Clinical trial NCT05238844: A Study of Safety and Efficacy of ATI-2173 and Vebicorvir in Combination With Tenofovir Disoproxil Fumarate in Subjects With Chronic Hepatitis B Virus Infection
Official title: A Phase 2a Randomized, Double-blinded, Placebo-controlled, Multi Center, Dose Ranging Study of the Safety and Efficacy of ATI-2173 and Vebicorvir in Combination With Tenofovir Disoproxil Fumarate in Subjects With Chronic Hepatitis B Virus Infection
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Chronic Hepatitis b
Lead sponsor: Antios Therapeutics, Inc
Sponsor class: INDUSTRY
First posted: 2022-02-14
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomized, double-blinded, placebo-controlled, multi center, dose ranging study of safety and efficacy in volunteers with chronic hepatitis B virus infection. Volunteers will be administered multiple oral doses of ATI-2173 vebicorvir in combination with tenofovir disoproxil fumarate 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.


Eligibility criteria: Inclusion Criteria:

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 non-hormonal intrauterine device, 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
      * Use of a double-barrier method
      * Male partner vasectomized at least 6 months prior to the first study drug administration Or
   2. 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 the subject engages in sexual relations, a barrier method (male or female condom) should be used to prevent the spread of HBV.
4. If male, meets one of the following criteria:

   a) 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. 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 c) Is unable to procreate; defined as surgically sterile (ie, has undergone a vasectomy at least 6 months prior to the first study drug administration). If the subject engages in sexual relations, a barrier method (male or female condom) should be used to prevent the spread of HBV.
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. 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)

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 exclusion criteria, as determined by an Investigator
7. Presence of clinically significant ECG abnormalities at the screening visit, as defined by medical judgment
8. Positive test result for alcohol and/or drugs of abuse at screening or prior to the first drug administration
9. Any history of tuberculosis
10. Active illicit drug use including, but not limited to, cocaine, heroin and methamphetamine (the use of cannabinoids is acceptable)
11. Significant history of drug dependency or alcohol abuse (\> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic)
12. Use of amiodarone in the 28 days prior to the first study drug administration
13. Presence or history of clinically significant gastrointestinal or kidney disease, or surgery that may affect drug bioavailability
14. Cirrhosis of the liver as determined by one of the following:

    * A score greater than F2 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 on liver biopsy within 12 months prior to screening or at the time of screening
15. History of or known presence of hepatocellular carcinoma
16. Acute infection or any other clinically significant illness within 14 days of Day 1 of the study
17. History of organ transplantation
18. Presence of uncontrolled hypertension
19. Positive screening results to HIV Ag/Ab combo or hepatitis C virus tests
20. 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
21. Intake of an Investigational Product (IP) in the 28 days prior to the first study drug administration
22. Donation of 50 mL or more of blood in the 28 days prior to the first study drug administration
23. Donation of 500 mL or more of blood in the 56 days prior to the first study drug administration
24. Previous approved or investigational treatment for HBV, 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.
25. Positive screening results to hepatitis D virus (HDV) tests
26. History of significant hypersensitivity to excipients of vebicorvir or its placebo
27. Current or prior use of prohibited concomitant medications as defined in Section 4.5.1.
28. Participation in the ANTT201 study

Primary outcomes:
measure: The percentage of subjects who experienced at least 1 treatment-emergent adverse event (TEAE)
timeFrame: Through study completion, an average of 1 year
measure: The percentage of subjects who experienced at least 1 treatment-emergent serious adverse event (TE SAE)
timeFrame: Through study completion, an average of 1 year
measure: The percentage of subjects who experienced a treatment-emergent dose-limiting toxicity (TE DLT)
timeFrame: Through study completion, an average of 1 year
measure: The percentage of subjects who experienced at least 1 treatment-emergent Division of AIDS (DAIDS) Grade 1, 2, 3, 4, or 5 laboratory abnormality
timeFrame: Through study completion, an average of 1 year
measure: The percentage of subjects who discontinued the study drug due to a TEAE
timeFrame: Through study completion, an average of 1 year
measure: Alanine aminotransferase and aspartate aminotransferase levels versus time
timeFrame: Through study completion, an average of 1 year
measure: Time to HBV viral load relapse in HBV-infected subjects as measured by HBV DNA viral load in IU/mL
timeFrame: Through study completion, an average of 1 year, which is 6 months after end of treatment
Secondary outcomes:
measure: Baseline-adjusted maximal reduction in HBV DNA viral load (Emax,HBV) through 6 months after end of treatment following ATI-2173 + vebicorvir + TDF or placebo + TDF for 90 days in HBV-infected subjects
timeFrame: Through study completion, an average of 1 year, which is 6 months after end of treatment
measure: TEmax,HBV through 6 months after end of treatment following ATI-2173 + vebicorvir + TDF or placebo + TDF for 90 days in HBV-infected subjects
timeFrame: Through study completion, an average of 1 year, which is 6 months after end of treatment
measure: AUEC(HBV) through 6 months after end of treatment following ATI-2173 + vebicorvir + TDF or placebo + TDF for 90 days in HBV-infected subjects
timeFrame: Through study completion, an average of 1 year, which is 6 months after end of treatment
measure: Proportion of subjects with HBV DNA sustained viral response as measured by HBV DNA viral load at 6 months after end of treatment
timeFrame: Through study completion, an average of 1 year, which is 6 months after end of treatment
measure: Cmax of ATI-2173, clevudine and M1 in plasma
timeFrame: Through study completion, an average of 1 year
measure: Tmax of ATI-2173, clevudine and M1 in plasma
timeFrame: Through study completion, an average of 1 year
measure: Ctrough of ATI-2173, clevudine and M1 in plasma
timeFrame: Through study completion, an average of 1 year
measure: Ctau of ATI-2173, clevudine and M1 in plasma
timeFrame: Through study completion, an average of 1 year
measure: AUC0-24 of ATI-2173, clevudine and M1 in plasma
timeFrame: Through study completion, an average of 1 year
measure: AUCtau of ATI-2173, clevudine and M1 in plasma
timeFrame: Through study completion, an average of 1 year
measure: t1/2 of ATI-2173, clevudine and M1 in plasma
timeFrame: Through study completion, an average of 1 year
measure: RAC(Cmax) of ATI-2173, clevudine and M1 in plasma
timeFrame: Through study completion, an average of 1 year
measure: RAC(AUC) of ATI-2173, clevudine and M1 in plasma
timeFrame: Through study completion, an average of 1 year
measure: Proportion of subjects with HBV SVR12, SVR18, and SVR24months
timeFrame: Through study completion, an average of 1 year, or through 24 months if applicable
measure: Proportion of subjects with on-treatment ALT flares
timeFrame: Through Day 90
measure: Proportion of subjects with off-treatment ALT flares
timeFrame: From Day 90 through end of study, about 6 months
measure: Rate of HBV viral load return to baseline off-treatment
timeFrame: From Day 90 through end of study, about 6 months
measure: Relationship between HBV RNA and HBV Sustained Viral Response at 6 months
timeFrame: Through study completion, an average of 1 year, which is 6 months after treatment
measure: Change from baseline value in HBV RNA at end of treatment and Sustained Viral Response at 6 months
timeFrame: Through study completion, an average of 1 year, 6 months after treatment
measure: Change from baseline in HBsAg over time and Sustained Viral Response at 6 months
timeFrame: Through study completion, an average of 1 year, 6 months after treatment
measure: Change from baseline value in HBcrAg at end of treatment and Sustained Viral Response at 6 months
timeFrame: Through study completion, an average of 1 year, 6 months after treatment
measure: Relationship between HBV DNA Sustained Viral Response and HBsAg
timeFrame: Through study completion, an average of 1 year
measure: Reduction from baseline in HBsAg following ATI-2173 + vebicorvir + TDF or placebo + TDF for 90 days in HBV-infected subjects
timeFrame: Through study completion, an average of 1 year
measure: Reduction from baseline in HBV RNA following ATI-2173 + vebicorvir + TDF or placebo + TDF for 90 days in HBV-infected subjects
timeFrame: Through study completion, an average of 1 year
measure: Reduction from baseline in HBcrAg following ATI-2173 + vebicorvir + TDF or placebo + TDF for 90 days in HBV-infected subjects
timeFrame: Through study completion, an average of 1 year
measure: Cmax of tenofovir in plasma
timeFrame: Through study completion, an average of 1 year
measure: Tmax of tenofovir in plasma
timeFrame: Through study completion, an average of 1 year
measure: Ctrough of tenofovir in plasma
timeFrame: Through study completion, an average of 1 year
measure: Ctau of tenofovir in plasma
timeFrame: Through study completion, an average of 1 year
measure: AUC0-24 of tenofovir in plasma
timeFrame: Through study completion, an average of 1 year
measure: t1/2 of tenofovir in plasma
timeFrame: Through study completion, an average of 1 year
measure: RAC(Cmax) of tenofovir in plasma
timeFrame: Through study completion, an average of 1 year
measure: RAC(AUC) of tenofovir in plasma
timeFrame: Through study completion, an average of 1 year
measure: Cmax of vebicorvir in plasma
timeFrame: Through study completion, an average of 1 year
measure: Tmax of vebicorvir in plasma
timeFrame: Through study completion, an average of 1 year
measure: Ctrough of vebicorvir in plasma
timeFrame: Through study completion, an average of 1 year
measure: Ctau of vebicorvir in plasma
timeFrame: Through study completion, an average of 1 year
measure: AUC0-24 of vebicorvir in plasma
timeFrame: Through study completion, an average of 1 year
measure: t1/2 of vebicorvir in plasma
timeFrame: Through study completion, an average of 1 year
measure: RAC(Cmax) of vebicorvir in plasma
timeFrame: Through study completion, an average of 1 year
measure: RAC(AUC) of vebicorvir in plasma
timeFrame: Through study completion, an average of 1 year
measure: Correlation between individual tie to viral load relapse and Day 90 clevudine, vebicorvir, and tenofovir Cmin and AUC
timeFrame: Through study completion, an average of 1 year
measure: Correlation between SVR6 and Day 90 clevudine, vebicorvir, and tenofovir Cmin and AUC
timeFrame: Through study completion, an average of 1 year
Other outcomes:
Locations:
city: Chisinau
country: Moldova, Republic of
facility: Republican Clinical Hospital "Timofei Mosneaga" Arensia EM Unit
state: Republic Of Moldova
city: Kyiv
country: Ukraine
facility: Medical Center of Limited Liability Company "Harmoniya krasy"
Study officials:
References: