24, Week 48, Week 72, Week 96, Week 144 and Week 192
• Change from baseline in HDV RNA at Week 12, Week 24, Week 48, Week 72, Week 96, Week 144 and Week 192
• Proportion of participants with ALT normalization at Week 12, Week 24, Week 48, Week 72, Week 96, Week 144 and Week 192
• Incidence of ADA and titers of ADA to VIR-3434 at specified study visits up to Week 192 (for cohorts with VIR-3434)
• Change from baseline in liver fibrosis at Week 48. Week 96, Week 144, and Week 192
• Change from baseline in Model for End Stage Liver Disease (MELD) score at Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 96, Week 144 and Week 192
• Change from baseline CPT score at Week 24, Week 48, Week 72, Week 96, Week 144 and Week 192 |
|
| 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 | Yes |
| 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 | Yes |
| 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 | Yes |
| 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.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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 |
| New Zealand |
| Moldova, Republic of |
| United Kingdom |
| Bulgaria |
| France |
| Germany |
| Italy |
| Netherlands |
| 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 is defined as the last scheduled visit (or scheduled contact) of the last participant. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 5 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 13 |
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