A Drug-Drug Interaction Study Between ATI-2173 and Midazolam or Clarithromycin in Healthy Subjects

Study Overview
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Brief Summary
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This study is a single-center, open-label, 2-cohort, fixed-sequence, DDI study in healthy adult subjects. Healthy volunteers will be administered multiple oral doses of ATI-2173 in combination with midazolam or clarithromycin and assessed for safety and tolerability including blood tests to show how the body metabolizes and eliminates the investigational drug as well as how the investigational drug interacts with midazolam or clarithromycin.

Official Title
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A Phase 1, Open-label, 2-cohort, Fixed-sequence, Drug-drug Interaction Study to Investigate the Potential Interaction Between ATI-2173 When Coadministered With Midazolam or Clarithromycin in Healthy Subjects

Conditions
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Drug Drug Interaction

Intervention / Treatment
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* Drug: ATI-2173
* Drug: Midazolam
* Drug: Clarithromycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated Informed Consent Form (ICF) Stated willingness to comply with all study procedures (including ability and willingness to abstain from alcohol from 48 hours prior to the first study drug administration until discharge) and availability for the duration of the study Healthy adult male or female Aged between 18 and 60 years, inclusive Body mass index (BMI) within 18.5 kg/m2 to 30.0 kg/m2, inclusively Non- or ex-smoker (an ex-smoker is defined as someone who completely stopped using nicotine products for at least 180 days prior to the first study drug administration) Suitable veins for cannulation or repeated venipuncture as assessed by an Investigator at Screening 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 60 days after the last dose of the study drug Non-hormonal intrauterine device (IUD) with a barrier method (eg, male condom) used from at least 28 days prior to the first study drug administration through to at least 60 days after the last dose of the study drug Double-barrier method (eg, male condom, spermicide and diaphragm or cervical cap used simultaneously )from Screening through to at least 60 days after the last dose of the study drug Male partner vasectomized at least 6 months prior to Screening 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), as confirmed by follicle-stimulating hormone levels (≥ 40 mIU/mL). 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. 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 Screening) Agrees to abstain from blood or plasma donation from the Screening visit until 3 months after the last study drug administration Have no clinically significant diseases captured in the medical history or evidence of clinically significant findings on the physical examination, vital signs, myopathy questionnaire, and/or ECG, as determined by an Investigator Cohort 1 only Have no clinically significant findings on the neurological examination and/or oxygen saturation measurement as determined by an Investigator Exclusion Criteria: Female who is lactating Female who is pregnant according to the pregnancy test at Screening or prior to the first study drug administration Female using the following systemic contraceptives: oral, patch or vaginal ring, in the 28 days prior to the first study drug administration Female using hormone replacement therapy in the 28 days prior to the first study drug administration Female using the following systemic contraceptives: injections or implant, or hormone-releasing IUD in the 13 weeks prior to the first study drug administration Seated pulse rate less than 50 beats per minute or more than 100 beats per minute at Screening or prior to the first study drug administration Seated blood pressure below 105/60 mmHg or higher than 140/90 mmHg at Screening or prior to the first study drug administration Estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73m2, calculated using the Modification of Diet in Renal Disease (MDRD) equation, at Screening or prior to the first study drug administration Presence of out-of-range cardiac interval (PR < 110 msec, PR > 200 msec, QRS < 60 msec, QRS >110 msec and QTcF > 440 msec) on the ECG at Screening or at Check-in or other clinically significant ECG abnormalities, unless deemed non-significant by an Investigator Hemoglobin value below the lower limit of the reference laboratory at Screening or prior to study drug administration Any other clinically significant abnormalities in laboratory test results at Screening. Subjects with alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), creatine kinase (CK) or total bilirubin outside the normal range at Screening or Day -1 will be excluded. Positive test result for alcohol and/or drugs of abuse at Screening or prior to the first drug administration Positive screening results to HIV Ag/Ab combo, hepatitis B surface antigen or hepatitis C virus antibody tests at Screening Positive screening results to SARS-CoV-2 virus tests prior to the first study drug administration History of significant hypersensitivity to ATI-2173, clevudine, midazolam, clarithromycin, or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs Presence or history of significant gastrointestinal, liver or kidney disease, or surgery that may affect drug bioavailability 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 Maintenance therapy with any drug or significant history of drug dependency or alcohol abuse (> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic) Any clinically significant illness in the 28 days prior to the first study drug administration Use of any prescription drugs (including hormonal contraceptives and hormone replacement therapy) or any CYP3A inhibitors, inducers, or substrates in the 30 days prior to the first study drug administration, that in the opinion of an Investigator would put into question the status of the participant as healthy Use of St. John's wort in the 30 days prior to the first study drug administration Use of over-the-counter (OTC) medications, herbal supplements, and vitamins in the 14 days prior to the first study treatment administration. Use of quinine-containing products (eg, tonic water), grapefruit products, pomelo products, Seville orange products, including supplements containing Citrus aurantium or bitter orange, in the 14 days prior to the first study drug administration Consumption of food or beverages containing xanthines (ie, tea, coffee, cola drinks, energy drinks or chocolate) in the 48 hours prior to the first study drug administration Any history of tuberculosis Immunization with a coronaviruse disease 2019 (COVID-19) vaccine in the 14 days prior to the first study drug administration Scheduled immunization with a COVID-19 vaccine (first or second dose) during the study that, in the opinion of an Investigator, could potentially interfere with subject participation, subject safety, study results, or any other reason Inclusion in a previous group for this clinical study Participation in another clinical study with a non-biologic investigational product (IP) or new formulation of a marketed non-biologic drug in the 30 days prior to Screening Participation in another clinical study with any marketed or investigational biologic product within 90 days or 5 half-lives, whichever is longer, prior to Screening 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 (Canadian Blood Services, Hema-Quebec, clinical studies, etc.) in the 56 days prior to the first study drug administration Cohort 1 Oxygen saturation (SpO2) below 95% at Screening or prior to the first study drug administration Family history of sudden cardiac death or known prolonged QTc

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ATI-2173 50 mg<br>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 | Drug: ATI-2173<br>* 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<br>|
| Experimental: Midazolam<br>Midazolam is a sensitive CYP3A index substrate | Drug: Midazolam<br>* Midazolam is a sensitive CYP3A index substrate<br>|
| Experimental: Clarithromycin<br>Clarithromycin is a sensitive P-gp index inhibitor to evaluate potential effect of P-gp inhibition on ATI-2173 and its metabolites | Drug: Clarithromycin<br>* Clarithromycin is a sensitive P-gp index inhibitor to evaluate potential effect of P-gp inhibition on ATI-2173 and its metabolites(clarithromycin)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of Midazolam |  | Through end of study, approximately 3 months | 
| AUC0-t of Midazolam |  | Through end of study, approximately 3 months | 
| AUC0-inf of Midazolam |  | Through end of study, approximately 3 months | 
| Cmax of ATI-2173 |  | Through end of study, approximately 3 months | 
| AUCtau of ATI-2173 |  | Through end of study, approximately 3 months | 
| AUC0-t of ATI-2173 |  | Through end of study, approximately 3 months | 
| AUCo-inf of ATI-2173 |  | Through end of study, approximately 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events |  | Through end of study, approximately 3 months |