| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic infection of Hepatitis B Virus. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| 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 safety and tolerability of regimens containing VIR-2218 +, VIR-3434, and/or PEG IFNα
- To evaluate the efficacy of regimens containing VIR-2218 +, VIR-3434, and/or PEG-IFNα |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the effect of regimens containing VIR-2218 +, VIR-3434, and/or PEG-IFNα on serum hepatitis B surface antigen (HBsAg)
- To assess the effect of regimens containing VIR-2218, VIR-3434, and/or PEG-IFNα on serum HBV DNA
- For hepatitis B e antigen (HBeAg)-) positive subjects: to assess the effect of regimens containing VIR- 2218 +, VIR-3434, and/or PEG-IFNα
on HBeAg and anti-HBe
- To assess the effect of regimens containing VIR-2218, VIR-3434, and/or PEG-IFNα on anti-HBs
- To characterize the pharmacokinetics (PK) of VIR-3434 (Parts A, B, C,
and D)
- To assess the immunogenicity of VIR-3434 (Parts A, B, C, and D)
- To evaluate proportion of subjects meeting criteria for nucleos(t)ide reverse transcriptase inhibitor (NRTI) discontinuation or retreatment |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥ 18 (or age of legal consent, whichever is older) to < 66 years
2. Body Mass Index (BMI) ≥ 18 kg/m2 to ≤ 35 kg/m2
3. 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)
4. On continuous NRTI therapy for at least 2 months prior to screening
5. HBV DNA < 100 IU/mL at screening
6. HBsAg > the lower limit of detection
7. Negative anti-HBs at screening
8. Besides chronic infection with HBV, must be in good health, determined from medical history, and no clinically significant findings from physical examination, vital signs, and laboratory values
9. Female subjects 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. 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 6.4) 14 days before study drug administration through 48 weeks after the last dose of study drug.
Female subjects must also agree to refrain from egg donation and in vitro fertilization from the time of study drug administration through 48
weeks after the last dose of study drug
10. Male subjects with female partners of child-bearing potential must agree to meet 1 of the following contraception requirements from the time of study drug administration through 48 weeks after the last dose of study drug: documentation of vasectomy or azoospermia, or male condom use plus partner use of 1 of the contraceptive options listed for contraception for WOCBP (Section 6.4).
Male subjects must also agree to not donate sperm from the time of first study drug administration through 48 weeks after the last dose of study
drug.
11. Willing to comply with the study requirements and able to provide written informed consent
12. Cohort 2b only: Previously enrolled in Cohort 1d of the VIR-2218-1001 study and completed the Treatment Period |
|
| E.4 | Principal exclusion criteria |
1. Significant fibrosis or cirrhosis as defined by having either a FibroScan result of > 8.5 kPa at screening or a liver biopsy within 1 year with Metavir F3 fibrosis or F4 cirrhosis.
2. History of clinically significant liver disease from non-HBV etiology
3. History of hepatic decompensation, including ascites, hepatic encephalopathy, and/or esophageal or gastric varices
4. History of immune complex disease
5. History of an autoimmune disorder
6. History of HBV-related extrahepatic disease, including but not limited to HBV-related rash, arthritis, or glomerulonephritis
7. History of allergic reactions hypersensitivity, or intolerance to monoclonal antibodies, antibody fragments or any excipients of VIR-3434
8. History of anaphylaxis
9. History 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); subjects under evaluation for malignancy are not eligible.
10. History of bone marrow or solid organ transplant
11. Known active infection other than chronic HBV infection or any clinically significant acute condition such as fever (> 38 C) or acute respiratory illness within 7 days prior to Day 1
12. Co-infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis D virus (subjects with HDV) Subjects who are
HCV antibody or HDV antibody positive but have a documented negative HCV , RNA or HDV RNA, respectively, are eligble.
13. Creatinine clearance (CLcr) < 60 mL/min as calculated by the Cockcroft-Gault formula at screening
14. Subject has the following laboratory parameters at screening by laboratory testing:
a. ALT or aspartate aminotransferase (AST) > 3x ULN
b. direct bilirubin or INR > ULN
c. platelets < the lower limit of normal (LLN)
Screening laboratory tests may be repeated (eg, for values thought to be erroneous) with Sponsor medical monitor approval.
15. Regular consumption of more than 10 units of alcohol per week (1 unit = 1 glass of wine [125 mL] = 1 measure of spirits [30 mL] = one-half pint of beer [284 mL]), or more than 2 units of alcohol per day
16. 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
17. Use of any of the following systemic medications within 14 days before study drug
administration and throughout the study:
a. Paracetamol (acetaminophen) ≥ 3 g/day
b. Isoniazid
c. Systemic steroids (prednisone equivalent of > 10 mg/day) or other immunosuppressive agents
d. Parts A, C and D only: theophylline
e. Parts A, C and D only: methadone
18. Received an investigational agent within 90 days or 5 half-lives (if known), whichever is
longer, before study drug administration or are active in the follow-up phase of another clinical study involving interventional treatment. Subjects 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 and NRTI Discontinuation Monitoring Period.
19. Receipt of an oligonucleotide (eg, siRNA, antisense oligonucleotide) with activity against HBV within 48 weeks before study drug administration
20. Receipt of VIR-2218 or VIR-3434 within 24 weeks prior to Day 1
21. Any clinically significant medical or psychiatric condition that may
interfere with study treatment, assessment, or compliance with the
protocol or otherwise makes the subject unsuitable for participation in
the study, as determined by the investigator.
22. Parts A, C and D only: Known hypersensitivity or contraindication to an
interferon product
23. Parts A, C and D only: Current or prior history of psychosis, bipolar
disorder, schizophrenia, moderate-severe depression, suicide ideation,
attempt, or gesture, or high risk for suicide
24. Parts A, C and D only: Current or prior history of clinically significant
retinal disease
25. Parts A, C and D only: Current or prior history of chronic uncontrolled
hypoglycemia, or
uncontrolled hyperglycemia/diabetes (defined as HbA1c ≥ 8%) at
screening
26. Parts A, C and D only: Current or prior history of colitis
27. Parts A, C and D only: Serum lipase ≥ 2 times the ULN
28. Parts A, C and D only: TSH and free T4 above the ULN or below the LLN
29. Parts A, C and D only: platelets < 90,000 cells/mm3
30. Parts A, C and D only: absolute neutrophil count < 1,500 cells/mm3
31. Clinically significant abnormalities on 12-lead ECG at screening |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoints are as follows:
• Proportion of subjects with treatment-emergent adverse events (TEAEs)
• Proportion of subjects with serious adverse events (SAEs)
• Proportion of subjects with HBsAg loss at end of treatment
• Proportion of subjects with HBsAg loss at 24 weeks post-end of treatment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Cohort 7a/1b: Up to 112 weeks
- Cohort 8a: up to 88 weeks
- Cohort 1c: up to 92 weeks
- Cohort 2c: up to 116 weeks
- Cohort 1d: up to 116 weeks |
|
| E.5.2 | Secondary end point(s) |
• Proportion of subjects achieving functional cure (defined as undetectable HBsAg and sustained suppression of HBV DNA [target not detected (TND)] ≥ 24 weeks after discontinuation of all treatment,
including NRTIs)
• Proportion of subjects with serum HBsAg < 10 IU/mL at end of treatment
• Proportion of subjects with serum HBsAg < 10 IU/mL at 24 weeks post-end of treatment
• Absolute serum HBsAg and change from baseline across timepoints in the study
• Nadir and maximum reduction of serum of HBsAg from baseline
• Time to achieve nadir and maximum reduction of serum HBsAg from baseline
• Time to achieve serum HBsAg loss
• For HBeAg-positive subjects: proportion of subjects with HBeAg loss (undetectable HBeAg) and/or anti-Hbe seroconversion
• For HBeAg-positive subjects: time to HBeAg loss (undetectable HBeAg) and/or anti-Hbe seroconversion
• Proportion of subjects with anti-HBs seroconversion
• VIR-3434 PK parameters
• Incidence and titers of anti-drug antibodies (ADA; if applicable) to VIR-3434
• Proportion of subjects meeting criteria for NRTI discontinuation
• Proportion of subjects meeting criteria for NRTI retreatment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Cohort 7a/1b: Up to 112 weeks
- Cohort 8a: up to 88 weeks
- Cohort 1c: up to 92 weeks
- Cohort 2c: up to 116 weeks
- Cohort 1d: up to 116 weeks |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| 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 | 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| 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 |
| Malaysia |
| New Zealand |
| Moldova, Republic of |
| Ukraine |
| Hong Kong |
| Taiwan |
| Canada |
| Korea, Republic of |
| United Kingdom |
| United States |
| Germany |
| Romania |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| Assessments for the final visit of the Follow-Up Period for the assigned cohort (eg, Week 68 for Cohorts 1a/2a, Week 52 for Cohorts 3a/4a, Week 59 for Cohorts 5a/6a) should be performed. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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