Pioglitazone for the Treatment of Alcohol Use Disorder

Study Overview
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Brief Summary
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Alcohol Use Disorder (AUD) is common among Veterans but medication treatment is used infrequently and the impact of these treatments are small to moderate at best. Pioglitazone, a medication FDA approved for diabetes, has been shown in pre-clinical studies to reduce alcohol. The proposed study will test the efficacy of pioglitazone to reduce alcohol use in a double-blind placebo controlled trial. Investigators plan to compare pioglitazone to placebo in 200 Veterans who have an AUD and who are currently drinking alcohol at two Veterans Affairs Health Care Centers. The primary hypothesis is that Veterans with an AUD who are currently drinking alcohol will have a greater reduction in alcohol use following treatment with pioglitazone compared to those treated with placebo.

Detailed Description
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Background: Alcohol use disorder (AUD) and heavy drinking are common among Veterans with 42.2% of Veterans having a life-time history of AUD and 14.8% screening positive for past-year probable AUD. Although treatments for AUD have improved over the past several decades, more effective interventions are needed. Pioglitazone is an FDA approved medication used to treat diabetes. Pioglitazone is a PPAR agonist and has been reported to decrease voluntary alcohol consumption of a 10% alcohol solution in rats genetically selected for high alcohol consumption. In addition, when rats had to perform an operant task to receive alcohol, pioglitazone reduced alcohol self-administration but not saccharin intake. These data suggest that pioglitazone reduces the motivation to consume alcohol. No clinical studies of pioglitazone are available in patients with AUD only. This proposed research study is a double-blind controlled clinical trial of 200 Veterans with AUD randomized to either pioglitazone or placebo. The primary hypothesis is that Veterans with AUD who are currently drinking alcohol will have a greater reduction in heavy drinking days per week compared to those who receive placebo. Methods: Male and Female Veterans who are above 18 years old, who are not seeking intensive outpatient alcohol treatment will be recruited from the Minneapolis and Long Beach VA Health Care Service's for the study. After screening visits and informed consent, participants who meet all inclusion and exclusion criteria and who sign the informed consent will be given a breathalyzer test and the following measures: The Structured Clinical Interview for DSM-5 (SCID), Obsessive Compulsive Drinking Scale (OCDS), Timeline Followback (TLFB), Beck Depression Inventory-2nd edition (BDI-II) and the PTSD Checklist (PCL-5). Participants will also provide a urine sample for a urine drug screen, Ethyl Glucuronide (EtG), and Ethyl Sulfate (EtS), and blood samples for ALT, AST and BNP (B-type natriuretic peptide). Women of childbearing potential will provide a urine sample for Beta-Human chorionic gonadotropin ( -HCG). Participants will then be randomized to receive either pioglitazone or placebo. The participants will be seen weekly for the first 4 weeks (visits 1,2,3,4- baseline or randomization visit will be visit 0) then every 2 weeks until the end of the study (week 6 or visit 5, week 8 or visit 6, week 10 or visit 7, week 12 or visit 8, and week 14 or visit 9) for a maximum of 12 visits (including the screening visit, baseline visit, and closeout visit). At week 16, there will be a termination or closeout visit after study medications have been tapered. During the first 2 weeks of the study, each subject will have their dose of pioglitazone (or placebo) increased to a dose of 45mg per day. In addition to the medication (pioglitazone or placebo all participants will receive Brief Behavioral Compliance Enhancement Treatment (BBCET) as their psychosocial treatment. This is a standardized 15-minute intervention that emphasizes medication adherence as a crucial element to change alcohol use behavior. Alcohol use will be measured by the Timeline Follow-back method and biomarkers of alcohol use will also be measured to determine whether a reduction in alcohol correlates with reduced markers of alcohol use. In addition, the impact of pioglitazone on rumination and safety will be assessed with a variety of measures. Relevance to Veterans Health: Veterans have high rates of AUD with significant impact on health, quality of life and mortality. In addition, the direct and indirect cost of AUD are high. Current medication treatment approaches are infrequently used and of only small to modest benefit. Pioglitazone has shown promise in several pre-clinical studies but no AUD clinically focused studies are available. If pioglitazone is found to be useful in reducing or eliminating alcohol use in Veterans it could be easily and rapidly repurposed to treat AUD, as it is already an FDA approved medication. Pioglitazone, given its unique mechanism of action, may offer an innovative approach to treating Veterans with AUD and thus help reduce the impact of this costly and difficult problem.

Official Title
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A Randomized Trial of Pioglitazone for the Treatment of Alcohol Use Disorder

Conditions
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Alcohol Use Disorder

Intervention / Treatment
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* Behavioral: Brief Behavioral Compliance Enhancement Treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: DSM-5 diagnosis of at least moderate alcohol use disorder using the SCID A mean of six heavy drinking days per month for the 3-months prior to baseline. Drinking at least 14 drinks for men or 7 drinks for women, or more per week for the 4 weeks preceding the screening visit. Willingness to provide contact information to confirm study follow-up appointments Ability to perform informed consent Female subjects: a negative pregnancy test Serum ALT < 3 times reference range Stable psychiatric medication doses the month prior to baseline visit (antidepressant, antipsychotic, subjects may have changes in trazodone for sleep) Exclusion Criteria: Current DSM-5 diagnosis of moderate to severe psychoactive substance use disorder (i.e. cocaine, opiates, methamphetamine) other than cannabis or nicotine Medical conditions contraindicating pioglitazone pharmacotherapy (e.g., congestive heart failure, clinically significant edema, clinically significant liver disease, hypoglycemia, diabetes, history of bladder cancer) Taking medications known to have significant drug interactions with the study medication (CYP2C8 inhibitors or inducers, antihyperglycemic medications) Cognitive or physical impairment that precludes study participation Currently and seriously suicidal (i.e., plan and intent) Currently being treated for AUD with a medication (naltrexone, naltrexone injectable, acamprosate, topiramate, disulfiram and gabapentin) Impending incarceration Pregnant or planning to become pregnant during the course of the trial or nursing for female patients Unwillingness to sign a written informed consent form Unwillingness to use a barrier method of birth control during the study for female patients

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Interventional Model Description: This is a randomized controlled parallel group study design
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pioglitazone<br>Pioglitazone titrated to 45mg by mouth each day | Behavioral: Brief Behavioral Compliance Enhancement Treatment<br>* This is a standardized 15-minute intervention that emphasizes medication adherence as a crucial element to change alcohol use behavior.<br>* Other names: BBCET;|
| Placebo Comparator: Placebo<br>placebo, identical 45mg pill | Behavioral: Brief Behavioral Compliance Enhancement Treatment<br>* This is a standardized 15-minute intervention that emphasizes medication adherence as a crucial element to change alcohol use behavior.<br>* Other names: BBCET;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| heavy drinking days per week change | The primary outcome is change in heavy drinking days per week as measured by the Timeline Follow-back. A heavy drinking day is defined as : >4 standard drinks in a day for men and >3 standard drinks in a day for women | baseline and weekly for 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| No heavy drinking for the last 8 weeks of the study | The rate of no heavy drinking over the last 8 weeks of the study (weeks 6-14) is a responder analysis measures. | heavy drinking between week 6 and 14. | 
| Number of drinks per week | Number of standard drinks per week as measured by the Timeline Follow-back | baseline and weekly for 14 weeks | 
| Alcohol craving | Craving will be measured by the Obsessive Compulsive Drinking Scale (OCDS). Range is 0-56, greater scores indicates greater craving. | baseline, weekly through week 8 then week 10, 12 and 14. | 
| ethyl glucuronide (EtG) and ethyl sulfate (EtS) concentration | EtG and EtS are direct metabolites of alcohol and remains in urine for up to 5 days after cessation from alcohol and they are highly sensitive with good specificity for alcohol use. | Baseline, week 4, 8 ,12 and 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Craving, Alcohol Use Disorder, Alcohol dependence