A Randomized Trial of Pioglitazone for the Treatment of Alcohol Use Disorder
Phase: NA
Conditions: Alcohol Use Disorder
Sponsor: VA Office of Research and Development

A Randomized Trial of Pioglitazone for 
the Treatment of Alcohol Use Disorder
Protocol Version 1.5
2021-03-12
 
Minneapolis VA Health Care System IRB (Institutional Review
Board)
Effective Date:
April 22, 2021

1. Background and Significance
1.1 Alcohol use disorders in VA: 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 probably AUD (1). AUD is associated with increased rates of accidents 
(2), domestic violence (3), neurocognitive impairments(4), poor medication adherence (5), 
increased mortality (6) and alcohol problems influence the course and treatment of many 
psychiatric and medical conditions (7, 8). Harmful alcohol use is common among Vietnam era 
Veterans (9, 10) and among returnees from Iraq and Afghanistan high rates of new onset heavy 
weekly drinking, binge drinking, and alcohol-related problems are reported (11). AUD is also a 
high cost disease within the VA. In Fiscal Year 2009, 334,130 Veterans had at least one VA 
encounter for an AUD. In a random sample of nearly 600,000 VA patients, Yu and colleagues 
found that the marginal yearly treatment cost (cost above the mean for the entire sample) 
associated with a diagnosis of an AUD was $3,124 per patient (12). This marginal cost 
multiplied by the number of Veterans with the disorder represents over 1 billion dollars in VA 
costs related to alcohol use disorders per year. Although treatments for AUD have improved 
over the past several decades (13), more effective interventions are needed. Pharmacological 
treatments for AUD are infrequently used in Veterans (14) and used less often than 
psychosocial interventions (15). However, without pharmacological adjunct to psychosocial 
therapy nearly 75% of patients resume alcohol use within one year (16).  Current 
pharmacological treatments are only modestly effective, at best; new medications that 
address AUD are needed.
1.2 Medications for the treatment of AUD: Current medications for AUD target various brain 
regions that are classically thought to be involved in substance abuse behavior. Some of these 
regions include the nucleus accumbens and ventral striatum, thought to be involved in 
reinforcement, the dorsal striatum involved in habit formation, the hippocampus for its role in 
processing drug and alcohol contexts, and the prefrontal cortex for its role in exerting executive 
control over these regions. Most research has focused on GABA, glutamate and dopamine 
receptors as pharmacological targets as the above brain regions are mostly connected by 
GABAergic, glutamatergic and dopaminergic projections. In addition, compounds targeting 
opiate receptors have also been intensively studied (17, 18). The relationship between 
dopamine/dopamine pathways and craving/ reward has led to the clinical development of drugs 
that target this neurotransmitter in alcohol dependence (19). The Food and Drug Administration 
(FDA) has approved several medications for alcohol use disorder: disulfiram, an aldehyde 
dehydrogenase blocker; naltrexone, an opioid antagonist; injectable naltrexone (long-acting) 
and acamprosate, a functional glutamate antagonist. A meta-analysis of disulfiram showed 
limited efficacy and no effect on alcohol craving (20).  Naltrexone has been shown to primarily 
reduce drinking severity rather than promote abstinence or non-heavy drinking (21). Early 
studies of naltrexone found the effect size of naltrexone was modestly higher than placebo but 
its clinical success for promoting abstinence and reducing heavy drinking has declined since the 
early single site studies (22).  In clinical trials people treated with naltrexone had higher rates of 
dizziness, nausea and vomiting (23). Finally, oral naltrexone is contraindicated in acute 
hepatitis, liver failure, current opioid use, or anticipated need for opioids (24). Acamprosate has 
been FDA approved for AUD since 2004 and is primarily used to maintain abstinence, 
especially after alcohol detoxification (25). The treatment effect size of acamprosate is moderate 
in magnitude (25) and is limited by three times per day dosing and side effects which include 
anxiety, diarrhea and vomiting and is contraindicated in those with severe renal impairment (23).
 
Minneapolis VA Health Care System IRB (Institutional Review
Board)
Effective Date:
April 22, 2021

Another drug that has shown efficacy in AUD studies is topiramate. Topiramate is FDA-
approved for use as an anticonvulsant and as a drug to prevent migraine headaches. Its 
proposed mechanism of action for reducing alcohol use involves dopamine and dopamine 
pathways responsible for craving/reward in AUD by antagonizing excitatory glutamate receptors 
and inhibiting dopamine release while enhancing inhibitory GABA pathways (26). An initial study 
reported moderate to high effect size for reducing heavy drinking and for improving abstinence 
(27) however a meta-analysis using seven RCT’s supported only a small to moderate effect size 
for topiramate (28). Also, adverse effects in those treated with topiramate are common and 
include cognitive dysfunction, paresthesias and taste abnormalities therefore drop-outs 
significantly impact its efficacy (23). Finally, gabapentin and baclofen are thought to act via 
GABAergic pathways. Most controlled trials of gabapentin have been small and of brief duration 
and none have included Veterans. Anton and colleagues added gabapentin to naltrexone during 
the first 6-weeks of a randomized controlled trial and found that the combination improved sleep 
and drinking outcomes as compared with naltrexone alone (and placebo) but the effect did not 
endure after gabapentin was discontinued (29). Furieri and colleagues showed that gabapentin 
reduced alcohol craving and alcohol consumption when compared to placebo; however, the 
study lasted only 28 days, used low dose (300mg twice per day) gabapentin and only included 
60 total subjects (30). In a dose-ranging trial, Mason and colleagues found a linear-dose 
response with 1800mg of gabapentin being most effective in rates of complete abstinence and 
no-heavy drinking over a 12-week study (31). Side effects included fatigue (23%), insomnia 
(18%) and headache (14%) and only 56% of the subjects completed the study which suggests a 
significant limitation of this medication. Baclofen, another GABAergic medication has shown 
mixed results. An early study by Addolorato found significant improvement in alcohol outcomes 
in patients with cirrhosis but the study was relatively small (32) and later studies including our 
CSR&D funded study did not differentiate baclofen from placebo (33, 34). Finally, one important 
limitation of most of these medications is that they do not influence important alcohol outcomes 
that are associated with improved health. Specifically, in 2015 the FDA provided guidance for 
the development of drugs to treat “alcoholism” and recommended using responder analyses 
based on definitions that predict clinical benefit rather than analyses of group means as mean 
differences are difficult to interpret in regard to clinical relevance. They recommend using 
complete abstinence and no heavy drinking for defined periods of time, as efficacy endpoints 
(35). A variety of data suggest that the outcome of no heavy drinking is associated with reduced 
alcohol consequences, reduced likelihood of meeting future criteria for AUD, reduced risk of 
relapse and lower rates of alcohol-related problems (35). Most AUD medication studies have 
not shown this level of evidence in support of their use.
In summary, these data suggest that medications to treat AUD have only small to 
moderate effect sizes; they are used infrequently and have limited impact on meaningful 
clinical outcomes that are associated with improved health. Thus, new medications with 
unique mechanisms of action and with improved tolerability and efficacy are needed to 
address AUD in Veterans.
1.3 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.
 
Minneapolis VA Health Care System IRB (Institutional Review
Board)
Effective Date:
April 22, 2021

1.4 Pioglitazone a novel treatment for AUD: Peroxisome proliferator-activated receptors (PPAR) 
are a group of nuclear receptor proteins that primarily regulate gene expression via their role as 
ligand-activated transcription factors. PPAR agonists have been shown to reduce addictive 
behaviors in pre-clinical models including reducing chronic alcohol intake, binge alcohol intake, 
stress induced relapse and withdrawal in alcohol preferring rats (36). In addition, PPAR agonists 
have been shown to reduce a variety of behaviors related to other drugs of abuse, including 
nicotine, cocaine and heroin (37).  There have been three PPAR isoforms identified, alpha, delta 
and gamma, each transcribed from different genes. Pioglitazone is a PPAR ɣ 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 (38). 
Peroxisome proliferator-activated receptor agonists may exert their effects on alcohol 
use in a variety of ways. Activation of PPAR ɣ has been shown to mediate neuroprotection from 
N-methyl-D-aspartate (NMDA) mediated excitotoxic processes and inflammatory damage (37). 
PPAR ɣ agonists also inhibit pro-inflammatory IL-1 beta, IL-6, and TNF-α production and may 
exert its effects via reduction in innate immune signaling (39). Peroxisome proliferator-activated 
receptors have been found to be expressed in neurons, oligodendrocytes, and astrocytes in the 
central nervous system (cite). PPAR ɣ are highly expressed in the lateral hypothalamus (LH), 
the paraventricular nucleus of the hypothalamus (PVN), the arcuate nucleus (ARC), and the 
ventral tegmental area (VTA). PPAR ɣ receptors co-localize with tyrosine hydroxylase in the 
VTA suggesting the expression of this receptor in dopaminergic cells and thus pioglitazone may 
reduce this rewarding/reinforcing effect in AUD (40-42). Although, several pre-clinical studies 
suggest a significant positive effect from PPAR agonists on alcohol and drug use, only one 
human study is available and that was focused on treating cocaine use disorder (43). The 12-
week pilot study randomized 31 patients with cocaine use disorder to either pioglitazone or 
placebo and found a higher likelihood of reduced cocaine craving in patients treated with 
pioglitazone. Adherence to pioglitazone was high and side effects were mild, no serious adverse 
events occurred. Twenty-six subjects also met criteria for AUD and the data suggest that 
pioglitazone was effective at reducing alcohol use over placebo (43).
1.5 Summary of Pioglitazone pharmacological and toxicological data: Pioglitazone was FDA 
approved in 1999 to improve glycemic control in patients with type 2 diabetes, thus side effects 
and risks are well known. The FDA package insert provides information on a variety of risks and 
potential side effects that is summarized: The most common side effects (>5%) include upper 
respiratory tract infection, pharyngitis, headache, sinusitis and myalgia. Although the overall 
risks of these problems are greater than 5%, the risks when compared to placebo are all less 
than 5%. Of note, there have also been several warnings issued regarding pioglitazone. First, 
pioglitazone alone or more commonly in combination with other antidiabetic agents (typically 
insulin) can cause fluid retention and edema which increases the risk of congestive heart failure. 
The risk of heart failure was more common when comparing pioglitazone to placebo in a high-
risk group of patients with diabetes and pre-existing cardiovascular disease (44). There have 
been several reports of hepatotoxicity but not enough data to establish probable causality.  
There was a small increased rate of fractures in women and a small increased risk of urinary 
bladder cancer in patients treated for 24 months or longer. Finally, pioglitazone is a category C 
medication and thus should not be used in pregnancy and it may also induce ovulation so 
individuals may be at greater risk for pregnancy when taking this medication (45).
 
Minneapolis VA Health Care System IRB (Institutional Review
Board)
Effective Date:
April 22, 2021

In addition to the package insert there are a variety of published data in a diverse 
number of conditions including four published reports in patients treated for depression and a 
recent study that used pioglitazone to treat cocaine use which included 26 individuals with 
alcohol use disorder- see above. Studies with important safety information are summarized 
here: A meta-analysis of pioglitazone used for reducing liver fibrosis in nonalcoholic 
steatohepatitis reviewed 8 RCT’s with 516 patients followed between 6 and 24 months and 
found weight gain and lower limb edema as the primary adverse events (46). A recently 
published article using pioglitazone, for 30 months, in a similar clinical population, found no 
difference of major drug-related adverse events with minimal weight gain being the primary 
difference between pioglitazone and placebo (47). Although prior retrospective studies led to the 
FDA boxed warning for bladder cancer, two recent prospective studies suggest no link between 
pioglitazone and bladder cancer (48, 49). There have been four published RCT’s of pioglitazone 
for major depressive disorder with a total of 161 patients enrolled (6-12 week studies) with no 
significant adverse events occurring (50-53). Pioglitazone has also been explored as a 
treatment for dementia. A recent meta-analysis using PPAR- γ agonists to treat dementia found 
9 studies in 4,327 participants and found no significant difference in adverse or serious adverse 
events (54). A recent placebo controlled trial of pioglitazone for 30 patients with cocaine use 
disorder of whom 26 had an AUD reported the most frequent side effects were sleep disruption, 
diarrhea, stomach pain, cough, and increased urination which were all rated as mild (43). 
Finally, a recent, very small randomized trial comparing pioglitazone to placebo in a 
“mechanistic proof or principle” study to determine the effect of pioglitazone on alcohol craving 
was stopped early after 16 subjects were randomized due to safety concerns. The study 
entailed two experimental manipulations designed to induce alcohol craving, guided imagery 
compared to intravenous lipopolysaccharide. A total of 14 subjects (6 pioglitazone and 8 
placebo) were analyzed. Five in the pioglitazone arm had elevated creatine kinase (CK), one 
was deemed serious and one receiving placebo had an elevated CK. The study did not report 
absolute values for CK nor whether or how the CK was related to the initiation of pioglitazone or 
other whether it was temporally related to other study procedures (Schwandt et al 
psychopharmacology 2020).   In summary, pioglitazone is well tolerated with few side 
effects or significant safety concerns, particularly in short term (less than 24 weeks) 
studies.
2.0 Preliminary Studies
 
 :  The Minneapolis and Long Beach VAHCS have a long history of 
scientific collaboration. We have completed two prior CSR&D funded randomized controlled 
trials in AUD. The first was a RCT of motivational enhancement therapy in patients with AUD 
and chronic hepatitis C. We were able to show that motivational enhancement therapy helped 
reduce alcohol use in this population (55). The second was a placebo controlled RCT of 
baclofen in patients with AUD and hepatitis C. This was the largest trial of baclofen and showed 
no effect of baclofen on reducing alcohol use in this population (34). As previously noted there 
are no published trials of pioglitazone focused on AUD. However, in a preliminary investigation 
at the Minneapolis VA, we identified 252 patients who had at least one prescription for 
pioglitazone during 2016, all of these patients were being treated for diabetes. Of these 252 
patients 51 had an AUDIT-C score of at least 3 prior to starting the pioglitazone. The average 
AUDIT-C score prior to starting pioglitazone was 4.18 (1.69) the average AUDIT-C score after 
Pioglitazone was started was 2.85 (1.76). Patients stopped and started pioglitazone at various 
times and we determined the effect of pioglitazone on AUDIT-C scores by using a mixed 
regression model to compare AUDIT-C scores while on pioglitazone with those scores when not 
on pioglitazone. This analysis suggested that pioglitazone was associated with a reduction in 
AUDIT-C scores (F (1,312.2)=14.29, p<.001).  These data, combined with preclinical studies 
and the Schmitz study of cocaine using patients, suggest that pioglitazone is an effective 
 
Minneapolis VA Health Care System IRB (Institutional Review
Board)
Effective Date:
April 22, 2021

medication for AUD. A well-designed trial of pioglitazone focused on AUD is warranted 
and needed.
3.0 Research Design and Methods
3.1 Overview
This proposed research study is a double-blind controlled clinical trial of 200 Veterans 
with AUD randomized to either pioglitazone or placebo. 
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 test result must 
be below 0.05 in order for potential participant to be enrolled (see Breathalyzer Testing section, 
precautions will be taken based on test result). Following the breathalyzer test, participants will 
complete the initial assessment instruments, which include the SCID, Obsessive Compulsive 
Drinking Scale (OCDS), Timeline Follow Back (TLFB), Beck Depression Inventory-2nd edition 
(BDI-II) and the PTSD Checklist (PCL-5). They 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.  Women of childbearing potential will provide a urine sample for Beta-Human chorionic 
gonadotropin (β-HCG).  Participants will then be randomized to receive either pioglitazone or a 
placebo (see Data Analysis Plan-Randomization section).
After randomization, all 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.  All study measures will be administered at each visit during the double-blind period 
from weeks 0 to 14 and week 16 or the closeout visit. In particular, the BDI-II and PCL-5, will be 
given at each study visit. If participants report significant depressive or other psychiatric 
symptoms during the study, the decision to exclude them will be based on whether they can 
safely participate in the remainder of the study (See Human Subjects section). Data will also 
be collected from participants’ medical records regarding enrollment and attendance at specialty 
alcohol treatment appointments. Follow-up assessments will be conducted in person by a rater 
blinded to the participant’s study condition. 
The initial screening and baseline visit (may be done at the same time) and week 4 and 
14 visits will be conducted in person.  However, to enhance subject safety and minimize the risk 
of COVID-19, all other visits will be conducted by phone but may be conducted in person if the 
patient requests or if in the opinion of the PI a face-to-face visit is necessary for subject safety. 
Participants will have medication adherence assessed at each study visit (total number 
of tablets dispensed – tablets reported taken divided by the total number of tablets dispensed 
taking into consideration that patients will be given additional study medication in the event of 
missed visits- 7 days of additional medication). Tablet counts will be confirmed at each of the 
face-to-face visits. Participants will have a breathalyzer test at each face-to-face visit and will 
not be allowed to complete assessments if their test result is above 0.05%. For phone visits, 
subjects will be evaluated clinically for intoxication ie coherent speech, slurred words, able to 
follow questions and respond appropriately. 
May occur at same 
visit
Double Blind Period
Week
Measure
Screening
Baseline
Week 
1
Week 
2
Week 
3
Week 
4 
Week 
6
Week 
8
Week 
10
Week 
12
Week 
14
Week 
16
Informed Consent
X
X
Eligibility 
Determination
X
 
Minneapolis VA Health Care System IRB (Institutional Review
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Effective Date:
April 22, 2021

SCID DSM-5
X
Randomization 
(pioglitazone or 
placebo)
X
Demographics/
Medical History
X
Pharmacy Dispenses 
Study Drug 
(pioglitazone or 
placebo)
X
X
X
X
X
X
X
X
X
X
Determination of 
Study Drug 
Compliance
X
X
X
X
X
X
X
X
X
X
BBCET
X
X
X
X
X
X
X
X
X
X
Breathalyzer
X
X
X
X
X
X
X
X
X
X
X
X
BSI
X
X
X
X
X
X
X
X
X
X
X
BDI-II
X
X
X
X
X
X
X
X
X
X
X
PCL-5 
X
X
X
X
X
X
X
X
X
X
X
OCDS
X
X
X
X
X
X
X
X
X
X
X
TLFB
X
X
X
X
X
X
X
X
X
X
X
X
EtG/EtS, (Urine)
X
X
X
ALT, AST, GGTP, 
BNP, CK
X
X
X
CRP
X
X
X
Inflammatory markers
X
X
X
Medication side effects
X
X
X
X
X
X
X
X
X
X
Attendance at EtOH 
Tx 
X
X
X
X
X
X
X
X
X
X
X
Urine Drug Screen, β-
HCG
X
Participants will provide a urine sample for EtG, EtS, and β-HCG (for women of childbearing 
potential), ALT, AST, GGTP, CK and BNP at baseline. The EtG, EtS, ALT, AST, GGTP and 
BNP, will be repeated at weeks 4, and 14.  
3.2 Participants: Male and female Veterans above the age of 18 will be recruited from outpatient 
clinics at the Minneapolis and Long Beach VAHCS’s and through advertisements at each site. 
3.3 Screening: The AUDIT-C will be used as a method to identify potential participants. The 
AUDIT-C is used clinically to screen for and identify heavy alcohol use in all VA’s.  Patients with 
an elevated AUDIT-C of 4 or greater will be contacted by study staff via letter and recruited to 
the study. Clinical staff can also refer patients with a similar AUDIT-C or if there is concern for 
heavy alcohol use.  
Individuals who are interested in the study will asked if they would like to participate in a 
qualifying assessment. If apparently qualified and interested in participating in the study, they 
will be given the consent form to read by a study staff member. The study staff member will 
answer their questions and determine whether the individual understands the study through a 
series of pre-determined questions. The questions will include whether the individual 
understands the key tasks, risks, benefits of participating in the study as described in the 
consent form. If the individual understands these details and chooses to sign the consent form, 
they will participate in the qualifying assessment. This assessment is designed to determine if 
the participant fully meets the inclusion and exclusion criteria for participation in the study. The 
results of the assessment are reviewed by the PI to make a final determination of eligibility for 
the study’s clinical trial. If the patient does not qualify this will be explained to the patient, they 
 
Minneapolis VA Health Care System IRB (Institutional Review
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Effective Date:
April 22, 2021

will be paid for the qualifying assessment and given referral information if deemed appropriate 
by the PI.
3.4 Inclusion criteria:
1) DSM-5 diagnosis of at least moderate alcohol use disorder using the SCID
2) A mean of six heavy drinking days per month for the 3-months prior to baseline.
3) Drinking at least 14 drinks for men or 7 drinks for women, or more per week for the 4 
weeks preceding the screening visit. 
4) Willingness to provide contact information to confirm study follow-up appointments
5) Ability to perform informed consent
6) Female subjects: a negative pregnancy test
7) Serum ALT < 3 times reference range 
8) Stable psychiatric medication doses the month prior to baseline visit (antidepressant, 
antipsychotic, subjects may have changes in trazodone for sleep)
3.5 Exclusion criteria:
1) Current DSM-5 diagnosis of moderate to severe psychoactive substance use disorder 
(i.e. cocaine, opiates, methamphetamine) other than cannabis or nicotine
2) Medical conditions contraindicating pioglitazone pharmacotherapy (e.g., congestive 
heart failure, clinically significant edema, clinically significant liver disease, 
hypoglycemia, diabetes, history of bladder cancer)
3) Taking medications known to have significant drug interactions with the study 
medication (CYP2C8 inhibitors or inducers, antihyperglycemic medications)
4) Cognitive or physical impairment that precludes study participation
5) Currently and seriously suicidal (i.e., plan and intent)
6) Currently being treated for AUD with a medication (naltrexone, naltrexone injectable, 
acamprosate, topiramate, disulfiram and gabapentin) 
7) Impending incarceration
8) Pregnant or planning to become pregnant during the course of the trial or nursing for 
female patients
9) Unwillingness to sign a written informed consent form
10) Unwillingness to use a barrier method of birth control during the study for female 
patients
3.6 Feasibility
Currently, the Minneapolis VAHCS serves approximately 100,000 unique Veterans and 9,550 
were diagnosed with an AUD. At the Long Beach VAHCS approximately 60,000 unique 
Veterans are seen each year and nearly 5,425 received a diagnosis of AUD. Furthermore, each 
site has a long history of research of AUD and a strong collaboration between researchers and 
clinical staff at each site. We have also collaborated on several similar studies and have 
experience in recruiting and maintaining participants with similar characteristics from our work 
on two prior CSR&D funded RCT’s, “Efficacy & safety of baclofen to reduce alcohol use in 
veterans with HCV” and “Motivating Chronic Hepatitis C patients to Reduce Alcohol Use”. In 
these studies we successfully recruited 180 subjects with AUD and hepatitis C (a much smaller 
subgroup of all Veterans with AUD) during the course of the studies. Thus, we expect to be able 
to easily meet our recruitment goal of 200 subjects during the 4 year study. Finally, we have 
 
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Effective Date:
April 22, 2021

already received an Investigational New Drug exemption for pioglitazone (see attachment) so 
this will not be a barrier to starting the study.
3.7 Intervention
At the baseline (week 0) visit participants will be randomized to receive either pioglitazone or a 
matching placebo by the research pharmacist (see Randomization section). Participants and 
study personnel will be unaware of the treatment assignment. In order to maintain study blind 
but insure patient safety, sealed envelopes that contain the identification of the study medication 
(pioglitazone or placebo) will be kept in the research pharmacy and opened only in case of 
emergency. Study medication will be dispensed in a double-blind fashion during the entire study 
period.  Study medication will be dispensed at baseline and weeks 1,2 and 3 sufficient for a 2-
week period (taking into consideration the possibility of missed visits) and will be given at weeks 
4,6,8,10, and 12 sufficient for a 3-week period (taking into consideration the possibility of missed 
visits). Placebo capsules will be of an identical size, shape and color as pioglitazone. Active 
medication will be started at 15mg per day and titrated over two weeks until reaching a target 
dose of 45mg per day. This is the FDA maximum dose and was selected based on a prior small 
study focused on the treatment of cocaine use (43).
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 (56). It 
will be administered at every visit. BBCET has been used in previous AUD medication trials as 
the psychosocial treatment (27, 57). We also used the BBCET for the CSR&D funded “Efficacy 
& safety of baclofen to reduce alcohol use in veterans with HCV” and have extensive knowledge 
in delivering this intervention (34). Study staff will be trained to administer the BBCET and 2% of 
sessions will be observed for adherence to the intervention.
3.8 Compensation
Participants will be compensated $20 for completion of study questionnaires and providing urine 
and blood samples at the baseline visit and $20 for completing each follow-up visit. If 
participants complete the data collection at all 11 time points they will receive a total of $220.
3.9 Measures
Screen for current intoxication. Blood alcohol concentration (BAC) will be measured 
using the AlcoMate Revo Breathalyzer which measures BAC% between 0.00% and 0.400% in 
0.01% steps. Sensor accuracy of the AlcoMate is +/- 0.02% BAC. This measure will be taken 
prior to any study related interactions with subjects to insure that they are not intoxicated at the 
time of evaluation. If a subject’s BAC is above 0.04% scheduled tasks for that day will be 
rescheduled. If the subject is driving, alternative arrangements will be made for their 
transportation home.
3.9.1 Rating Scales
The Structured Clinical Interview for DSM-5 (SCID). The SCID will be used at the initial 
assessment to identify alcohol use disorder and other substance use disorder (58). All SCID 
interviewers will be trained by a qualified SCID trainer (including PI and CO-I’s) and will 
 
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Effective Date:
April 22, 2021

demonstrate competency in administering the SCID. Research has shown that this method for 
determining psychiatric diagnostic information is reliable and valid (59). 
The Time Line Follow-Back (TLFB). The TLFB interview will be used to identify daily 
drinking patterns of subjects in the three months before treatment and the intervals between 
study assessments (60). The TLFB has been shown to have adequate psychometric qualities in 
both clinical and research populations (61). Using a calendar, the respondent provides 
retrospective estimates of daily alcohol drinking over a specified amount of time. All primary and 
secondary outcomes will be derived from the TLFB assessment including: 1) heavy drinking 
over the last 8 weeks of the study; 2) percent or number (depending on the distribution) days 
drinking per month; 3) number of drinks per drinking day; and 4) number of heavy drinking days 
per month (heavy drinking days defined as for men: >4 drinks in a day or women: >3 drinks in a 
day).
Beck Depression Inventory-2
 
 nd   edition.
 
  The BDI-II is a 21-item self-report instrument that 
will be used to assess depressive symptomatology. Total score of 0-13 is considered minimal 
range, 14-19 is mild, 20-28 is moderate and 29-63 is severe symptoms. The BDI-II has been 
shown to have good validity and reliability in various psychiatric populations (62). The BDI-II will 
be administered at the initial and all follow-up assessments. The suicide ideation item will be 
reviewed at every visit prior to completion of visit and if positive will prompt a suicide risk 
assessment and further evaluation and/or referral for treatment.
Brief Symptom Inventory (BSI). The BSI is a 53-item self-report measure that will be 
used to assess several dimensions of psychopathology. The scale has nine primary symptom 
dimensions and three global indices. It is a reliable and valid instrument and has been normed 
to both adult non-patients as well as adult psychiatric patients (63). It will be administered at 
baseline and all follow-up assessments.
PTSD Checklist for DSM-5 (PCL-5). The PCL-5 is a brief 20-item self-report instrument 
that will be used to assess Post Traumatic Stress Disorder symptoms.  Total score of 0-33 is 
considered not indicative of severe symptoms of PTSD, 34-80 is considered indicative of 
symptoms of PTSD. The PCL-5 has been shown to have good validity and reliability in various 
populations (64). The PCL-5 will be administered at the initial and all follow-up visits.
Medication Side-effect checklist: We will develop a side effect checklist to monitor any 
adverse effects from the medication. We will base the checklist on the package insert and data 
from prior studies, including the Schmitz et al study. 
3.9.2 Biological measures of Alcohol and other substance use 
Urine drug screens (UDS). Participants will be asked to provide a urine sample for UDS 
at the baseline visit. The results will be used as an objective measure of recent drug use to 
supplement self-reported measures. Results will be issued as either positive or negative for a 
substance; no quantification of the concentration of the substance in the urine will be given. 
UDS will be obtained at baseline and at all follow up assessments.
Ethyl Glucuronide (EtG). Participants will be asked to provide a urine sample to assess 
EtG at baseline, 4, 8 and 12 weeks. Results will be correlated with self-report measures of 
alcohol use and GGT in order to test the hypothesis that changes in alcohol consumption and 
GGT will be reflected by changes in EtG. EtG is a direct metabolite of alcohol; it remains in urine 
 
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for up to 5 days after cessation from alcohol, is highly sensitive and has good specificity for 
alcohol use (65).
Ethyl Sulfate (EtS). Participants will be asked to provide a urine sample to assess EtS at 
baseline, 4, 8 and 12 weeks. EtS is a direct metabolite of alcohol; it remains in urine for up to 5 
days after cessation from alcohol, is highly sensitive and has good specificity for alcohol use 
(65). Additionally, we are already collecting urine for EtG and the laboratory that tests for EtG is 
already combining the EtS with EtG at no additional cost. 
Gamma-glutamyl transferase (GGT): is an enzyme that transfers gamma-glutamyl 
functional groups. It is found in many tissues, the most notable the liver, and has significance in 
medicine as a diagnostic marker of alcohol use (66).
Alanine Aminotransferase (ALT): is an enzyme that converts alanine into pyruvate. It is 
mainly found in the liver and be increased with liver injury.
Aspartate Aminotransferase (AST): is a pyridoxal phosphate-dependent transaminase 
enzyme that catalyzes the reversible transfer of an α-amino group between aspartate and 
glutamate. It is mainly found in the liver and may be increased with liver injury. An AST to ALT 
ration of 2:1 is suggestive of alcohol related liver injury (66).
Creatine Kinase (CK): is an enzyme expressed in various tissues and as a blood test is 
a marker of muscle injury. 
3.9.3 Laboratory Safety Measure
B-type natriuretic peptide (BNP): is a hormone secreted by cardiomyocytes in response 
to stretching caused by increased ventricular blood volume. A plasma BNP (≤ 100 ng/L) 
provides an excellent ability to exclude heart failure with high sensitivity (67).
3.9.4 Inflammatory Markers
C-Reactive protein (CRP): is a protein found in the blood plasma that rises in response 
to inflammation. CPR will be assessed to check inflammatory responses to pioglitazone. Other 
inflammatory markers such as interleukin-6,8 and 12 as well as tumor necrosis factor- alpha and 
SB100 a marker of blood brain barrier inflammation will be tested. One of pioglitazone’s 
purported mechanism of action is via inflammation thus we will test for these markers.
3.10 Potential hazards to personnel and precautions: Collection of blood and urine samples may 
pose a hazard to study personnel. Contact with blood or urine has the potential to transmit 
disease. The collection of blood will be performed in the existing Minneapolis and Long Beach 
VAHCS laboratories where lab technicians are already trained and utilize universal precautions. 
The collection of urine samples will be completed in the clinics by research staff. All staff will be 
trained in universal precautions and the study will comply with all safety regulations and training 
stipulated by VA.
3.11 Follow-up: At each visit, research coordinators will administer all measures, dispense 
medication and deliver the BBCET. Any concerning side effects or lab abnormalities will be 
reviewed with the PI or site PI. Appropriate medical evaluation will be undertaken as deemed 
necessary by the PI’s. Subjects who miss three consecutive visits will stop the medication as 
they will have been off of medication for minimum of 1 week. Any serious adverse side effects 
where the blind needs to be broken will result in stopping the assigned treatment. However, 
every effort will be made to gather research data through the end of the study.  
 
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3.12
 
  Randomization:
 
  Participants will be randomly assigned to one of two groups (pioglitazone 
or control/ placebo) using a minimization method of Pocock and Simon (1975)(68). 
Randomization will be stratified by site (Minneapolis and Long Beach) and will be handled 
centrally by the Data Coordinating Center at the Minneapolis VA, and a special randomization 
program will be developed in consultation with a statistician in Minneapolis (Dr. Paul Thuras). 
The program will track the balance of stratification variables (i.e., site) for each condition and 
change the probability of assignment if the variables are unbalanced. This method assures that 
the two groups are comparable with respect to the stratification variables throughout the study 
period. 
Each site will be provided a number of envelopes with randomization results sealed 
inside. Privacy envelopes will ensure that the results cannot be detected without breaking the 
seal. The envelopes will be numbered and will be opened in that order. The number of 
envelopes will be the number of expected enrollees plus 10 extra in order to account for non-
compliant participants and dropouts. These envelopes will only be opened by the research 
pharmacist. This procedure will be used to maintain the blind for the PI, research assistants, 
study coordinators and therapists. Only the research pharmacy will be allowed to know the 
randomization for each participant. The pharmacist will keep all envelopes containing the 
randomizations. When a subject signs the informed consent form, the pharmacist will be called 
and asked to select the next envelope and open it, fill out the participant number and dispense 
study medication according to the randomization.  If a physician or medical professional needs 
to know whether the patient is taking the study drug, a wallet card given to the participant will 
contain the number of the research pharmacy. The professional can call the pharmacy to 
access the list of participants and can break the blind for that participant. 
Statistical Considerations 
4.0 Data Analysis Plan
4.1 Data Management. 
Study data will be collected and managed using VA REDCap (Research Electronic Data 
Capture) hosted behind the VA firewall on a VINCI server. REDCap is a secure, web-based 
application designed to support data capture for research studies, providing 1) an intuitive 
interface for validated data entry; 2) audit trails for tracking data manipulation and export 
procedures; 3) automated export procedures for seamless data downloads to common 
statistical packages; and 4) procedures for importing data from external sources. 
 
4.2 Data quality/integrity. 
All data will be obtained by an assessor (the research coordinator) who will be blinded to 
the treatment condition. All data will be inspected for missing and outlier values and response 
set patterns. Distributions will be graphically represented and inspected visually and 
quantitatively for departures from normality and other irregularities. All data will be characterized 
in terms of means, standard deviations, histograms, and response ranges for continuous 
variables and frequencies and counts for categorical variables. A random sample of 5% of 
 
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cases will have all hard copy data compared to entered data for accuracy, including all 
measures scored by computer algorithms. The need for data re-entry or recoding, data 
transformations and non-linear or non-parametric analyses will be based on these results.
4.3 Descriptive analyses
To confirm that the randomization scheme achieved the intended aim of evenly 
distributing important study characteristics, groups will be statistically compared on baseline 
demographic and clinical variables. Any significant group differences on these baseline 
variables will be factored into study analyses (e.g., using covariates).
4.4 Primary and secondary outcome measures
For the primary outcome we will use change in number of heavy drinking days per week. 
Secondary outcome measures will include a responder analysis, the rate of no heavy drinking 
over the last 8 weeks of the study, and another continuous measure of alcohol use including 
number of drinks per week over the entire study period. Heavy drinking days per week was 
chosen as it is a standard outcome used previously used in clinical AUD trials (34, 55). The 
responder analysis measure of no heavy drinking days over the last 8 weeks of the active study 
period (weeks 6-14) was chosen as a secondary outcome as it was recently recommended by 
the FDA in their guidance to industry for the development of drugs for alcoholism (35). The FDA 
report indicated that a responder analysis is preferable to analysis of group means as mean 
differences are difficult to interpret with regard to clinical relevance. In addition, changes in this 
measure is associated with good clinical outcomes (35). Each subject will be assessed for the 
outcome variables (alcohol consumption) at baseline (date of randomization), 1,2,3,4,6,8,10,12 
and 14 weeks (week 16 is a safety check as medications will be tapered off starting at week 14). 
For the responder analysis, we will use Chi -square to test the difference between pioglitazone 
and placebo for the rate of no heavy drinking over the last 8 weeks (week 6-14) of the study. 
Hypotheses will also be tested across all time points to establish temporal patterns of group 
effects.  For the continuous measures of alcohol use we will use mixed effects models if data 
residuals are normally distributed and generalized estimating equations (GEE) if the data are 
non-normally distributed (69, 70). Both are flexible regression methods for incomplete repeated 
measures data and allow continuous and categorical covariates, fixed and time-dependent 
covariates, and a specification of unstructured as well as structured covariance matrix. 
Secondary hypotheses will be evaluated using chi-square tests of proportions and logistic 
regression, with statistical significance criterion also set at p < 0.05 for categorical outcomes.  
Zero-inflated negative binomial analyses will be used to contrast the study groups on count 
variables if warranted by a high percentage of zero alcohol use days over the follow-up (71). 
4.5 Power Estimate
The primary intention to treat population will include all participants randomized. The 
effect size of pioglitazone is estimated based on studies. Schmitz et al found a small effect size 
favoring pioglitazone (94% likelihood of decrease in alcohol use versus 83% in placebo) which 
is likely low as all the subjects studied had a primary cocaine use disorder diagnosis with an 
AUD secondary. Based on a sample of Veterans at the Minneapolis VAHCS who had taken 
 
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pioglitazone during fiscal year 2016 we found that taking pioglitazone was associated with 
decreased alcohol use as measured by the AUDIT-C with and effect size of d=.48. 
Using G*power we estimated samples size for various base rates of drinking (heavy 
drinking days per week) by various differences in reductions in rate produced by pioglitazone 
versus placebo across the 14 weeks follow-up period using Poisson regression. Baseline heavy 
drinking days per week in our Baclofen study, was 3.5 per week. Based on this we estimate that 
we are adequately powered to find clinically meaningful differences in reduction (20% or 
greater) given our proposed sample size.
Base Rate 
per week 
(Heavy 
Drinking 
Days)
Reductio
n in rate.
Power
Total N
4
19%
80%
164
3
19%
80%
217
2
19%
80%
321
 
 
 
 
4
20%
80%
147
3
20%
80%
194
2
20%
80%
288
 
 
 
 
4
21%
80%
132
3
21%
80%
175
2
21%
80%
260
 
 
 
 
4
22%
80%
120
3
22%
80%
159
2
22%
80%
235
 
 
 
 
4
23%
80%
109
3
23%
80%
145
2
23%
80%
214
Thus, we feel that the sample size of 200 (100 per site) is still warranted. 
 
For secondary outcomes including the categorical outcome (no heavy drinking days in 
the last 8 weeks of the study) with 90 patients in each group (100 recruited subjects in each 
group, assuming 20% attrition) we estimate that this sample size will allow us to find a 22% 
difference (OR=2.45) in heavy drinking days with 80% power at p<.05. Both mixed models and 
GEE allow us to take full advantage of the ITT sample and thus power is based on 90 subjects 
per group. Other secondary measures including biomarkers of alcohol use (EtG/EtS and GGT) 
and for craving we will use linear mixed models to compare change in biomarkers and change 
in OCDS scores. Estimates for comparisons of these continuously distributed outcomes indicate 
 
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that we will be able to find effect sizes of d=.47 with 72 subjects or larger with 100 subjects per 
group.
4.6 Attrition: We anticipate an attrition rate of 20% and this has been considered when 
calculating the budget and in the power analysis.  Rationale for this estimate includes several 
factors. The attrition rate in our prior studies ranged from 14% (55) to 24% (34).  Second, some 
patients may be more interested in remaining in a medication study with high perceived efficacy. 
The medication will be dispensed at the outpatient clinic, which should reduce the stigma 
typically associated with specialty alcohol treatment. Finally, participant compensation will 
provide an incentive to complete the follow-up sessions. However, we have reviewed other VA 
alcohol treatment studies that showed great variation in attrition rates, therefore we are 
projecting a conservative estimate that 80% of the participants consented will complete 
the study. 
4.7 Missing Data:  We will perform an intent-to-treat analysis, meaning that all subjects 
randomized into two treatment groups will be included in the analysis regardless of the extent of 
compliance with the treatment or withdrawals during the trial.  This will create incomplete data 
because some subjects will withdraw from the study during the course of the treatment, thereby 
their responses will be considered missing after withdrawal.  If the dropout process is related 
to the outcome measures (i.e., alcohol use), this will present a challenge in the analysis.  
The majority of the currently available statistical methods assume that data are missing at 
random.  However, in this study, it is plausible that the likelihood of dropout is related to the 
level of or change in alcohol use.  For example, those with increase or no reduction in alcohol 
use may be more likely to drop out of the study.  When subjects drop out of the study, we will 
attempt to obtain data on reasons for dropout.  We will analyze whether the dropout process is 
at random with respect to the outcome measures. If the dropout process is related to the 
outcome measures, we will utilize models that incorporate a nonrandom dropout mechanism 
(Little, 1995). These analyses will be carried out as the secondary analyses for hypothesis-
generating purposes. Use of the EM algorithm in the analysis will allow inclusion of observations 
with missing datapoints. This increases power and improves the ability to produce estimates 
with less bias. 
5.0 Summary
The proposed work seeks to improve alcohol outcomes in Veterans with an AUD and 
current alcohol use. Current medications for AUD are of only modest benefit and relapse and 
continued alcohol use are common. Preclinical data strongly suggests that pioglitazone will be 
helpful in reducing alcohol use in humans. This project will provide important data regarding the 
efficacy of pioglitazone. Should the results prove positive, we would seek funding for a larger 
multi-site study (potentially a cooperative study) to confirm the results. Finally, as pioglitazone is 
already an FDA approved medication it could easily be re-purposed and used immediately to 
help Veterans with AUD.
6.0 Project Timeline
 
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Months 
Activities
1 to 3 
1) hire staff; 2) purchase supplies; 3) create study documents and database; 4) 
obtain pioglitazone and placebo
4 to 12
1) recruit 44 participants or 5.5 subjects per month- this is 2-3 subjects per site and 
very feasible; 2) begin follow-up data collection; 3) begin data entry; 4) quarterly 
DSMB reports.
13 to 
24
1) recruit 64 participants; 2) follow-ups continues; 3) continue data entry; 4) quarterly 
DSMB reports
25 to 
36
1) recruit 64 participants; 2) follow-ups continues; 3) continue data entry; 4) quarterly 
DSMB reports
37 to 
42
1) recruit 28 participants; 2) follow-ups continues; 3) continue data entry; 4) quarterly 
DSMB reports
43 to 
48
1) recruitment complete follow-up data collection only; 2) clean data; 3) break blind; 
4) begin data analysis
2) complete data analysis; 2) manuscript preparation and submission
 
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