Clinical trial NCT04596267: Pitolisant Effects on Alcohol Self-Administration in Heavy Drinkers
Official title: The Effects of the Histamine-3 Receptor Inverse Agonist Pitolisant on Alcohol Self-Administration in Heavy Drinkers
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Alcohol Use Disorder
Alcohol Drinking
Keywords: pitolisant
Wakix
Lead sponsor: Boston Medical Center
Sponsor class: OTHER
Collaborators: name: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
First posted: 2020-10-22
Enrollment: 9
Sex: ALL
Minimum age (years): 21
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This is a double-blind, randomized, placebo-controlled, crossover design trial that will test the effect of pitolisant on alcohol self-administration and craving following a priming dose of alcohol.
Primary purpose: TREATMENT

Brief summary: This is a double-blind, randomized, placebo-controlled, crossover design trial that will test the effect of pitolisant on alcohol self-administration and craving following a priming dose of alcohol. The specific objective of this proposal is to determine whether pitolisant has effects on alcohol consumption and craving

Detailed description: The present proposal is intended to answer the call for accelerating drug development by exploring the potential of a novel anticonvulsant, Pitolisant as a candidate medication for the treatment of AUD. Pitolisant is an H-3 receptor inverse agonist that is FDA-approved for treating narcolepsy which has been found to have effects of on alcohol craving and consumption in preclinical studies. The aims of this study are to test the effects of Pitolisant on alcohol self-administration and craving among a sample of non-treatment seeking heavy drinkers. The effects of 5-days of pitolisant (8.9mg) or placebo will be evaluated in a human laboratory using an alcohol self-administration methodology. In this within-subjects crossover design, heavy drinkers (N=28) will be randomized to the order of exposure (Pitolisant or placebo) prior to completing two alcohol self-administration trials. Subjects will receive a priming drink of alcohol and will have access to 8 alcoholic drinks over a 2-hour period. The investigators anticipate that subjects will consume less alcohol during an alcohol self-administration trial when receiving Pitolisant compared to when they are receiving placebo. Significant Pitolisant-induced reductions in the quantity of alcohol self-administered will be considered to be an indication that this drug may have value as an AUD medication. This study may provide a rationale for phase II clinical studies testing Pitolisant with a treatment-seeking AUD population.

Eligibility criteria: Inclusion Criteria:

1. 21-55 years of age
2. Able to verify age with a state or federal picture identification
3. Exceeds safe weekly drinking limits during the 28 days prior to consent (average of 14 drinks for women or 21 drinks for men per week)
4. Reports at least one episode of binge drinking (\>3 drinks for women, \>4 drinks for men) in the 28 days prior consent.
5. Meets DSM-5 criteria for mild alcohol use disorder or greater severity.
6. Has a smartphone to complete medication exposure period study assessments.

Exclusion Criteria:

1. Seeking treatment for alcohol problems
2. Clinical Institute Withdrawal Assessment at ≥10
3. DSM-5 diagnosis of current major depression, bipolar disorder, schizophrenia, bulimia/anorexia, dementia, insomnia disorder or a substance use disorder other than alcohol, nicotine, marijuana or caffeine
4. If female, pregnant, nursing, have plans to become pregnant
5. If female, does not agree to use an accepted form of birth control
6. Has a medical contraindication to the use of pitolisant
7. Has medical or mental condition for which further alcohol exposure at the planned dose range would be contraindicated
8. Current risk of suicidality (MINI suicidality score greater than 8 (low risk) or Yes to the ideation question #4 of the C-SSRS)
9. BMI is greater than 40 or less than 18
10. Impaired renal function (GFR \<80 mL/min)
11. Have a history of any clinically significant renal or hepatic disease
12. Child-Pugh Score equal to or greater than Class B (evaluated based on presence or absence of encephalopathy and ascites, INR, bilirubin, and albumin) \[https://www.mdcalc.com/child-pugh-score-cirrhosis-mortality\]
13. Have a clinically significant ECG as determined by the investigator or abnormal ECG heart rate (\<45 or \>100 bpm) or QTc interval corrected for heart rate using the Fridericia formula (QTcF) \> 450 msec
14. Have a history of cardiac arrhythmias or who for other reasons are at risk for developing Torsade de Pointes including those with bradycardia, hypokalemia, and congenital QT interval prolongation
15. Has received alcohol counseling or other non-pharmacologic intervention to treat AUD in the past 90 days
16. Has taken medications that are used to treat AUD in the past 90 days
17. Has urine toxicology results positive for cocaine, opioids, amphetamines, buprenorphine, methadone, methamphetamines, oxycontin, barbiturates, or benzodiazepines.
18. Subject is taking a medication which will significantly alter drug metabolism (e.g., strong CYP2D6 inhibitors, strong CYP3A4 inducers, or H1 receptor antagonists that cross the blood barrier (e.g. diphenhydramine or meclizine).
19. Subject is known to be a poor CYP2D6 metabolizer.
20. Subject is unable to comfortably abstain from nicotine for a period of 8 hours.
21. Has Chronic Obstructive Pulmonary Disease (COPD), history of solid organ transplant, sickle cell disease, severe heart disease or other health condition for which exposure to COVID-19 represents an unreasonable risk as determined by the study staff physician using accepted COVID-19 guidance (e.g. Centers for Disease Control, etc.).

Primary outcomes:
measure: Alcohol Consumption in Alcohol Self-Administration Trials
timeFrame: 2.6 hours
measure: Alcohol Consumption (BAC): Observation Period, Minute 10
timeFrame: 1 minute
measure: Alcohol Consumption (BAC): Observation Period, Minute 20
timeFrame: 1 minute
measure: Alcohol Consumption (BAC): Observation Period, Minute 30
timeFrame: 1 minute
measure: Alcohol Consumption (BAC): Observation Period, Minute 40
timeFrame: 1 minute
measure: Alcohol Consumption (BAC): Self-administration Block 1, Minute 30
timeFrame: 1 minute
measure: Alcohol Consumption (BAC): Self-administration Block 1, Minute 60
timeFrame: 1 minute
measure: Alcohol Consumption (BAC): Self-administration Block 2, Minute 30
timeFrame: 1 minute
measure: Alcohol Consumption (BAC): Self-administration Block 2, Minute 60
timeFrame: 1 minute
Secondary outcomes:
measure: Alcohol Craving During 12-day Drug Exposure
timeFrame: 12 days
measure: Alcohol Consumption During the 12-day Drug Exposure
timeFrame: 12 days
measure: Alcohol-induced Stimulation: Observation Period, Minute 10
timeFrame: 1 minute
measure: Alcohol-induced Stimulation: Observation Period, Minute 20
timeFrame: 1 minute
measure: Alcohol-induced Stimulation: Observation Period, Minute 30
timeFrame: 1 minute
measure: Alcohol-induced Stimulation: Observation Period, Minute 40
timeFrame: 1 minute
measure: Alcohol-induced Stimulation: Self-Administration Block 1, Minute 30
timeFrame: 1 minute
measure: Alcohol-induced Stimulation: Self-Administration Block 1, Minute 60
timeFrame: 1 minute
measure: Alcohol-induced Stimulation: Self-Administration Block 2, Minute 30
timeFrame: 1 minute
measure: Alcohol-induced Stimulation: Self-Administration Block 2, Minute 60
timeFrame: 1 minute
measure: Alcohol-induced Sedation: Observation Period, Minute 10
timeFrame: 1 minute
measure: Alcohol-induced Sedation: Observation Period, Minute 20
timeFrame: 1 minute
measure: Alcohol-induced Sedation: Observation Period, Minute 30
timeFrame: 1 minute
measure: Alcohol-induced Sedation: Observation Period, Minute 40
timeFrame: 1 minute
measure: Alcohol-induced Sedation: Self-Administration Block 1, Minute 30
timeFrame: 1 minute
measure: Alcohol-induced Sedation: Self-administration Block 1, Minute 60
timeFrame: 1 minute
measure: Alcohol-induced Sedation: Self-administration Block 2, Minute 30
timeFrame: 1 minute
measure: Alcohol-induced Sedation: Self-administration Block 2, Minute 60
timeFrame: 1 minute
measure: Alcohol Urge: Self-administration Block 1, Minute 30
timeFrame: 1 minute
measure: Alcohol Urge: Self-administration Block 1, Minute 60
timeFrame: 1 minute
measure: Alcohol Urge: Self-administration Block 2, Minute 30
timeFrame: 1 minute
measure: Alcohol Urge: Self-administration Block 2, Minute 60
timeFrame: 1 minute
measure: Alcohol Craving: Observation Period, Minute 10
timeFrame: 1 minute
measure: Alcohol Craving: Observation Period, Minute 20
timeFrame: 1 minute
measure: Alcohol Craving: Observation Period, Minute 30
timeFrame: 1 minute
measure: Alcohol Craving: Observation Period, Minute 40
timeFrame: 1 minute
measure: Alcohol Craving: Self-administration Block 1, Minute 30
timeFrame: 1 minute
measure: Alcohol Craving: Self-administration Block 1, Minute 60
timeFrame: 1 minute
measure: Alcohol Craving: Self-administration Block 2, Minute 30
timeFrame: 1 minute
measure: Alcohol Craving: Self-administration Block 2, Minute 60
timeFrame: 1 minute
Other outcomes:
Locations:
city: Boston
country: United States
facility: Boston University Psychiatry Research Center, Clinical Studies Unit
state: Massachusetts
Study officials:
affiliation: Boston Medical Center
name: Eric Devine, PhD
role: PRINCIPAL_INVESTIGATOR
References: