Hepatitis B, Chronic
Conditions
Brief summary
This is a prospective, multi-centre, randomized, double-blind, placebo-controlled, Phase 2a experimental study of oral FXR modulator EYP001a/placebo combined with NAs in virologically suppressed CHB patients to improve functional cure rates.
Detailed description
A total of 49 eligible patients will be enrolled and randomized at approximately 14 study sites. Patients will be randomized prior to study drug (EYP001a or placebo and NA) administration on Day 1 in the ratio of 3:1 into 2 arms: * Experimental Arm: EYP001a Dose A QD + NA daily (37 patients) * Control Arm: Placebo + NA daily (12 patients) The maximum total engagement duration for eligible patients in this study is up to 370 days: 90 days screening, 112 days (16 weeks) treatment period and 168 days (24 weeks) follow-up. Patients enrolled in the study will be assessed as outpatients. Patient screening will occur no more than 90 days prior to the Day 1 visit. Eligible patients will undergo further assessments on Day 1 to qualify for study drug administration on Day 1. The visits during the study are planned as below: * Screening visit: 12 weeks (90 days) * 16 weeks treatment period: * Treatment Visit 1 (Week 1 \[Day 1\]) * Treatment Visit 2 (Week 2 \[Day 14 ±3 days\]) * Treatment Visit 3 (Week 4 \[Day 28 ±3 days\]) * Treatment Visit 4 (Week 6 \[Day 42 ±3 days\]) * Treatment Visit 5 (Week 8 \[Day 56 ±3 days\]) * Treatment Visit 6 (Week 10 \[Day 70 ± 3 days\]) * Treatment Visit 7 (Week 12 \[Day 84 ± 3 days\]) * Treatment Visit 8 (Week 14 \[Day 98 ± 3 days\]) * Treatment Visit 9 (Week 16 \[Day 112±3 days\]) * 24 weeks safety follow-up period: * Follow-up Visit 1 (Week 20 \[Day 140 ±7 days\]) * Follow-up Visit 2 (Week 28 \[Day 196 ±7 days\]) * Follow-up Visit 3 (Week 40 \[Day 280 ±7 days\]) Note: during follow-up patients are kept on NA until the end of the trial: Week 40 (consolidation Phase).
Interventions
DRUGEYP001a
Oral tablets
DRUGPlacebo
Oral tablets
DRUGNucleotide analogue (Entecavir or Tenofovir Disoproxil)
Oral tablets
Sponsors
Novotech (Australia) Pty Limited
Synteract, Inc.
Eurofins
Parexel
Enyo Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Triple blind
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: * Are on stable NA therapy at least 12 months from the screening date (ETV or TDF) * Has virally suppressed CHB: HBV DNA \<LLOQ and serum HBsAg \>100 IU/mL * Has liver imaging to screen for hepatocellular carcinoma or concomitant pancreaticobiliary disease either in the prior 6 months or at screening. * Is not of childbearing potential or, if of childbearing potential, is not pregnant as confirmed by a negative serum human chorionic gonadotropin test at screening and is not planning a pregnancy during the course of the study. Main
Exclusion criteria
* Is an employee of a contract research organization (CRO), vendor, or Sponsor involved with this study. * Has known hepatocellular carcinoma or pancreaticobiliary disease. * Neutropenia (defined by two confirmed values within screening period of \<1500/μL). * Has Gilbert syndrome. * Shows evidence of worsening liver function, defined as either a confirmed (two assessments at least 3 days apart) increase \>2 ULN ALT or AST or an increase of \>1.5 × first assessed value of TBL or associated with clinical signs or symptoms of liver impairment. * Has known or suspected non-CHB liver disease * History of cirrhosis or liver decompensation, including ascites, hepatic encephalopathy, or presence of oesophageal varices. * Probable or possible F3 stage with a vibration controlled transient elastography (VCTE). Patients with normal baseline ALT and VCTE \>8.8 kPa are excluded. Patients with baseline ALT \>ULN (but \<2ULN per EC5) and who have VCTE \>10.5 kPa at baseline are excluded 11. * Has known history of alcohol abuse or daily heavy alcohol consumption * Has clinically relevant immunosuppression, including, but not limited to, immunodeficiency conditions such as common variable hypogammaglobulinemia. * Has used anti-HBV medications other than NAs within 90 days prior to screening. * Has any of the following exclusionary laboratory results at screening: 1. Estimated glomerular filtration rate \<60 mL/min/1.73 m2 (the Modification of Diet in Renal Disease formula). 2. Thyroid-stimulating hormone \>1.5× ULN or abnormal free triiodothyronine or free thyroxine.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HBsAg Change (Δ log10) From Day 1 to Week 16 of Treatment | LS mean at week 16 (Day 1, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Week 14, and Week 16) | Efficacy of Vonafexor on top of NA assessed as HBsAg decline (Δ log10) from Day 1 to Week 16 of treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Virologic Failure Rate | 40 weeks | Virologic failure rate (breakthrough)2 of HBV-DNA (% patients with a confirmed quantifiable HBV DNA increase of ≥ 1log10 HBV DNA copies/mL above LLOQ3) assessed at Week 16 of treatment period and Weeks 20, 28 and 40 during follow-up period |
Countries
Australia, Hong Kong, Poland, South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experimental Arm Experimental Arm: EYP001a Dose A QD + NA daily (37 patients)
EYP001a: Oral tablets
Nucleotide analogue (Entecavir or Tenofovir Disoproxil): Oral tablets | 19 |
| Control Arm Control Arm: Placebo + NA daily (12 patients)
Placebo: Oral tablets
Nucleotide analogue (Entecavir or Tenofovir Disoproxil): Oral tablets | 7 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Experimental Arm | Control Arm | Total |
|---|---|---|---|
| Age, Continuous | 45.16 years STANDARD_DEVIATION 8.32 | 46.29 years STANDARD_DEVIATION 8.46 | 45.46 years STANDARD_DEVIATION 8.2 |
| Height | 168.763 cm STANDARD_DEVIATION 9.333 | 172.529 cm STANDARD_DEVIATION 11.342 | 169.777 cm STANDARD_DEVIATION 9.823 |
| Race/Ethnicity, Customized Asian | 19 participants | 5 participants | 24 participants |
| Race/Ethnicity, Customized Black or African American | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White | 0 participants | 1 participants | 1 participants |
| Sex: Female, Male Female | 5 Participants | 1 Participants | 6 Participants |
| Sex: Female, Male Male | 14 Participants | 6 Participants | 20 Participants |
| Weight | 68.821 kg STANDARD_DEVIATION 11.293 | 82.857 kg STANDARD_DEVIATION 21.084 | 72.600 kg STANDARD_DEVIATION 15.454 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 7 |
| other Total, other adverse events | 17 / 19 | 3 / 7 |
| serious Total, serious adverse events | 0 / 19 | 0 / 7 |
Outcome results
Primary
HBsAg Change (Δ log10) From Day 1 to Week 16 of Treatment
Efficacy of Vonafexor on top of NA assessed as HBsAg decline (Δ log10) from Day 1 to Week 16 of treatment
Time frame: LS mean at week 16 (Day 1, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Week 14, and Week 16)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Experimental Arm | HBsAg Change (Δ log10) From Day 1 to Week 16 of Treatment | -0.029 log10 IU/mL | Standard Error 0.0195 |
| Control Arm | HBsAg Change (Δ log10) From Day 1 to Week 16 of Treatment | -0.066 log10 IU/mL | Standard Error 0.0348 |
Secondary
Virologic Failure Rate
Virologic failure rate (breakthrough)2 of HBV-DNA (% patients with a confirmed quantifiable HBV DNA increase of ≥ 1log10 HBV DNA copies/mL above LLOQ3) assessed at Week 16 of treatment period and Weeks 20, 28 and 40 during follow-up period
Time frame: 40 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental Arm | Virologic Failure Rate | Week 16 | 0 participants |
| Experimental Arm | Virologic Failure Rate | Week 20 | 0 participants |
| Experimental Arm | Virologic Failure Rate | Week 28 | 0 participants |
| Experimental Arm | Virologic Failure Rate | Week 40 | 0 participants |
| Control Arm | Virologic Failure Rate | Week 40 | 0 participants |
| Control Arm | Virologic Failure Rate | Week 16 | 0 participants |
| Control Arm | Virologic Failure Rate | Week 28 | 0 participants |
| Control Arm | Virologic Failure Rate | Week 20 | 0 participants |