Development of Ibudilast for Alcohol Use Disorder

Study Overview
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Brief Summary
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The objective of this proposal is to advance medication development for alcoholism by conducting a safety and initial efficacy study of ibudilast, a neuroimmune modulator and phosphodiesterase inhibitor, for alcohol use disorders.

Detailed Description
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Alcohol dependence (AD) is a chronic and relapsing condition affecting 10 million Americans. To date, only four pharmacotherapies are approved by the FDA for the treatment of alcoholism and their efficacy is modest. Therefore, medication development for AD represents a high priority area. Ibudilast (IBUD) is a glial cell modulator that inhibits phosphodiesterases (PDE) -4 and -10 and macrophage migration inhibitory factor (MIF). Preclinical data suggest that neuroimmune modulation is critical to the rewarding properties of drugs of abuse, including alcohol. Further, IBUD has been shown to enhance GDNF release in vivo and GDNF modulation has been implicated in alcohol reinstatement in animals, while PDE inhibition has been shown to reduce alcohol intake in mice. Together, these findings suggest that neuroimmune modulation constitutes a novel target for the treatment of alcoholism. The objective of this study is to advance medication development for alcoholism by conducting an initial Phase II study of IBUD for AD. Specifically, the proposed study consists of a randomized, double-blind, placebo-controlled within-subject crossover design to determine the safety, tolerability, and initial human laboratory efficacy of IBUD in a sample of 24 non-treatment seeking individuals with either alcohol abuse or dependence treated with IBUD (50mg BID) and placebo. Participants will complete two separate 7-day inpatient stays at the UCLA CTRC during which they will take the study medication, complete an IV alcohol challenge, and take part in a stress-exposure and cue-exposure paradigms. Specific aims are to test whether IBUD (a) is safe in the context of alcohol administration, (b) attenuates alcohol-induced reinforcement, and (c) dampens stress-induced and cue-induced alcohol craving. In sum, this study will efficiently evaluate safety and initial efficacy of IBUD thereby screening novel medications for AD and elucidating potential mechanisms by which IBUD may be clinically efficacious. Results from this study will inform whether a randomized controlled trial of IBUD for alcoholism is warranted.

Official Title
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Development of Ibudilast as a Novel Treatment for Alcohol Dependence

Conditions
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Alcohol Use Disorders

Intervention / Treatment
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* Drug: Ibudilast
* Other: Matched placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age between 21 and 65 meet DSM-IV diagnostic criteria for alcohol abuse or dependence report drinking at least 48 standard drinks in a 30-day period, during the 90 days before enrollment Exclusion Criteria: current treatment for alcohol problems, a history of treatment in the 30 days before enrollment or current treatment seeking; current (last 12 months) DSM-IV diagnosis of dependence on any psychoactive substances other than alcohol and nicotine; 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); 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; attempted suicide in the past 3 years and/or serious suicidal intention or plan in the past year; currently on prescription medication that contraindicates use of IBUD; 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: Ibudilast<br>Ibudilast will be administered for 7 days at the target dose of 50 mg/bid | Drug: Ibudilast<br>* Ibudilast is a glial cell modulator that inhibits phosphodiesterases -4 and -10 and macrophage migration inhibitory factor.<br>* Other names: MN-166, AV411;|
| Placebo Comparator: Sugar pill<br>Placebo pills will be administered for 7 days and taken twice daily | Other: Matched placebo<br>* A matched placebo (suggar pill) will be administered as a control condition.<br>* Other names: Suggar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjective response to alcohol | Biphasic Alcohol Effects Scale (BAES) Alcohol Urge Questionnaire (AUQ) | During the alcohol administration and observation period which is expected to last a total of 4 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stress-Induced Craving | Alcohol Urge Questionnaire (AUQ) & Differential Emotion Scale (DES) | During the stress exposure and observation period which is expected to last a total of 2 hours | 
| Cue-Induced Alcohol Craving | Alcohol Urge Questionnaire (AUQ) | During the cue-exposure and observation period which is expected to last a total of 2 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ibudilast, alcoholism