Pitolisant Effects on Alcohol Self-Administration in Heavy Drinkers

Phase 1

Terminated

Conditions: Alcohol Drinking
Alcohol Use Disorder

Interventions: Drug: Placebo
Drug: Pitolisant

Registration Number: NCT04596267

Lead Sponsor: Boston Medical Center

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 9

Inclusion Criteria

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

Exclusion Criteria

Seeking treatment for alcohol problems
Clinical Institute Withdrawal Assessment at ≥10
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
If female, pregnant, nursing, have plans to become pregnant
If female, does not agree to use an accepted form of birth control
Has a medical contraindication to the use of pitolisant
Has medical or mental condition for which further alcohol exposure at the planned dose range would be contraindicated
Current risk of suicidality (MINI suicidality score greater than 8 (low risk) or Yes to the ideation question #4 of the C-SSRS)
BMI is greater than 40 or less than 18
Impaired renal function (GFR <80 mL/min)
Have a history of any clinically significant renal or hepatic disease
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]
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
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
Has received alcohol counseling or other non-pharmacologic intervention to treat AUD in the past 90 days
Has taken medications that are used to treat AUD in the past 90 days
Has urine toxicology results positive for cocaine, opioids, amphetamines, buprenorphine, methadone, methamphetamines, oxycontin, barbiturates, or benzodiazepines.
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).
Subject is known to be a poor CYP2D6 metabolizer.
Subject is unable to comfortably abstain from nicotine for a period of 8 hours.
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.).

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Subjects will take an placebo once per day on day 1 through 4. On day 5, a placebo will be taken in front of staff prior to an alcohol self administration trial.
Pitolisant	Pitolisant	Subjects will take an 8.9 mg dose (two 4.45 mg pills) of pitolisant once per day on day 1 through 4. On day 5, 8.9 mg will be taken in front of staff prior to an alcohol self administration trial.

Primary Outcome Measures

Name	Time	Method
Alcohol Consumption (BAC): Observation Period, Minute 20	1 minute	Alcohol consumption will be measured throughout the study by their Blood Alcohol Content (BAC) measured by a breathalyzer test. Lower BACs are favorable.
Alcohol Consumption in Alcohol Self-Administration Trials	2.6 hours	Alcohol consumption will be measured by using a graduated cylinder to determine the amount of alcohol given to the subject that was not consumed. This outcome will be measured as standard drink units (SDU). A standard drink contains approximately 0.6 fluid ounces of pure alcohol. Lower SDUs are favorable.
Alcohol Consumption (BAC): Observation Period, Minute 10	1 minute	Alcohol consumption will be measured throughout the study by their Blood Alcohol Content (BAC) measured by a breathalyzer test. Lower BACs are favorable
Alcohol Consumption (BAC): Observation Period, Minute 40	1 minute	Alcohol consumption will be measured throughout the study by their Blood Alcohol Content (BAC) measured by a breathalyzer test. Lower BACs are favorable.
Alcohol Consumption (BAC): Self-administration Block 2, Minute 60	1 minute	Alcohol consumption will be measured throughout the study by their Blood Alcohol Content (BAC) measured by a breathalyzer test. Lower BACs are favorable.
Alcohol Consumption (BAC): Observation Period, Minute 30	1 minute	Alcohol consumption will be measured throughout the study by their Blood Alcohol Content (BAC) measured by a breathalyzer test. Lower BACs are favorable.
Alcohol Consumption (BAC): Self-administration Block 1, Minute 30	1 minute	Alcohol consumption will be measured throughout the study by their Blood Alcohol Content (BAC) measured by a breathalyzer test. Lower BACs are favorable.
Alcohol Consumption (BAC): Self-administration Block 1, Minute 60	1 minute	Alcohol consumption will be measured throughout the study by their Blood Alcohol Content (BAC) measured by a breathalyzer test. Lower BACs are favorable.
Alcohol Consumption (BAC): Self-administration Block 2, Minute 30	1 minute	Alcohol consumption will be measured throughout the study by their Blood Alcohol Content (BAC) measured by a breathalyzer test. Lower BACs are favorable.

Secondary Outcome Measures

Name	Time	Method
Alcohol-induced Stimulation: Observation Period, Minute 30	1 minute	Whether pitolisant increases the stimulant effects of a priming drink of alcohol will be assessed using the Biphasic Alcohol Effects Scale (BAES). It is a self-report, unipolar adjective rating scale that is designed to measure both stimulant and sedative effects of alcohol. It consists of fourteen items, that comprise two subscales (stimulant and sedative). Items are rated on a eleven-point scale from 0 (not at all) to 10 (extremely). The stimulant subscale can range from 0 to 70 and the sedative scale can rage from 0 to 50. Higher scores are associated with more stimulant and sedative effects, respectively. This section focuses solely on stimulation. Lower BAES scores are favorable.
Alcohol-induced Stimulation: Self-Administration Block 1, Minute 30	1 minute	Whether pitolisant increases the stimulant effects of a priming drink of alcohol will be assessed using the Biphasic Alcohol Effects Scale (BAES). It is a self-report, unipolar adjective rating scale that is designed to measure both stimulant and sedative effects of alcohol. It consists of fourteen items, that comprise two subscales (stimulant and sedative). Items are rated on a eleven-point scale from 0 (not at all) to 10 (extremely). The stimulant subscale can range from 0 to 70 and the sedative scale can rage from 0 to 50. Higher scores are associated with more stimulant and sedative effects, respectively. This section focuses solely on stimulation. Lower BAES scores are favorable.
Alcohol-induced Stimulation: Self-Administration Block 2, Minute 60	1 minute	Whether pitolisant increases the stimulant effects of a priming drink of alcohol will be assessed using the Biphasic Alcohol Effects Scale (BAES). It is a self-report, unipolar adjective rating scale that is designed to measure both stimulant and sedative effects of alcohol. It consists of fourteen items, that comprise two subscales (stimulant and sedative). Items are rated on a eleven-point scale from 0 (not at all) to 10 (extremely). The stimulant subscale can range from 0 to 70 and the sedative scale can rage from 0 to 50. Higher scores are associated with more stimulant and sedative effects, respectively. This section focuses solely on stimulation. Lower BAES scores are favorable.
Alcohol-induced Sedation: Self-administration Block 2, Minute 30	1 minute	Whether pitolisant increases the sedative effects of a priming drink of alcohol will be assessed using the Biphasic Alcohol Effects Scale (BAES). It is a self-report, unipolar adjective rating scale that is designed to measure both stimulant and sedative effects of alcohol. It consists of fourteen items, that comprise two subscales (stimulant and sedative). Items are rated on a eleven-point scale from 0 (not at all) to 10 (extremely). The stimulant subscale can range from 0 to 70 and the sedative scale can rage from 0 to 50. Higher scores are associated with more stimulant and sedative effects, respectively. This section focuses solely on sedation. Lower BAES scores are favorable.
Alcohol Consumption During the 12-day Drug Exposure	12 days	Alcohol consumption during the 12 days of drug exposure will be measured using the timeline followback method. Lower (Standard Drink Units) SDUs are favorable.
Alcohol-induced Stimulation: Observation Period, Minute 20	1 minute	Whether pitolisant increases the stimulant effects of a priming drink of alcohol will be assessed using the Biphasic Alcohol Effects Scale (BAES). It is a self-report, unipolar adjective rating scale that is designed to measure both stimulant and sedative effects of alcohol. It consists of fourteen items, that comprise two subscales (stimulant and sedative). Items are rated on a eleven-point scale from 0 (not at all) to 10 (extremely). The stimulant subscale can range from 0 to 70 and the sedative scale can rage from 0 to 50. Higher scores are associated with more stimulant and sedative effects, respectively. This section focuses solely on stimulation. Lower BAES scores are favorable.
Alcohol-induced Sedation: Observation Period, Minute 20	1 minute	Whether pitolisant increases the sedative effects of a priming drink of alcohol will be assessed using the Biphasic Alcohol Effects Scale (BAES). It is a self-report, unipolar adjective rating scale that is designed to measure both stimulant and sedative effects of alcohol. It consists of fourteen items, that comprise two subscales (stimulant and sedative). Items are rated on a eleven-point scale from 0 (not at all) to 10 (extremely). The stimulant subscale can range from 0 to 70 and the sedative scale can rage from 0 to 50. Higher scores are associated with more stimulant and sedative effects, respectively. This section focuses solely on sedation. Lower BAES scores are favorable.
Alcohol-induced Sedation: Observation Period, Minute 40	1 minute	Whether pitolisant increases the sedative effects of a priming drink of alcohol will be assessed using the Biphasic Alcohol Effects Scale (BAES). It is a self-report, unipolar adjective rating scale that is designed to measure both stimulant and sedative effects of alcohol. It consists of fourteen items, that comprise two subscales (stimulant and sedative). Items are rated on a eleven-point scale from 0 (not at all) to 10 (extremely). The stimulant subscale can range from 0 to 70 and the sedative scale can rage from 0 to 50. Higher scores are associated with more stimulant and sedative effects, respectively. This section focuses solely on sedation. Lower BAES scores are favorable.
Alcohol-induced Sedation: Self-Administration Block 1, Minute 30	1 minute	Whether pitolisant increases the sedative effects of a priming drink of alcohol will be assessed using the Biphasic Alcohol Effects Scale (BAES). It is a self-report, unipolar adjective rating scale that is designed to measure both stimulant and sedative effects of alcohol. It consists of fourteen items, that comprise two subscales (stimulant and sedative). Items are rated on a eleven-point scale from 0 (not at all) to 10 (extremely). The stimulant subscale can range from 0 to 70 and the sedative scale can rage from 0 to 50. Higher scores are associated with more stimulant and sedative effects, respectively. This section focuses solely on sedation. Lower BAES scores are favorable.
Alcohol Craving: Observation Period, Minute 30	1 minute	Alcohol craving will be measured by self report with the Visual Analog Scale (VAS). The VAS is a straight line with one end meaning no alcohol craving (score of 0) and the other end meaning intense alcohol craving (score of 100). The Participant marks a point on the line that matches their amount of alcohol craving. Lower VAS score is favorable.
Alcohol Craving: Self-administration Block 2, Minute 60	1 minute	Alcohol craving will be measured by self report with the Visual Analog Scale (VAS). The VAS is a straight line with one end meaning no alcohol craving (score of 0) and the other end meaning intense alcohol craving (score of 100). The Participant marks a point on the line that matches their amount of alcohol craving. Lower VAS score is favorable.
Alcohol-induced Stimulation: Observation Period, Minute 10	1 minute	Whether pitolisant increases the stimulant effects of a priming drink of alcohol will be assessed using the Biphasic Alcohol Effects Scale (BAES). It is a self-report, unipolar adjective rating scale that is designed to measure both stimulant and sedative effects of alcohol. It consists of fourteen items, that comprise two subscales (stimulant and sedative). Items are rated on a eleven-point scale from 0 (not at all) to 10 (extremely). The stimulant subscale can range from 0 to 70 and the sedative scale can rage from 0 to 50. Higher BAES scores are associated with more stimulant and sedative effects, respectively. This section focuses solely on stimulation. Lower BAES scores are favorable.
Alcohol-induced Stimulation: Self-Administration Block 2, Minute 30	1 minute	Whether pitolisant increases the stimulant effects of a priming drink of alcohol will be assessed using the Biphasic Alcohol Effects Scale (BAES). It is a self-report, unipolar adjective rating scale that is designed to measure both stimulant and sedative effects of alcohol. It consists of fourteen items, that comprise two subscales (stimulant and sedative). Items are rated on a eleven-point scale from 0 (not at all) to 10 (extremely). The stimulant subscale can range from 0 to 70 and the sedative scale can rage from 0 to 50. Higher scores are associated with more stimulant and sedative effects, respectively. This section focuses solely on stimulation. Lower BAES scores are favorable.
Alcohol-induced Sedation: Self-administration Block 1, Minute 60	1 minute	Whether pitolisant increases the sedative effects of a priming drink of alcohol will be assessed using the Biphasic Alcohol Effects Scale (BAES). It is a self-report, unipolar adjective rating scale that is designed to measure both stimulant and sedative effects of alcohol. It consists of fourteen items, that comprise two subscales (stimulant and sedative). Items are rated on a eleven-point scale from 0 (not at all) to 10 (extremely). The stimulant subscale can range from 0 to 70 and the sedative scale can rage from 0 to 50. Higher scores are associated with more stimulant and sedative effects, respectively. This section focuses solely on sedation. Lower BAES scores are favorable.
Alcohol Craving: Self-administration Block 1, Minute 30	1 minute	Alcohol craving will be measured by self report with the Visual Analog Scale (VAS). The VAS is a straight line with one end meaning no alcohol craving (score of 0) and the other end meaning intense alcohol craving (score of 100). The Participant marks a point on the line that matches their amount of alcohol craving. Lower VAS score is favorable.
Alcohol Craving: Self-administration Block 2, Minute 30	1 minute	Alcohol craving will be measured by self report with the Visual Analog Scale (VAS). The VAS is a straight line with one end meaning no alcohol craving (score of 0) and the other end meaning intense alcohol craving (score of 100). The Participant marks a point on the line that matches their amount of alcohol craving. Lower VAS score is favorable.
Alcohol-induced Stimulation: Observation Period, Minute 40	1 minute	Whether pitolisant increases the stimulant effects of a priming drink of alcohol will be assessed using the Biphasic Alcohol Effects Scale (BAES). It is a self-report, unipolar adjective rating scale that is designed to measure both stimulant and sedative effects of alcohol. It consists of fourteen items, that comprise two subscales (stimulant and sedative). Items are rated on a eleven-point scale from 0 (not at all) to 10 (extremely). The stimulant subscale can range from 0 to 70 and the sedative scale can rage from 0 to 50. Higher scores are associated with more stimulant and sedative effects, respectively. This section focuses solely on stimulation. Lower BAES scores are favorable.
Alcohol-induced Stimulation: Self-Administration Block 1, Minute 60	1 minute	Whether pitolisant increases the stimulant effects of a priming drink of alcohol will be assessed using the Biphasic Alcohol Effects Scale (BAES). It is a self-report, unipolar adjective rating scale that is designed to measure both stimulant and sedative effects of alcohol. It consists of fourteen items, that comprise two subscales (stimulant and sedative). Items are rated on a eleven-point scale from 0 (not at all) to 10 (extremely). The stimulant subscale can range from 0 to 70 and the sedative scale can rage from 0 to 50. Higher scores are associated with more stimulant and sedative effects, respectively. This section focuses solely on stimulation. Lower BAES scores are favorable.
Alcohol-induced Sedation: Observation Period, Minute 10	1 minute	Whether pitolisant increases the sedative effects of a priming drink of alcohol will be assessed using the Biphasic Alcohol Effects Scale (BAES). It is a self-report, unipolar adjective rating scale that is designed to measure both stimulant and sedative effects of alcohol. It consists of fourteen items, that comprise two subscales (stimulant and sedative). Items are rated on a eleven-point scale from 0 (not at all) to 10 (extremely). The stimulant subscale can range from 0 to 70 and the sedative scale can rage from 0 to 50. Higher scores are associated with more stimulant and sedative effects, respectively. This section focuses solely on sedation. Lower BAES scores are favorable.
Alcohol-induced Sedation: Observation Period, Minute 30	1 minute	Whether pitolisant increases the sedative effects of a priming drink of alcohol will be assessed using the Biphasic Alcohol Effects Scale (BAES). It is a self-report, unipolar adjective rating scale that is designed to measure both stimulant and sedative effects of alcohol. It consists of fourteen items, that comprise two subscales (stimulant and sedative). Items are rated on a eleven-point scale from 0 (not at all) to 10 (extremely). The stimulant subscale can range from 0 to 70 and the sedative scale can rage from 0 to 50. Higher scores are associated with more stimulant and sedative effects, respectively. This section focuses solely on sedation. Lower BAES scores are favorable.
Alcohol Craving: Observation Period, Minute 10	1 minute	Alcohol craving will be measured by self report with the Visual Analog Scale (VAS). The VAS is a straight line with one end meaning no alcohol craving (score of 0) and the other end meaning intense alcohol craving (score of 100). The Participant marks a point on the line that matches their amount of alcohol craving. Lower VAS score is favorable.
Alcohol Urge: Self-administration Block 1, Minute 30	1 minute	The Alcohol Urge questionnaire (AUQ) is an 8 item measure of self-reported urges to drink in human laboratory studies that assesses the participant's urge for an alcoholic drink at the time the questionnaire is completed, Questions are in the form of a 7-point Likert scale (from strongly disagree to strongly agree) and participants select the extent to which they disagree or agree with the 8 statements relating to desire to drink, expectation of a desired outcome from drinking, and inability to avoid drinking if alcohol was available. The minimum AUQ score is 8 and the maximum score is 56. Lower AUQ scores are associated with less urge for an alcoholic drink, and therefore more favorable.
Alcohol Urge: Self-administration Block 1, Minute 60	1 minute	The Alcohol Urge questionnaire (AUQ) is an 8 item measure of self-reported urges to drink in human laboratory studies that assesses the participant's urge for an alcoholic drink at the time the questionnaire is completed, Questions are in the form of a 7-point Likert scale (from strongly disagree to strongly agree) and participants select the extent to which they disagree or agree with the 8 statements relating to desire to drink, expectation of a desired outcome from drinking, and inability to avoid drinking if alcohol was available. The minimum AUQ score is 8 and the maximum score is 56. Lower AUQ scores are associated with less urge for an alcoholic drink, and therefore more favorable.
Alcohol Urge: Self-administration Block 2, Minute 60	1 minute	The Alcohol Urge questionnaire (AUQ) is an 8 item measure of self-reported urges to drink in human laboratory studies that assesses the participant's urge for an alcoholic drink at the time the questionnaire is completed, Questions are in the form of a 7-point Likert scale (from strongly disagree to strongly agree) and participants select the extent to which they disagree or agree with the 8 statements relating to desire to drink, expectation of a desired outcome from drinking, and inability to avoid drinking if alcohol was available. The minimum AUQ score is 8 and the maximum score is 56. Lower AUQ scores are associated with less urge for an alcoholic drink, and therefore more favorable.
Alcohol Craving: Observation Period, Minute 20	1 minute	Alcohol craving will be measured by self report with the Visual Analog Scale (VAS). The VAS is a straight line with one end meaning no alcohol craving (score of 0) and the other end meaning intense alcohol craving (score of 100). The Participant marks a point on the line that matches their amount of alcohol craving. Lower VAS score is favorable.
Alcohol Craving: Self-administration Block 1, Minute 60	1 minute	Alcohol craving will be measured by self report with the Visual Analog Scale (VAS). The VAS is a straight line with one end meaning no alcohol craving (score of 0) and the other end meaning intense alcohol craving (score of 100). The Participant marks a point on the line that matches their amount of alcohol craving. Lower VAS score is favorable.
Alcohol-induced Sedation: Self-administration Block 2, Minute 60	1 minute	Whether pitolisant increases the sedative effects of a priming drink of alcohol will be assessed using the Biphasic Alcohol Effects Scale (BAES). It is a self-report, unipolar adjective rating scale that is designed to measure both stimulant and sedative effects of alcohol. It consists of fourteen items, that comprise two subscales (stimulant and sedative). Items are rated on a eleven-point scale from 0 (not at all) to 10 (extremely). The stimulant subscale can range from 0 to 70 and the sedative scale can rage from 0 to 50. Higher scores are associated with more stimulant and sedative effects, respectively. This section focuses solely on sedation. Lower BAES scores are favorable.
Alcohol Urge: Self-administration Block 2, Minute 30	1 minute	The Alcohol Urge questionnaire (AUQ) is an 8 item measure of self-reported urges to drink in human laboratory studies that assesses the participant's urge for an alcoholic drink at the time the questionnaire is completed, Questions are in the form of a 7-point Likert scale (from strongly disagree to strongly agree) and participants select the extent to which they disagree or agree with the 8 statements relating to desire to drink, expectation of a desired outcome from drinking, and inability to avoid drinking if alcohol was available. The minimum AUQ score is 8 and the maximum score is 56. Lower AUQ scores are associated with less urge for an alcoholic drink, and therefore more favorable.
Alcohol Craving: Observation Period, Minute 40	1 minute	Alcohol craving will be measured by self report with the Visual Analog Scale (VAS). The VAS is a straight line with one end meaning no alcohol craving (score of 0) and the other end meaning intense alcohol craving (score of 100). The Participant marks a point on the line that matches their amount of alcohol craving. Lower VAS score is favorable.
Alcohol Craving During 12-day Drug Exposure	12 days	The Visual Analog Scale (VAS) will be used to assess alcohol craving during the medication exposure period. The VAS is a 10 cm straight line with one end meaning no alcohol craving and the other end meaning intense alcohol craving. Higher VAS scores are associated with more cravings. Lower VAS scores are favorable.