- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04847440
A Study of Safety and Efficacy of ATI-2173 in Combination With Tenofovir Disoproxil Fumarate in Subjects With Chronic Hepatitis B Virus Infection and in Subjects With Hepatitis D Virus Coinfection
A Phase 2A Randomized, Double-blinded, Placebo-controlled, Multicenter, Dose Ranging Study of Safety and Efficacy of ATI-2173 in Combination With Tenofovir Disoproxil Fumarate in Subjects With Chronic Hepatitis B Virus Infection and in Subjects With Hepatitis D Virus Coinfection
Study Overview
Status
Conditions
Intervention / Treatment
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Republic Of Moldova
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Chisinau, Republic Of Moldova, Moldova, Republic of
- Republican Clinical Hospital "Timofei Mosneaga" Arensia EM Unit
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Kyiv, Ukraine
- Medical Center of Limited Liability Company "Harmoniya Krasy"
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
ALL SUBJECTS:
- Provision of signed and dated informed consent form (ICF)
- Stated willingness to comply with all study procedures and availability for the duration of the study
If female, meets one of the following criteria:
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
- 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
- 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)
If male, meets one of the following criteria:
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
- Is unable to procreate; defined as surgically sterile (ie, has undergone a vasectomy at least 6 months prior to the first study drug administration)
- Male or female aged at least 18 years but not older than 70 years
- Body mass index (BMI) within 18.0 kg/m2 to 35.0 kg/m2, inclusively
- 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)
- Serum HBsAg positive at screening and at least 6 months prior to screening
- 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
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:
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:
- Serum HBsAg levels ≥ 100 IU/mL at screening
Exclusion Criteria:
- Female who is lactating at screening
- Female who is pregnant according to the pregnancy test at screening or prior to the first study drug administration
- 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
- History of significant cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, immunologic or dermatologic disease
- Presence of clinically significant muscle disorders, myopathies or other forms of liver disease
- 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 exclusion criteria, as determined by an Investigator
- Presence of clinically significant ECG abnormalities at the screening visit, as defined by medical judgment
- Positive test result for alcohol and/or drugs of abuse at screening or prior to the first drug administration
- Any history of tuberculosis
- Active illicit drug use including, but not limited to, cocaine, heroin and methamphetamine (the use of cannabinoids is acceptable)
- Significant history of drug dependency or alcohol abuse (> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic)
- Use of amiodarone in the 28 days prior to the first study drug administration
- Presence or history of clinically significant gastrointestinal or kidney disease, or surgery that may affect drug bioavailability
Cirrhosis of the liver as determined by one of the following:
- A score greater than F2 (or greater than F3 for HBV/HDV coinfected subjects) for liver fibrosis by FibroScan or FibroSure test within 6 months prior to screening or at the time of screening Or
- A score greater than F2 (or greater than F3 for HBV/HDV coinfected subjects) on liver biopsy within 12 months prior to screening or at the time of screening
- History of or known presence of hepatocellular carcinoma
- Acute infection or any other clinically significant illness within 14 days of Day 1 of the study
- History of organ transplantation
- Presence of uncontrolled hypertension
- Positive screening results to HIV Ag/Ab combo or hepatitis C virus tests
- Any other clinically significant abnormalities in laboratory test results at screening that would, in the opinion of an Investigator, increase the subject's risk of participation, jeopardize complete participation in the study, or compromise interpretation of study data
- Inclusion in another cohort for this clinical study
- Intake of an Investigational Product (IP) in the 28 days prior to the first study drug administration
- Donation of 50 mL or more of blood in the 28 days prior to the first study drug administration
- Donation of 500 mL or more of blood in the 56 days prior to the first study drug administration
Previous approved or investigational treatment for HBV or HDV, including nucleoside therapy, other than treatment by tenofovir or interferon alpha. Prior treatment with tenofovir or interferon alpha must have been discontinued at least 6 months prior to Screening.
SUBJECTS WITH CHRONIC HBV (COHORTS A, B, AND D):
Positive screening results to HDV tests
SUBJECTS IN COHORT D ONLY:
- History of significant hypersensitivity to excipients of AB-729, any siRNAs, or antisense oligonucleotides (ASOs)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: ATI-2173 and Viread
ATI-2173 + Tenofovir disoproxil fumarate (Viread)
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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.
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Active Comparator: Placebo and Viread
ATI-2173 Placebo + Tenofovir disoproxil fumarate
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Viread is a nucleotide analogue reverse transcriptase inhibitor used for chronic hepatitis B virus.
Other Names:
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Experimental: ATI-2173, Viread and AB-729
ATI-2173 + Tenofovir disoproxil fumarate (Viread) + AB-729
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AB-729 is a potent, selective, subcutaneously administered, N-acetylgalactosamine (Ga1NAc)-conjugated small interfering ribonucleic acid (siRNA) inhibitor of HBV
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Active Comparator: Placebo, Viread and AB-729 Placebo
ATI-2173 Placebo + Tenofovir disoproxil fumarate (Viread) + AB-729 Placebo
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Viread is a nucleotide analogue reverse transcriptase inhibitor used for chronic hepatitis B virus.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
The percentage of subjects who experienced at least 1 treatment-emergent adverse event (TEAE)
Time Frame: Through study completion, an average of 1 year
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Through study completion, an average of 1 year
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The percentage of subjects who experienced at least one treatment emergent serious AE (SAE).
Time Frame: Through study completion, an average of 1 year
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Through study completion, an average of 1 year
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Percentage of subjects who experienced a treatment-emergent dose limiting toxicity (DLT)
Time Frame: Through study completion, an average of 1 year
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Through study completion, an average of 1 year
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Percentage of subjects who experienced at least one treatment emergent Grade 1, 2, 3, 4 or 5 laboratory abnormality
Time Frame: Through study completion, an average of 1 year
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Through study completion, an average of 1 year
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Percentage of subjects who discontinued study drug due to a TEAE
Time Frame: Through study completion, an average of 1 year
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Through study completion, an average of 1 year
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Alanine aminotransferase and aspartate aminotransferase levels versus time
Time Frame: Through study completion, an average of 1 year
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Through study completion, an average of 1 year
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Time to HBV viral load relapse in HBV-infected subjects
Time Frame: Through study completion, an average of 1 year
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Through study completion, an average of 1 year
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The reduction of HDV RNA on-treatment for HBV/HDV coinfected subjects
Time Frame: Through study completion, an average of 1 year
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Through study completion, an average of 1 year
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Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
TE(max, HBV) up to Day 90 and through end of study with or without AB-729 or placebo + tenofovir
Time Frame: Through study completion, an average of 1 year
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Through study completion, an average of 1 year
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AUEC(HBV) up to Day 90 and through end of study with or without AB-729 of placebo + tenofovir
Time Frame: Through study completion, an average of 1 year
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Through study completion, an average of 1 year
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TE(max, HDV) up to Day 90 and through end of study
Time Frame: Through study completion, an average of 1 year
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Through study completion, an average of 1 year
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AUEC(HDV) up to Day 90 and through end of study
Time Frame: Through study completion, an average of 1 year
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Through study completion, an average of 1 year
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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
Time Frame: Through study completion at 6 months follow up
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Through study completion at 6 months follow up
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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
Time Frame: Through study completion at 6 months follow up
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Through study completion at 6 months follow up
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Cmax of ATI-2173, clevudine, tenofovir and M1 in plasma
Time Frame: Through Day 120
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Through Day 120
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Tmax of ATI-2173, clevudine, tenofovir and M1 in plasma
Time Frame: Through Day 120
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Through Day 120
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Ctrough of ATI-2173, clevudine, tenofovir and M1 in plasma
Time Frame: Through Day 120
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Through Day 120
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Ctau of ATI-2173, clevudine, tenofovir and M1 in plasma
Time Frame: Through Day 120
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Through Day 120
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AUC0-24 of ATI-2173, clevudine, tenofovir and M1 in plasma
Time Frame: Through Day 120
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Through Day 120
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T1/2 of ATI-2173, clevudine, tenofovir and M1 in plasma
Time Frame: Through Day 120
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Through Day 120
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RAC(Cmax) of ATI-2173, clevudine, tenofovir and M1 in plasma
Time Frame: Through Day 120
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Through Day 120
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RAC(AUC) of ATI-2173, clevudine, tenofovir and M1 in plasma
Time Frame: Through Day 120
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Through Day 120
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Correlation between individual Day 90 clevudine and tenofovir Cmin and Emax,HBV or Emax, HDV of viral load
Time Frame: Through Day 90
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Through Day 90
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Proportion of subjects with HBV SVR6 by treatment arm
Time Frame: Through study completion, an average of 1 year
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Through study completion, an average of 1 year
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Proportion of subjects with HDV SVR6 by treatment arm (HBV/HDV coinfected subjects only)
Time Frame: Through study completion, an average of 1 year
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Through study completion, an average of 1 year
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Proportion of subjects by treatment arm with HBV SVR12, SVR18, and SVR24
Time Frame: Through study completion, an average of 1 year
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Through study completion, an average of 1 year
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Proportion of subjects by treatment arm with HDV SVR12, SVR18, and SVR24 (HBV/HDV coinfected subjects only)
Time Frame: Through study completion, an average of 1 year
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Through study completion, an average of 1 year
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Proportion of subjects by treatment arm with on-treatment ALT flares
Time Frame: Through Day 90
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Through Day 90
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Proportion of subjects by treatment arm with off-treatment ALT flares, with no on-treatment ALT flares by treatment arm
Time Frame: From Day 90 through end of study, an average of 1 year
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From Day 90 through end of study, an average of 1 year
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HBV DNA slope off-treatment
Time Frame: Through end of study, an average of 1 year
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Through end of study, an average of 1 year
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Effect on HBV pgRNA in subjects who reach SVR6 as measured by percentage of subjects by validated assay
Time Frame: Through end of study, an average of 1 year
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Through end of study, an average of 1 year
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HBV pgRNA at end of treatment by treatment arm
Time Frame: Through Day 90
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Through Day 90
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Effect on HBsAg in subjects who reach HBV SVR6 as measured by percentage of subjects by validated assay
Time Frame: Through end of study, an average of 1 year
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Through end of study, an average of 1 year
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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
Time Frame: Through end of study, an average of 1 year
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Through end of study, an average of 1 year
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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
Time Frame: Through end of study, an average of 1 year
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Through end of study, an average of 1 year
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T(Emax,HBV) through 6 months after end of treatment following ATI-2173 + tenofovir for 90 days in HBV/HDV coinfected subjects
Time Frame: Through end of study, an average of 1 year
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Through end of study, an average of 1 year
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AUEC(HDV) through 6 months after end of treatment following ATI-2173 + tenofovir for 90 days in HBV/HDV coinfected subjects
Time Frame: Through end of study, an average of 1 year
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Through end of study, an average of 1 year
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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
Time Frame: Through end of study, an average of 1 year
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Through end of study, an average of 1 year
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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
Time Frame: Through end of study, an average of 1 year
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Through end of study, an average of 1 year
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Correlation between individual time to viral load relapse and Day 90 clevudine and/or tenofovir Cmin and AUC
Time Frame: Through Day 90
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Through Day 90
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Correlation between SVR6 and Day 90 clevudine and/or tenofovir Cmin and AUC
Time Frame: Through Day 90
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Through Day 90
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Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Digestive System Diseases
- RNA Virus Infections
- Infections
- Blood-Borne Infections
- Communicable Diseases
- Liver Diseases
- Hepatitis, Viral, Human
- Hepadnaviridae Infections
- DNA Virus Infections
- Enterovirus Infections
- Picornaviridae Infections
- Hepatitis, Chronic
- Hepatitis B
- Hepatitis
- Hepatitis A
- Virus Diseases
- Hepatitis D
- Hepatitis B, Chronic
- Herpesviridae Infections
- Coinfection
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antiviral Agents
- Reverse Transcriptase Inhibitors
- Nucleic Acid Synthesis Inhibitors
- Enzyme Inhibitors
- Anti-HIV Agents
- Anti-Retroviral Agents
- Tenofovir
Other Study ID Numbers
- ANTT201
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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