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The Influence of ANS-6637 on Midazolam Pharmacokinetics in Healthy Volunteers

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ClinicalTrials.gov Identifier: NCT03831971
Recruitment Status : Active, not recruiting
First Posted : February 6, 2019
Last Update Posted : October 15, 2019
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC)

Tracking Information
First Submitted Date  ICMJE February 5, 2019
First Posted Date  ICMJE February 6, 2019
Last Update Posted Date October 15, 2019
Actual Study Start Date  ICMJE March 1, 2019
Actual Primary Completion Date August 9, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 27, 2019)
The primary endpoints of this study will be assessed by characterization of plasma area under the concentration time curve0-infinity (AUC0-inf), maximum total plasma concentration (Cmax), time to maximum plasma concentration (tmax),apparent e... [ Time Frame: Day 1 and Day 8 ]
Pharmacokinetics of midazolam before and after steady state ANS-6637
Original Primary Outcome Measures  ICMJE
 (submitted: February 5, 2019)
The impact of steady state ANS-6637/GS-548351 on the single dose pharmacokinetics of midazolam (MDZ) and 1-hydroxymidazolam in healthy volunteers. [ Time Frame: At the time of data analysis ]
Change History Complete list of historical versions of study NCT03831971 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 27, 2019)
  • Number of Grade 1-4 adverse events, as defined by the DAIDS Toxicity Table Version 2.1, July, 2017 [ Time Frame: From Day 1 to completion of study participation. ]
    Evaluate the safety and tolerability of administration of ANS-6637 alone or in combination with MDZ.
  • Plasma area under the concentration time curve 0-24 hours (AUC0-24), Plasma area under the concentration time curve 0-last quantifiable point (AUC0-last), time to maximum plasma concentration(tmax),apparent elimination rate constant (?Z), ter... [ Time Frame: Day 8 ]
    Describe the steady state pharmacokinetics of ANS- 6637 and GS-548351.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 5, 2019)
  • Evaluate the safety and tolerability of administration of ANS-6637 alone or in combination with MDZ. [ Time Frame: Throughout the defined study and folow-up period. ]
  • Describe the steady state pharmacokinetics of ANS-6637 and GS-548351. [ Time Frame: At the time of data analysis ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Influence of ANS-6637 on Midazolam Pharmacokinetics in Healthy Volunteers
Official Title  ICMJE The Influence of ANS-6637 on Midazolam Pharmacokinetics in Healthy Volunteers (SEARCH PK)
Brief 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.

Detailed Description

Opioid use causes a myriad of effects which contribute to significant morbidity and early mortality, and is associated with risky sexual behavior and injection drug use (IDU), two major forms of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) transmission in urban and suburban United States. Through these high-risk behaviors, persons with opioid use disorder (OUD) develop both direct comorbidities (e.g. blood stream infections and infectious endocarditis), as well as risk-associated illnesses (e.g. sexually transmitted infections, HCV and hepatitis B virus [HBV]) which have considerable downstream health care effects. As such, there is a need for pharmacologic agents in the treatment of OUD that go beyond avoidance of withdrawal and facilitate decreased frequency or complete cessation of opioid use.

The biologic mechanism of OUD, common to all forms of addiction, is a conditioned drug cue-related response in the CNS, causing a dopamine surge. If effective, a central pharmacologic strategy targeting the aberrant reward circuitry seen in OUD could potentially reduce drug craving and result in opioid abstinence.

In the SEARCH Pharmacokinetic (PK) investigation, we aim to understand the pharmacokinetic signal of the novel, oral agent ANS-6637, an aldehyde dehydrogenase 2 (ALDH-2) inhibitor that has the potential to reduce dopamine surge in the CNS and inhibit opioid craving. In preclinical studies, the active metabolite of ANS-6637, GS-548351, showed substrate dependent inhibition of CYP3A in vitro, with little or no inhibitory effect on the activities of other cytochrome P450 (CYP) enzymes. As such, the current investigation seeks to explore the potential inhibition of CYP3A by ANS-6637 with the FDA-recommended CYP3A probe substrate, midazolam.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Opiod Use Disorder
Intervention  ICMJE Drug: ANS-6637
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
Study Arms  ICMJE Experimental: 1
Midazolam PK assessment before and after steadystate ANS-6637
Intervention: Drug: ANS-6637
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: February 5, 2019)
50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 6, 2020
Actual Primary Completion Date August 9, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

-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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03831971
Other Study ID Numbers  ICMJE 190052
19-CC-0052
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC)
Study Sponsor  ICMJE National Institutes of Health Clinical Center (CC)
Collaborators  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Investigators  ICMJE
Principal Investigator: Henry Masur, M.D. National Institutes of Health Clinical Center (CC)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date October 8, 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP