The Influence of ANS-6637 on Midazolam Pharmacokinetics in Healthy Volunteers
Condition: Opiod Use Disorder
Intervention: ANS-6637
Intervention description: Subjects will receive (1) midazolam 5 mg po single dose on Day 1 followed by (2) Drug free period on Day 2 followed by (3) ANS-6637 600 mg po daily (Days 3-7) to reach steady state followed by (4) ANS-6637 600 mg po single dose + midazolam 5mg po single dose on Day 8
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 26.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Reward Pathway; Pharmacokinetics; Dopamine; Opioid Use; Addiction

Summary:

      Background:

      Opioids are medicines that control pain. But they are often misused, which can lead to
      illness and death. Opioids increase dopamine to the brain, which makes people feel good and
      often causes them to crave drugs, leading to misuse and addiction. An investigational drug
      ANS-6637 may lower the dopamine surge and stop opioid craving. Midazolam is a drug approved
      for anxiety. Researchers want to give the two drugs together and see if ANS-6637 affects
      midazolam levels, to help understand how ANS-6637 is used in the body.

      Objective:

      To study the safety, tolerability, and effects of ANS-6637 taken with and without midazolam.

      Eligibility:

      Healthy adults 18 65 years old

      Design:

      Participants will be screened with a medical history, physical exam, and blood and heart
      tests. Participants who can get pregnant will have a pregnancy test.

      Participants must agree to use 2 types of birth control during the study, if applicable.

      Participants will stay at the clinic for 10 days. Meals will be provided. Participants will
      not be allowed to:

      Leave NIH campus

      Eat or drink anything with caffeine, alcohol, or certain juices

      Use any nicotine or related products (including vaping)

      Use any medicines (including herbal)

      During the clinic stay, participants will:

      Fast overnight several times

      Have blood drawn most days. Twice, a small tube will be inserted in an arm vein for frequent
      blood samples.

      Repeat screening tests and answer questions about their mood several times

      Get midazolam syrup in water on 1 day

      Take 6 ANS-6637 tablets by mouth on 5 days

      Take both study drugs on 1 day

      A few days later, participants will have a follow-up visit to repeat screening tests and
      answer questions about their mood.
    

Eligibility criteria:

        -INCLUSION CRITERIA:

          1. Must have the ability to understand and must personally sign a written informed
             consent form, which must be obtained prior to initiation of study procedures.

          2. Must be between 18 and 65 years of age, inclusive.

          3. Must have discontinued use of nicotine and nicotine containing products including
             vaping or juuling from 90 days prior to study drug dosing and throughout the study
             duration.

          4. Must be willing to abstain from any food or beverages containing alcohol 72 hours
             prior to first dose and through follow-up visit.

          5. Must be willing to abstain from cannabis 72 hours prior to first dose and through
             follow-up visit.

          6. Must be willing to abstain from caffeine (including tea, coffee, chocolate) or
             grapefruit, Seville orange juice or other methyl xanthine containing foods (e.g.
             theophylline, theobromine, tea leaves, yerba mate, kola nuts and guarana berries) 72
             hours prior to the first dose and through follow- up visit.

          7. Must have a body mass index (BMI) from 19 to 30 kg/m^2 (inclusive) at screening.

          8. Must be human immunodeficiency virus type 1 (HIV-1) antibody negative at screening.

          9. Must be hepatitis B (HBV) surface antigen negative at screening.

         10. Must be hepatitis C (HCV) antibody or RNA negative at screening.

         11. Male subjects must refrain from sperm donation from clinic admission, throughout the
             study period, and continuing for at least 90 days following the last dose of study
             drug.

         12. Subjects must refrain from blood donation from clinic admission, throughout the study
             period, and continuing for at least 30 days following the last dose of study drug.

         13. Must be willing to comply with contraception guidelines below Contraception:

             The fetal risks associated with ANS-6637 are not known, but pre- clinical animal data
             demonstrate some risk. Subjects must agree not to become pregnant or impregnate a
             female. Females of childbearing potential must have a reproductive risk assessment
             done to determine the risk of undetectable pregnancy at study start [i.e. sexual and
             contraceptive history for 30 days preceding screening] pregnancy test at screening and
             baseline (Day 0). For the duration of the study, subject and their partners must
             practice two non-hormonal methods of birth control, having begun no less than 30 days,
             without interruption, prior to screening. They must continue to use both methods until
             3 months after stopping the study drug. Two of the three methods of birth control
             listed below MUST be used, or an alternative combination offering very high efficacy,
             per the PI, in consultation with the Sponsor Medical Monitor may be considered:

               -  Male or female condoms [but not both] with a spermicide

               -  Diaphragm with a spermicide

               -  Intrauterine device (IUD)

             If pregnancy is suspected or should occur, subjects must notify the study staff
             immediately.

         14. Must, in the opinion of the Investigator, be in good health based upon medical history
             and physical examination, and screening laboratory evaluations.

         15. Judged to be healthy based on medical history, physical examination, vital signs, and
             clinical laboratory tests at screening and Day 0: liver function tests (AST, ALT,
             Tbili) less than or equal to upper limit of normal [ULN], platelets (PLT) >150,000/
             microliter, hemoglobin (Hgb) >13 g/dL (males); >12 g/dL (females), CK less than or
             equal to 2x ULN, Amylase/lipase < ULN, thyroid function tests [TSH and T4] within
             normal range, fasting total cholesterol <240 mg/dL, or fasting triglycerides <240
             mg/dL, per DAIDS AE table and Toxicity Grading Scale for Healthy Adult and Adolescent
             Volunteers Enrolled in Preventive Vaccine Trials AE table for total bilirubin [Tbili]
             only.

         16. Must be willing and able to comply with all study requirements.

        EXCLUSION CRITERIA:

          1. Therapy with any prescription, over-the-counter (OTC), herbal, or holistic
             medications, including hormonal contraceptives by any route, within 5 half- lives of
             the agent prior to receipt of any study medications will not be permitted with the
             following exception: Intermittent or short-course therapy (<14 days) with prescription
             or OTC medications, herbals, or holistic medications within the screening period prior
             to starting study drugs may be permitted after review by the investigators on a
             case-by-case basis for potential drug interactions. Receipt of influenza vaccination
             will be allowed prior to, during, and/or after the study.

          2. Have any serious or active medical, surgical, or psychiatric conditions which, in the
             opinion of the Investigator, would interfere with subject treatment, assessment, or
             compliance with the protocol.

          3. Have previously participated in an investigational trial involving administration of
             any investigational compound within 30 days prior to screening.

          4. Have current, or a history of mild to severe alcohol use, cannabis or other substance
             use disorder including any use of illicit drugs as defined by DSM-5 criteria, within
             12 months of first study dose

          5. Renal impairment (chronic renal insufficiency of any chronic kidney disease stage, or
             acute renal failure not induced by drug therapy defined as eGFR <90 ml/min)

          6. Have a positive urine drug test (ethanol, cannabis, barbiturates, cocaine, opiates, or
             amphetamines) at Screening or Day 0.

          7. History of flushing or intolerance related to alcohol consumption using the NIAAA
             screening assessment questionnaire tool for alcohol flushing

          8. Inability to obtain venous access for sample collection.

          9. Have a history of significant drug sensitivity or drug allergy to any benzodiazepines.

         10. Known hypersensitivity to formulation excipients: microcrystalline cellulose,
             croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide,
             polyethylene glycol, and talc.

         11. Have been treated with systemic steroids, immunosuppressant therapies or
             chemotherapeutic agents within 3 months of study screening or expected to receive
             these agents during the study (e.g., corticosteroids, immunoglobulins, and other
             immune- or cytokine-based therapies).

         12. Presence or history of clinically significant cardiovascular disease, cardiomyopathy,
             and/or cardiac conduction abnormalities.

         13. Have clinically significant ECG abnormalities or any of the following ECG
             abnormalities at Screening: PR >220 msec; QRS >120 msec; QTcF >450 msec; HR <40 beats
             per minute; second or third degree heart block.

         14. Have a history or family history of Long QT Syndrome, Brugada syndrome,
             Wolfe-Parkinson-White Syndrome, or have a family history of sudden cardiac death or
             unexplained death in an otherwise healthy individual between the ages of 1 and 30
             years.

         15. Have history of syncope, palpitations, unexplained dizziness or chronic nausea or
             headaches.

         16. Have an implanted defibrillator or pacemaker.

         17. Have a history of liver disease, including Gilbert's Disease.

         18. Any clinically significant electrolyte abnormality (outside of NIH normal reference
             ranges) at screening (e.g., hypokalemia, hypocalcemia, hypomagnesemia) or any
             condition that could lead to abnormal electrolyte disturbances (eg, eating disorder).

         19. Have a history of taking dopamine antagonists/anti-psychotics.

         20. Are unable to comply with study requirements.

         21. Positive urine toxicology screen