Development of Ivermectin for Alcohol Use Disorders

Phase 1

Completed

Conditions: Alcohol Use Disorder

Interventions: Drug: Ivermectin
Drug: Placebo
Drug: Alcohol

Registration Number: NCT02046200

Lead Sponsor: University of California, Los Angeles

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 11

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Ivermectin	Ivermectin	Ivermectin 30 mg single dose
Sugar pill	Placebo	Matched placebo, single dose
Ivermectin	Alcohol	Ivermectin 30 mg single dose
Sugar pill	Alcohol	Matched placebo, single dose

Primary Outcome Measures

Name	Time	Method
Heart Rate	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	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.
Systolic Blood Pressure	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	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.
Diastolic Blood Pressure	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	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.
Subjective Effects of Alcohol Using the Alcohol Urge Questionnaire (AUQ)	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 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).
Subjective Effects of Alcohol Using the Biphasic Alcohol Effects Scale (BAES) - Sedative Subscale	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 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.
Subjective Effects of Alcohol Using the Drug Effects Questionnaire (DEQ) - "Feel" Subscale	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 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).
Subjective Effects of Alcohol Using the Drug Effects Questionnaire (DEQ) - "Like" Subscale	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 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).
Subjective Effects of Alcohol Using the Drug Effects Questionnaire (DEQ) - "More" Subscale	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 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).
Subjective Effects of Alcohol Using the Drug Effects Questionnaire (DEQ) - "High" Subscale	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 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).
Subjective Effects of Alcohol Using the Biphasic Alcohol Effects Scale (BAES) - Stimulant Subscale	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 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.
Cue-induced Craving Using the Alcohol Urge Questionnaire (AUQ)	6 hours post-medication administration	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.
Adverse Effects	During alcohol infusion at BrAC = 0.00, 0.04, 0.08 g/dl	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.

Secondary Outcome Measures

Name	Time	Method
Ivermectin Pharmacokinetics: Area Under the Time-concentration Curve (AUC)	Hours post-drug administration: 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24, 48	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.
Ivermectin Pharmacokinetics: Half-life (T1/2)	Hours post-drug administration: 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24, 48	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.
Stress-induced Alcohol Craving	pre-post exposure to an imaginal stress script	Alcohol Urge Questionnaire (AUQ)
Ivermectin Pharmacokinetics: Peak Concentration (Cmax)	Hours post-drug administration: 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24, 48	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.
Ivermectin Pharmacokinetics: Time to Cmax (Tmax)	Hours post-drug administration: 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24, 48	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.