| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis B (CHB) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Long term infection with hepatitis B virus |
|
| 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 safety and tolerability of study treatment(s)
- To evaluate the efficacy of study treatment(s) as measured by the proportion of participants who achieve functional cure, defined as HBsAg loss and HBV DNA < LLOQ at FU Week 24 |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the proportion of participants with HBsAg loss with and without anti-HBsAg seroconversion during the study
- To evaluate in participants with CHB who are hepatitis B e antigen (HBeAg)-positive at baseline, the proportion of participants who achieve HBeAg loss with and without anti-HBeAg seroconversion during the study
- To evaluate the proportion of participants who remain off NUC treatment during FU
- To evaluate the proportion of participants experiencing HBV virologic breakthrough (defined as HBV DNA ≥ LLOQ after 2 consecutive HBV DNA < LLOQ in participants who are complying with NUC therapy OR confirmed HBV DNA ≥ 1 log10 IU/mL increase from nadir on treatment) during study treatment(s) |
|
| 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 |
Optional Intensive Pharmacokinetic Substudy (separate consent required).
Participants who are willing to consent will be eligible to participate in the optional PK substudy for an intensive serial PK sample collection to expand our knowledge and understanding of SLGN and VIR-2218 PK in CHB-infected participants. If a participant chooses to participate in this substudy, intensive PK blood samples will be collected as described below instead of the sparse plasma PK samples for that specific analyte on that specific visit.
For VIR-2218 and metabolite PK evaluation
Serial PK blood samples will be collected on Day 1 and at Week 20 in-clinic treatment visits in Cohorts 1, 2 (Group A), and 3 relative to VIR- 2218 dosing in clinic on the morning of intensive PK visit at the time points listed below:
- Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, 10, 12, and 24 hours postdose (8, 10, and 12 hour collections are optional)
For SLGN PK evaluation
Serial PK blood samples will be collected at any one in-clinic treatment visit between Weeks 20 through 32 (in Cohorts 1 and 2 [Group A]) and Weeks 12 through 20 (in Cohorts 2 [Group B], and 3) relative to SLGN dosing in clinic on the morning of intensive PK visit at the time points
listed below:
- Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, 10, 12, and 24 hours postdose (8, 10, and 12 hour collections are optional)
Pharmacogenomic Research:
All participants who are willing to provide separate written consent will be eligible to participate in the PG research. This PG blood sample should be drawn at the Baseline/Day 1 visit. However, if the sample is not obtained at Baseline/Day 1 visit the sample may then be drawn at any time during the study. The sample will be stored, for future PG analysis.
Samples for Optional Future Research:
Participants will be requested to consent to allow for the use of the remainder of their already collected specimens for optional future research. |
|
| E.3 | Principal inclusion criteria |
1. Must have the ability to understand and sign a written informed consent form (ICF), which must be obtained prior to initiation of study procedures
2. Adult male and nonpregnant, nonlactating female participants, 18 to 65 years (19-65 years of age in Republic of Korea) of age inclusive based on the date of the screening visit
3. Documented evidence of chronic HBV infection (eg, HBsAg positive for more than 6 months) with detectable HBsAg levels (> 1.5 log10 IU/mL) at screening
4. Screening electrocardiogram (ECG) without clinically significant abnormalities and with QTcF interval (QT corrected using Fridericia’s formula) ≤ 450 msec for males and ≤ 470 msec for females.
5. Females of childbearing potential (as defined in Appendix 4 of the protocol must have a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline prior to enrollment
6. Male and female participants of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception as described in Appendix 4 of the protocol. Must be willing and able to comply with all study requirements.
Participants in Cohort 1 should meet the following additional criteria to be eligible to participate in this study:
7. Have been on a commercially available HBV NUC treatment(s) (ie, TAF, TDF, entecavir, adefovir, lamivudine, telbivudine, either as single agents or in combination) with no change in regimen for 3 months prior to screening and willing to initiate TAF 25 mg.
8. Have a historical HBV DNA < LLOQ, measured at least once at local laboratory, 6 or more months prior to screening.
9. HBV DNA < LLOQ by central laboratory at screening
Participants in Cohort 2 and 3 should meet the following additional criterion at screening to be eligible to participate in this study:
10. HBV DNA > 2000 IU/mL (HBeAg-negative) and HBV DNA > 20,000 IU/mL (HBeAgpositive) |
|
| E.4 | Principal exclusion criteria |
1. Extensive bridging fibrosis or cirrhosis as defined clinically by any 1 of the following:
a) Metavir ≥ 3 or Ishak fibrosis score ≥ 4 by a liver biopsy within 1 year of screening, or, in the absence of an appropriate liver biopsy, either:
b) Screening FibroTest score of > 0.48 and AST to platelet ratio index (APRI) > 1 by central laboratory, or
c) Historical (within ≤ 6 months of screening) or current FibroScan with a result > 9 kPa
If liver biopsy is available, the liver biopsy result supersedes (b) and/or (c, if available)
If an appropriate liver biopsy is not available, fibrosis will be evaluated by (b) and/or (c, if available). In the event of discordance between (b) and (c), the FibroScan results will take precedence.
2. Participants meeting any of the following laboratory parameters at screening:
a) Hemoglobin < 12 g/dL (for males) or < 11 g/dL (for females)
b) White blood cell (WBC) count < 2500 cells/mm3
c) Neutrophil count < 1500 cell/mm3 (or < 1000 cell/mm3 if considered a physiological variant in a participant of African descent)
d) ALT ≥ 2 x ULN (Cohort 1 only), ALT > 5 x ULN (Cohorts 2 and 3)
e) International normalized ratio (INR) > ULN unless the participant is stable on an anticoagulant regimen affecting INR
f) Albumin < 3.5 g/dL
g) Direct bilirubin > 1.5 x ULN
h) Platelet Count < 100,000/μL
i) Positive autoantibodies, defined as any one or more of the following:
i. Antinuclear antibodies (ANA) > 1:80
ii. Smooth muscle antibodies (anti-SMA) > 1:80
iii. Antimitochondrial antibodies (AMA) > 1:40
iv. Anti-thyroid peroxidase (anti-TPO) > 35 IU/mL
j) Estimated creatinine clearance (CLcr) < 60 mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at the screening evaluation, ie,
Male: ((140 – Age [years]) x (Weight [kg])) / (72 x (Serum Creatinine [mg/dl])) = CLcr (mL/min)
Female: ((140 – Age [years]) x (Weight [kg])) x 0.85 / (72 x (Serum Creatinine [mg/dL])) = CLcr (mL/min)
3. Participants in Cohort 2 and 3: Received OAV treatment for HBV within 6 months of screening. Participants who meet criteria for initiation of NUC treatment as judged by the principal investigator (PI) during screening should be excluded from Cohorts 2 and 3.
4. Co-infection with HIV, HCV, or hepatitis D virus (HDV). Participants who are HCV Ab or HDV Ab positive, but have a documented negative HCV RNA or HDV RNA, respectively, are eligible.
5. Current or prior history of HCC (eg, as evidenced by prior imaging) or screening α-fetoprotein ≥ 50 ng/mL without imaging to rule out HCC
6. Current or prior history of clinical hepatic decompensation (eg, ascites, encephalopathy, or variceal hemorrhage).
7. Malignancy within 5 years prior to screening, with the exception of specific cancers that are cured by surgical resection (eg, basal cell skin cancer). Participants under evaluation for possible malignancy are not eligible
8. Significant cardiovascular, ophthalmological, pulmonary, or neurological disease in the opinion of the investigator
9. Diagnosis of any autoimmune disease (eg, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, pneumonitis, autoimmune hepatitis, sarcoidosis, psoriasis of greater than mild severity, autoimmune uveitis, autoimmune nephritis, thyroiditis), poorly controlled diabetes mellitus, significant psychiatric illness, severe chronic obstructive pulmonary disease (COPD), hemoglobinopathy, retinal disease, or are immunosuppressed
10. Chronic liver disease of a non-HBV etiology (eg, Wilson’s disease, hemochromatosis, alpha-1-antitrypsin deficiency, cholangitis), except for nonalcoholic fatty liver disease
11. Received solid organ or bone marrow transplant
12. Received prolonged therapy with immunomodulators (eg, corticosteroids) or biologics (eg, monoclonal antibody, interferon, nivolumab) within 6 months of screening
13. Have received inactivated vaccinations (eg, injectable influenza or pneumococcal) within 4 weeks prior to randomization or received live vaccinations within 4 weeks prior to screening
14. Use of another investigational agent within 90 days of screening, unless allowed by the sponsor
15. Current alcohol or substance abuse judged by the investigator to potentially interfere with participants compliance
16. Known hypersensitivity to study drug or formulation excipients
17. Women who are breastfeeding, pregnant, or who wish to become pregnant during the course of the study
18. Female participants unwilling to refrain from egg donation and in vitro fertilization during and until at least 5 months after last study drug dose.
19. Male participants unwilling to refrain from sperm donation during and until at least 5 months after the last study drug dose
20. Use of any prohibited concomitant medications as described in Section 5.4 of the protocol.
21. Believed by the study investigator to be inappropriate for study participation for any reason not otherwise listed. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The proportion of participants who achieve functional cure, defined as HBsAg loss and HBV DNA < LLOQ at FU Week 24 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- The proportion of participants with HBsAg loss with and without anti-HBsAg seroconversion during the study
- The proportion of participants with HBeAg loss with and without anti-HBeAg seroconversion during the study in participants with CHB who are HBeAg-positive at baseline
- The proportion of participants who remain off NUC treatment during FU
- The proportion of participants experiencing HBV virologic breakthrough during study treatment(s) as defined in Section 2 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Primary analysis - all participants within each cohort have completed FU Week 24
|
|
| 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 | No |
| 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 | 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 | No |
| E.8.1.2 | Open | No |
| 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 | 4 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
| Australia |
| Hong Kong |
| Korea, Democratic People's Republic of |
| New Zealand |
| Singapore |
| Thailand |
| Denmark |
| United Kingdom |
|
| 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
|
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | 7 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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