Development of Ivermectin for Alcohol Use Disorders

Study Overview
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Brief Summary
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Current pharmacotherapies for alcohol use disorders (AUDs) have limited efficacy. Thus, the development of effective treatments for AUDs represents an important public health objective. Repositioning, i.e. using existing approved drugs for other indications, represents a fast and economically feasible approach for drug development. Ivermectin (IVM) is an FDA-approved antiparasitic medication that can significantly reduce alcohol intake in mice, suggesting that it may be useful in the treatment of AUDs in humans. The goal of this project is to provide key clinical evidence that IVM can be repositioned as a novel therapeutic agent to treat AUDs.

Detailed Description
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Current pharmacotherapies for alcohol use disorders (AUDs) have limited efficacy. Thus, the development of effective treatments for AUDs represents an important public health objective. Repositioning, i.e. using existing approved drugs for other indications, represents a fast and economically feasible approach for drug development. Ivermectin (IVM) is an FDA-approved antiparasitic medication that can significantly reduce alcohol intake in mice, suggesting that it may be useful in the treatment of AUDs in humans. The goal of this project is to provide key clinical evidence that IVM can be repositioned as a novel therapeutic agent to treat AUDs. We will enroll 10 alcohol dependent individuals in a placebo-controlled randomized pilot safety trial of IVM (30 mg orally once) over a 2-day (1-night) inpatient stay at the UCLA CTRC and employ a well-characterized battery of behavioral paradigms (i.e., alcohol administration and cue exposure). The goals of the study are to test: (a) the safety of combining IVM, at a dose currently shown to be safe in humans (30 mg), with moderate doses of alcohol (0.08 g/dl); and (b) whether IVM reduces the reinforcing effects of alcohol during alcohol administration and whether it reduces alcohol craving during cue exposure, as compared to placebo.

Official Title
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Repositioning Ivermectin for the Treatment of Alcohol Use Disorders

Conditions
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Alcohol Use Disorder

Intervention / Treatment
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* Drug: Ivermectin
* Drug: Placebo
* Drug: Alcohol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age between 21 and 65; meet current DSM-V diagnostic criteria for an alcohol use disorder Exclusion Criteria: current treatment for alcohol problems, a history of treatment in the 30 days before enrollment or current treatment seeking; a current (last 12 months) DSM-V diagnosis of dependence on any psychoactive substances other than alcohol and nicotine; a lifetime DSM-IV diagnosis of schizophrenia, bipolar disorder, or any psychotic disorder; positive urine screen for narcotics, amphetamines, or sedative hypnotics; serious alcohol withdrawal symptoms as indicated by a score ≥ 10 on the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-R); pregnancy, nursing, or refusal to use reliable method of birth control (if female); a medical condition that may interfere with safe study participation (e.g., unstable cardiac, renal, or liver disease, uncontrolled hypertension or diabetes); AST, ALT, or GGT ≥ 3 times upper normal limit; currently on prescription medication that contraindicates use of IVN; any other circumstances that, in the opinion of the investigators, compromises participant safety.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ivermectin<br>Ivermectin 30 mg single dose | Drug: Ivermectin<br>* Ivermectin is a semi-synthetic macrocyclic lactone used worldwide as a broad-spectrum antiparasitic avermectin.<br>* Other names: Stromectol;Drug: Alcohol<br> <br> * Other names: 5% ethanol IV solution;|
| Placebo Comparator: Sugar pill<br>Matched placebo, single dose | Drug: Placebo<br>* Matched placebo<br>* Other names: Sugar pill;Drug: Alcohol<br> <br> * Other names: 5% ethanol IV solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heart Rate | Heart rate (measured in beats per minute; BPM) will be monitored to determine the safety of combining IVM (30 mg) with moderate doses of alcohol (0.08 g/dl). During the infusion, the times for collecting HR will vary based on how long it takes participants to reach the targeted BrACs. | Post-medication administration (hours): 0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48; During alcohol infusion at BrAC = 0.00, 0.02, 0.04, 0.06, 0.08 g/dl | 
| Systolic Blood Pressure | Blood pressure (measured in mmHg) will be monitored to determine the safety of combining IVM (30 mg) with moderate doses of alcohol (0.08 g/dl). Blood pressure is measured at 0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-medication administration; and during alcohol infusion at BrAC = 0.00, 0.02, 0.04, 0.06, 0.08 g/dl. During the infusion, the times for collecting BP will vary based on how long it takes participants to reach the targeted BrACs. | Post-medication administration (hours): 0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48; During alcohol infusion at BrAC = 0.00, 0.02, 0.04, 0.06, 0.08 g/dl | 
| Diastolic Blood Pressure | Blood pressure (measured in mmHg) will be monitored to determine the safety of combining IVM (30 mg) with moderate doses of alcohol (0.08 g/dl). Blood pressure is measured at 0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-medication administration; and during alcohol infusion at BrAC = 0.00, 0.02, 0.04, 0.06, 0.08 g/dl. During the infusion, the times for collecting BP will vary based on how long it takes participants to reach the targeted BrACs. | Post-medication administration (hours): 0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48; During alcohol infusion at BrAC = 0.00, 0.02, 0.04, 0.06, 0.08 g/dl | 
| Subjective Effects of Alcohol Using the Alcohol Urge Questionnaire (AUQ) | Subjective effects of alcohol will be measured using the Alcohol Urge Questionnaire (AUQ), which consists of 8 items associated with urge to drink alcohol, rated on a 7 point scale (1 = strongly disagree, 7 = strongly agree). | During alcohol infusion at BrAC = 0.00, 0.02, 0.04, 0.06, 0.08 g/dl period; which is expected to last approximately 6 hours. | 
| Subjective Effects of Alcohol Using the Drug Effects Questionnaire (DEQ) - Feel Subscale | Subjective effects of alcohol will be measured using the Drug Effects Questionnaire, which consists of 4 items that capture subjective effects, (feeling effects, liking effects, wanting more and being high). The question Do you feel any drug effects? was rated on an 11 point scale from 0 to 10 (higher values represent more effects). | During alcohol infusion at BrAC = 0.00, 0.02, 0.04, 0.06, 0.08 g/dl period; which is expected to last approximately 6 hours. | 
| Subjective Effects of Alcohol Using the Drug Effects Questionnaire (DEQ) - Like Subscale | Subjective effects of alcohol will be measured using the Drug Effects Questionnaire, which consists of 4 items that capture subjective effects, (feeling effects, liking effects, wanting more and being high). The question Do you like the effects you are feeling right now? was rated on an 11 point scale from 0 to 10 (higher values represent more effects). | During alcohol infusion at BrAC = 0.00, 0.02, 0.04, 0.06, 0.08 g/dl period; which is expected to last approximately 6 hours. | 
| Subjective Effects of Alcohol Using the Drug Effects Questionnaire (DEQ) - More Subscale | Subjective effects of alcohol will be measured using the Drug Effects Questionnaire, which consists of 4 items that capture subjective effects, (feeling effects, liking effects, wanting more and being high). The question Would you like more of the drug right now? was rated on an 11 point scale from 0 to 10 (higher values represent more effects). | During alcohol infusion at BrAC = 0.00, 0.02, 0.04, 0.06, 0.08 g/dl period; which is expected to last approximately 6 hours. | 
| Subjective Effects of Alcohol Using the Drug Effects Questionnaire (DEQ) - High Subscale | Subjective effects of alcohol will be measured using the Drug Effects Questionnaire, which consists of 4 items that capture subjective effects, (feeling effects, liking effects, wanting more and being high). The question Are you high? was rated on an 11 point scale from 0 to 10 (higher values represent more effects). | During alcohol infusion at BrAC = 0.00, 0.02, 0.04, 0.06, 0.08 g/dl period; which is expected to last approximately 6 hours. | 
| Subjective Effects of Alcohol Using the Biphasic Alcohol Effects Scale (BAES) - Stimulant Subscale | Subjective effects of alcohol will be measured using the Biphasic Alcohol Effects Scale (BAES) , which consists of 14 items designed to capture the stimulant and sedative effects of alcohol, each rated on an 11-point scale (0 = not at all, 10 = extremely). The total score for the Stimulant Subscale ranges from 0 to 70. Mean scores across all subjects are reported below. | During alcohol infusion at BrAC = 0.00, 0.02, 0.04, 0.06, 0.08 g/dl period; which is expected to last approximately 6 hours. | 
| Subjective Effects of Alcohol Using the Biphasic Alcohol Effects Scale (BAES) - Sedative Subscale | Subjective effects of alcohol will be measured using the Biphasic Alcohol Effects Scale (BAES) , which consists of 14 items designed to capture the stimulant and sedative effects of alcohol, each rated on an 11-point scale (0 = not at all, 10 = extremely). The total score for the Sedative Subscale ranges from 0 to 70. Mean scores across subjects are reported below. | During alcohol infusion at BrAC = 0.00, 0.02, 0.04, 0.06, 0.08 g/dl period; which is expected to last approximately 6 hours. | 
| Cue-induced Craving Using the Alcohol Urge Questionnaire (AUQ) | Cue-induced craving will be measured using the Alcohol Urge Questionnaire (AUQ), which consists of 8 items associated with urge to drink alcohol, rated on a 7 point scale (0 = strongly disagree, 6 = strongly agree). Item scores were averaged and the total score also ranges from 0-6. | 6 hours post-medication administration | 
| Adverse Effects | Adverse effects will be monitored to determine the safe of combining IVM (30 mg) with moderate doses of alcohol (0.08 g/dl) using the Systematic Assessment for Treatment Emergent Effects (SAFTEE). The SAFTEE is a 24-item checklist in which the participant can identify whether a symptom is present (yes/no), its severity (mild, moderate, severe) and whether it was caused by the medication (yes/no). Data below represents a count of individual adverse effects reported on the SAFTEE during the alcohol infusion. | During alcohol infusion at BrAC = 0.00, 0.04, 0.08 g/dl | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ivermectin Pharmacokinetics: Peak Concentration (Cmax) | This study will collect blood samples for pharmacokinetic (PK) and pharmacodynamic profiling in order to examine whether IVM metabolism corresponds to its effects on alcohol response. Maximum plasma concentration (Cmax), measured in ng/mL, provided below. | Hours post-drug administration: 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24, 48 | 
| Ivermectin Pharmacokinetics: Time to Cmax (Tmax) | This study will collect blood samples for pharmacokinetic (PK) and pharmacodynamic profiling in order to examine whether IVM metabolism corresponds to its effects on alcohol response. Time to Cmax (Tmax), measured in hours, provided below. | Hours post-drug administration: 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24, 48 | 
| Ivermectin Pharmacokinetics: Area Under the Time-concentration Curve (AUC) | This study will collect blood samples for pharmacokinetic (PK) and pharmacodynamic profiling in order to examine whether IVM metabolism corresponds to its effects on alcohol response. Area under the time-concentration curve (AUC) from 0 to 48 hours after IVM administration, provided below. | Hours post-drug administration: 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24, 48 | 
| Ivermectin Pharmacokinetics: Half-life (T1/2) | This study will collect blood samples for pharmacokinetic (PK) and pharmacodynamic profiling in order to examine whether IVM metabolism corresponds to its effects on alcohol response. Half-life of ivermectin (T1/2), measured in hours, provided below. | Hours post-drug administration: 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24, 48 | 
| Stress-induced Alcohol Craving | Alcohol Urge Questionnaire (AUQ) | pre-post exposure to an imaginal stress script | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ivermectin, alcoholism, alcohol use disorder, treatment