Pioglitazone for the Treatment of Alcohol Use Disorder

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.

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