Hepatitis B, Chronic, Hepatitis D
Conditions
Brief summary
This is a randomized, double-blinded, placebo-controlled, multi center, dose ranging study of safety and efficacy in both volunteers with chronic hepatitis B virus infection and in volunteers with hepatitis D virus coinfection. Volunteers will be administered multiple oral doses of ATI-2173 and assessed for safety and efficacy including blood tests to show how the body metabolizes and eliminates the investigational drug as well as how the drug effects the virus infection.
Interventions
DRUGATI-2173
ATI-2173 is a liver-targeted phosphoramidate prodrug of clevudine designed to enhance anti-HBV activity while decreasing systemic exposure to clevudine. It will be dosed as a capsule by mouth. Viread is a nucleotide analogue reverse transcriptase inhibitor used for chronic hepatitis B virus.
DRUGViread
Viread is a nucleotide analogue reverse transcriptase inhibitor used for chronic hepatitis B virus.
DRUGAB-729
AB-729 is a potent, selective, subcutaneously administered, N-acetylgalactosamine (Ga1NAc)-conjugated small interfering ribonucleic acid (siRNA) inhibitor of HBV
Sponsors
Antios Therapeutics, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
ALL SUBJECTS: 1. Provision of signed and dated informed consent form (ICF) 2. Stated willingness to comply with all study procedures and availability for the duration of the study 3. If female, meets one of the following criteria: 1. Is of childbearing potential and agrees to use an acceptable contraceptive method. Acceptable contraceptive methods include: * Abstinence from heterosexual intercourse from the first study drug administration through to at least 6 months after the last dose of the study drug or until completion of the study, whichever is longer * Use a systemic contraceptive or an intrauterine device (with or without hormones), from at least 28 days prior to the first study drug administration through to at least 6 months after the last dose of the study drug or until completion of the study, whichever is longer, with a male condom or a diaphragm/cervical cap plus spermicide from the first study drug administration through to at least 30 days after the last dose of the study drug or until completion of the study, whichever is longer * Male partner vasectomized at least 6 months prior to the first study drug administration OR 2. Male partner has had a vasectomy less than 6 months prior to dosing, and the female subject agrees to use an additional acceptable contraceptive method from the first study drug administration through to at least 6 months after the last dose of the study drug or until completion of the study, whichever is longer Or 3. Is of non-childbearing potential, defined as surgically sterile (ie, has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or is in a postmenopausal state (ie, at least 1 year without menses without an alternative medical condition prior to the first study drug administration and follicle-stimulating hormone \[FSH\] levels within the normal ranges for postmenopausal state of the clinical site at screening) 4. If male, meets one of the following criteria: 1. Is able to procreate and agrees to use one of the accepted contraceptive regimens and not to donate sperm from the first study drug administration to at least 90 days after the last drug administration. Only for Cohort D: male subjects able to procreate must agree to use an accepted contraceptive regimen and not to donate sperm from the first study drug administration to at least 6 months after the last drug administration. An acceptable method of contraception includes one of the following: * Abstinence from heterosexual intercourse * Male condom with spermicide or male condom with a vaginal spermicide (gel, foam, or suppository) Or 2. Is unable to procreate; defined as surgically sterile (ie, has undergone a vasectomy at least 6 months prior to the first study drug administration) 5. Male or female aged at least 18 years but not older than 70 years 6. Body mass index (BMI) within 18.0 kg/m2 to 35.0 kg/m2, inclusively 7. Light-, non- or ex-smoker (A light smoker is defined as someone using 10.0 nicotine units or less per day for at least 90 days prior to the first study drug administration \[refer to APPENDIX 7 for conversions of nicotine usage\]. An ex-smoker is defined as someone who completely stopped using nicotine products for at least 6 months prior to the first study drug administration) 8. Serum HBsAg positive at screening and at least 6 months prior to screening 9. For Cohorts A, B and E only, serum HBeAg positive and HBV DNA ≥ 20,000 IU/mL, or serum HBeAg negative and HBV DNA ≥ 2,000 IU/mL at screening 10. ALT and AST \< 5 times the upper limit of normal (ULN) at screening and on the day prior to the first study drug administration (Day -1) SUBJECTS COINFECTED WITH CHRONIC HBV AND HDV ONLY: 11. HDV RNA in serum ≥ 500 IU/mL at screening and evidence of HDV infection (HDVAb or HDV RNA) at least 6 months prior to screening SUBJECTS IN COHORT D ONLY: 12. Serum HBsAg levels ≥ 100 IU/mL at screening
Exclusion criteria
1. Female who is lactating at screening 2. Female who is pregnant according to the pregnancy test at screening or prior to the first study drug administration 3. History of significant hypersensitivity to clevudine, tenofovir disoproxil fumarate or any related products (including excipients of ATI-2173, tenofovir disoproxil fumarate, and the placebo) as well as severe hypersensitivity reactions (like angioedema) to any drugs 4. History of significant cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, immunologic or dermatologic disease 5. Presence of clinically significant muscle disorders, myopathies or other forms of liver disease 6. Presence of any clinically significant disease, as captured in the medical history or evidence of findings on the physical examination, vital sign assessment and/or ECG assessment, and that would otherwise exclude subject from eligibility in the context of all other listed inclusion and
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The percentage of subjects who experienced at least 1 treatment-emergent adverse event (TEAE) | Through study completion, an average of 1 year |
| The percentage of subjects who experienced at least one treatment emergent serious AE (SAE). | Through study completion, an average of 1 year |
| Percentage of subjects who experienced a treatment-emergent dose limiting toxicity (DLT) | Through study completion, an average of 1 year |
| Percentage of subjects who experienced at least one treatment emergent Grade 1, 2, 3, 4 or 5 laboratory abnormality | Through study completion, an average of 1 year |
| Percentage of subjects who discontinued study drug due to a TEAE | Through study completion, an average of 1 year |
| Alanine aminotransferase and aspartate aminotransferase levels versus time | Through study completion, an average of 1 year |
| Time to HBV viral load relapse in HBV-infected subjects | Through study completion, an average of 1 year |
| The reduction of HDV RNA on-treatment for HBV/HDV coinfected subjects | Through study completion, an average of 1 year |
Secondary
| Measure | Time frame |
|---|---|
| Baseline-adjusted maximal reduction in HDV RNA viral load (Emax,HDV) through 6 months after end of treatment following ATI-2173 + tenofovir or placebo + tenofovir for 90 days in HBV/HDV coinfected subjects | Through study completion at 6 months follow up |
| Cmax of ATI-2173, clevudine, tenofovir and M1 in plasma | Through Day 120 |
| Tmax of ATI-2173, clevudine, tenofovir and M1 in plasma | Through Day 120 |
| Ctrough of ATI-2173, clevudine, tenofovir and M1 in plasma | Through Day 120 |
| Ctau of ATI-2173, clevudine, tenofovir and M1 in plasma | Through Day 120 |
| AUC0-24 of ATI-2173, clevudine, tenofovir and M1 in plasma | Through Day 120 |
| Correlation between individual Day 90 clevudine and tenofovir Cmin and Emax,HBV or Emax, HDV of viral load | Through Day 90 |
| Proportion of subjects with HBV SVR6 by treatment arm | Through study completion, an average of 1 year |
| Proportion of subjects with HDV SVR6 by treatment arm (HBV/HDV coinfected subjects only) | Through study completion, an average of 1 year |
| Proportion of subjects by treatment arm with HBV SVR12, SVR18, and SVR24 | Through study completion, an average of 1 year |
| Proportion of subjects by treatment arm with HDV SVR12, SVR18, and SVR24 (HBV/HDV coinfected subjects only) | Through study completion, an average of 1 year |
| Proportion of subjects by treatment arm with on-treatment ALT flares | Through Day 90 |
| Proportion of subjects by treatment arm with off-treatment ALT flares, with no on-treatment ALT flares by treatment arm | From Day 90 through end of study, an average of 1 year |
| HBV DNA slope off-treatment | Through end of study, an average of 1 year |
| Effect on HBV pgRNA in subjects who reach SVR6 as measured by percentage of subjects by validated assay | Through end of study, an average of 1 year |
| HBV pgRNA at end of treatment by treatment arm | Through Day 90 |
| Effect on HBsAg in subjects who reach HBV SVR6 as measured by percentage of subjects by validated assay | Through end of study, an average of 1 year |
| T1/2 of ATI-2173, clevudine, tenofovir and M1 in plasma | Through Day 120 |
| AUEC(HBV) through 6 months after end of treatment following ATI-2173 + tenofovir for 90 days in HBV-infected subjects and in HBV/HDV coinfected subjects | Through end of study, an average of 1 year |
| T(Emax,HBV) through 6 months after end of treatment following ATI-2173 + tenofovir for 90 days in HBV/HDV coinfected subjects | Through end of study, an average of 1 year |
| AUEC(HDV) through 6 months after end of treatment following ATI-2173 + tenofovir for 90 days in HBV/HDV coinfected subjects | Through end of study, an average of 1 year |
| Change from baseline in HBsAg, HBV pgRNA, and HBcrAg at end of treatment and SVR6 in HBV-infected and in HBV/HDV coinfected subjects by treatment arm | Through end of study, an average of 1 year |
| Reduction from baseline in HBsAg, HBV pgRNA, and HBcrAg following ATI-2173 + tenofovir (with or without AB-729) or placebo + tenofovir for 90 days in HBV-infected and HBV/HDV coinfected subjects | Through end of study, an average of 1 year |
| Correlation between individual time to viral load relapse and Day 90 clevudine and/or tenofovir Cmin and AUC | Through Day 90 |
| Correlation between SVR6 and Day 90 clevudine and/or tenofovir Cmin and AUC | Through Day 90 |
| T(Emax,HBV) through 6 months after end of treatment following ATI-2173 + tenofovir for 90 days in HBV-infected subjects and in HBV/HDV coinfected subjects | Through end of study, an average of 1 year |
| RAC(Cmax) of ATI-2173, clevudine, tenofovir and M1 in plasma | Through Day 120 |
| RAC(AUC) of ATI-2173, clevudine, tenofovir and M1 in plasma | Through Day 120 |
| TE(max, HBV) up to Day 90 and through end of study with or without AB-729 or placebo + tenofovir | Through study completion, an average of 1 year |
| AUEC(HBV) up to Day 90 and through end of study with or without AB-729 of placebo + tenofovir | Through study completion, an average of 1 year |
| TE(max, HDV) up to Day 90 and through end of study | Through study completion, an average of 1 year |
| AUEC(HDV) up to Day 90 and through end of study | Through study completion, an average of 1 year |
| Baseline-adjusted maximal reduction in HBV DNA viral load (Emax,HBV) through 6 months after end of treatment following ATI-2173 + tenofovir (with or without AB-729) or placebo + tenofovir for 90 days in HBV-infected and HBV/HDV coinfected subjects | Through study completion at 6 months follow up |
Countries
Moldova, Ukraine
Outcome results
None listed