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 : July 11, 2019
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.
To study the safety, tolerability, and effects of ANS-6637 taken with and without midazolam.
Healthy adults 18 65 years old
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.
|Condition or disease||Intervention/treatment||Phase|
|Opiod Use Disorder||Drug: ANS-6637||Phase 1|
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 :||Interventional (Clinical Trial)|
|Estimated Enrollment :||50 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|Official Title:||The Influence of ANS-6637 on Midazolam Pharmacokinetics in Healthy Volunteers (SEARCH PK)|
|Actual Study Start Date :||March 1, 2019|
|Estimated Primary Completion Date :||August 9, 2019|
|Estimated Study Completion Date :||August 9, 2019|
Midazolam PK assessment before and after steadystate 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
- 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
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03831971
|United States, Maryland|
|National Institutes of Health Clinical Center|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Henry Masur, M.D.||National Institutes of Health Clinical Center (CC)|