Effects of Pioglitazone on Stress Reactivity and Alcohol Craving
Phase: PHASE1
Conditions: Alcohol Use Disorder
Sponsor: The University of Texas Health Science Center, Houston

 
 
 
 
 
 
 
 
 
 
 
 
 
 
Effects of Pioglitazone on Stress Reactivity and Alcohol Craving 
 
NCT05107765 
 
Version Date: 10/11/2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 ABSTRACT 
 
Alcohol use disorder (AUD) is significant public health concern. Stress is a central component in modern 
theories of alcohol use, and stress is intimately related to drinking for many individuals. There are a number of 
approved medications for AUD, but the majority of individuals do not respond to these medications and no 
medications address the role of stress. The current proposal looks affect alcohol use by targeting stress-related 
systems in the body through peroxisome proliferator-activated receptors (PPARs), which may effect stress 
reactivity, stress-induced alcohol craving, and alcohol use. Pioglitazone (Actos) targets PPARγ and is FDA- 
approved for treating individuals with diabetes and metabolic disorders. Promising results from both human 
trials and animal research suggest that pioglitazone holds great promising for addressing AUD, including 
preliminary data from our own research. The current proposal will attempt to expand on our preliminary 
findings targeting alcohol use among treatment-seeking individuals with AUD and elevated stress and/or 
anxiety with the following specific aims: 1) to assess if pioglitazone decreases stress reactivity and stress- 
induced craving in a human laboratory model; and 2) to assess if pioglitazone changes weekly psychometric 
reports of stress/anxiety, craving, and alcohol consumption. Notable strengths of the current proposal include: 
1) targeting individuals with elevated stress/anxiety and AUD; 2) biological assessment of stress reactivity 
(heart rate, blood pressure, salivary cortisol); 3) a multi-dimensional assessment of alcohol craving 
incorporating relatively novel behavioral economic measures (i.e., alcohol demand, delay discounting); and 4) 
inclusion of powerful Bayesian statistical tools that are well suited for smaller samples, such as the current 
proposal. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB NUMBER: HSC-MS-18-0922 
IRB APPROVAL DATE: 10/11/2023 

 INTRODUCTION TO THE REVISED PROPOSAL 
 
We thank the Reviewers for their thoughtful comments regarding the initial grant submission. Overall 
enthusiasm for the initial application was strong, with Reviewers highlighting the strength of the research team 
and sound study design. Below, we provide responses to the major Reviewers’ concerns. Relatively minor 
concerns have been addressed within the proposal. We believe that the application has been substantially 
strengthened as a result of addressing these concerns. 
 
The study would be improved by targeting individuals with elevated stress/anxiety that drink to cope. 
Response: As suggested, the revised proposal now targets individuals with elevated stress/anxiety (as done in 
our initial feasibility study, see Preliminary Data) as well as those who report drinking to cope with 
stress/anxiety as measured by the Drinking Motives Questionnaire - Revised (DMQ-R)1,2. Additionally, the 
revised statistical analyses will directly examine the relationship between changes in stress/anxiety and alcohol 
use, as affected by pioglitazone. 
Transdermal alcohol concentration (TAC) as measured by SCRAMx has limitations. Response: Reviewers’ 
comments were mixed regarding the SCRAMx. However, we acknowledge limitations of the system and have 
removed the SCRAMx in the revised submission. Removal of SCRAMx has also allowed us to address concerns 
regarding the trial duration, which has now been increased from 4 weeks to 8 weeks, and fits well within the 
scope of an R21 project and budget. 
Outcome measures related to alcohol consumption need to be operationalized and justified and the role of 
behavioral economic measures (delay discounting, alcohol demand) needs to be clarified. The revised 
submission now defines alcohol-related dependent measures as heavy drinking days in the past week (as 
highlighted by the Reviewers) and average drinks/day for the past week. Abstinence will be verified using ethyl 
glucuronide (ETG) test strips. The revised submission now clarifies that delay discounting and alcohol demand 
using a purchasing task will be assessed at weekly clinic visits to examine changes in craving and alcohol 
reward value, whereas a brief assessment of alcohol demand will examine changes in craving during the human 
laboratory model of stress reactivity. Previous studies have demonstrated that demand assessments are 
sensitive to experimental manipulations, including acute laboratory stress inducers3. 
The PI has very limited experience in human laboratory models, clinical alcohol studies, and limited 
leadership on extramural projects. Response: Dr. Yoon’s biosketch has been edited to highlight his recent work 
in human laboratory model studies and studies involving pharmacotherapies that target stress/anxiety systems 
for substance use disorders. We agree that Dr. Yoon has relatively little experience with clinical alcohol studies 
and limited leadership on extramural projects, but he does have extensive and broad experience in addictions 
research for a variety of drugs of abuse as well as in implementing the behavioral economic measures proposed 
in the current study. He also has related experience in assessing medications for drug addiction that target 
stress related systems4. 
The current proposal is also supported by a number of experienced researcher. Dr. Lane (Co-I) is the Vice 
Chair for Research in the Department of Psychiatry and Behavioral Sciences and Director of Research at 
UTHealth Harris County Psychiatric Center (HCPC). He has conducted numerous human laboratory studies, 
including among individuals with AUD5,6. Dr. Weaver (Co-I) is the Medical Director of the Center for 
Neurobehavioral Research on Addiction (CNRA) and is experienced in addictions research and will provide 
medical guidance and ensure participant safety over the course of the study. He has an extensive history 
serving on a number of NIH-funded studies for alcohol and has published broadly on treatments and 
interventions for alcohol use disorders (AUD)7–12. Drs. Haass-Koffler (Consultant) and Vujanovic (Consultant) 
both have extensive experience in studies evaluating stress/anxiety and AUD13–24. They have provided valuable 
input in developing this resubmission and will continue to lend their expert guidance over the course of the 
study. Dr. Suchting is an experienced biostatistician with expertise in Bayesian statistics, a unique strength of 
the current proposal. He also has expertise in analyzing medication effect data in addictions, including those 
that effect stress-related systems4. 
Importantly, Dr. Yoon recently completed a pilot study supporting the current proposal (see Preliminary 
Data). Treatment-seeking individuals with elevated baseline stress/anxiety and AUD (N = 4) were 
administered pioglitazone (45 mg) in a single-blind manner for 4 weeks and completed stress-reactivity 
assessments at baseline and study week 4. All participants completed the study and systematic decreases in 
stress reactivity, self-reported stress/anxiety, alcohol craving, and alcohol use were observed. We hope this 
information provides Reviewers with additional confidence in the PI and study team with regard to the success 
of the current R21 proposal. 
IRB NUMBER: HSC-MS-18-0922 
IRB APPROVAL DATE: 10/11/2023 

 SPECIFIC AIMS 
 
Alcohol use disorder (AUD) is a public health problem associated with significant health, social, and 
economic costs to society. Alcohol and stress/anxiety are intimately related. Alcohol activates the 
hypothalamic-pituitary-adrenocortical (HPA)-axis and stress can increase the reward value of drinking. As 
time progresses, excessive drinking results in a number of behavioral changes marked by increased compulsive 
drinking, stress reactivity, and neuro-inflammation25. FDA-approved pharmacotherapies for AUD (e.g., 
naltrexone, acamprosate, disulfiram) are effective in less than one-third of treated individuals26. Importantly, 
none of the currently approved medications for AUD directly addresses stress reactivity, underscoring the 
need to develop novel pharmacotherapies targeting stress-related processes associated with AUD. 
Peroxisome proliferator-activated receptors (PPARs) are promising therapeutic targets for addiction that 
exhibit both anti-inflammatory and neuro-protective responses in the brain27,28. Building on a strong and 
growing body of pre-clinical findings, recent trials in humans have shown promising effects for opioids and 
nicotine29,30. In regards to alcohol, the PPARγ agonist pioglitazone 1) significantly reduced free-access alcohol 
consumption;and, 2) attenuated alcohol consumption and withdrawal symptoms following stress exposure 
in rats bred to highly prefer alcohol31,32. We recently conducted a single-blind pilot study in treatment-seeking 
individuals with AUD and elevated baseline stress/anxiety that demonstrated feasibility and showed promising 
decreases in stress reactivity, stress/anxiety, alcohol craving, and alcohol consumption following 4 weeks of 
pioglitazone (see Preliminary Data). 
The current proposal will build on our pilot study and utilize a double-blind, mixed-model design with a 
between-groups factor of dose (pioglitazone vs. placebo) and a within-subjects factor of time. Eligible 
participants will consist of treatment-seeking individuals with AUD who score high on screening measures of 
stress/anxiety and stress-related drinking. Study medication (pioglitazone or placebo) will be administered for 
8 weeks. Relapse risk outcomes will be assessed using both a human laboratory paradigm of stress reactivity 
and stress-induced craving (Specific Aim 1) and real-life measures of stress/anxiety, craving, and alcohol 
consumption (Specific Aim 2). 
Strengths of the current proposal include: 1) targeting individuals with elevated stress/anxiety and AUD; 2) 
biological assessment of stress reactivity (heart rate, blood pressure, salivary cortisol); 3) a multi-dimensional 
assessment of alcohol craving incorporating relatively novel behavioral economic measures (i.e., alcohol 
demand, delay discounting); and 4) inclusion of powerful Bayesian statistical tools that are well suited for 
smaller samples, such as the current proposal. 
 
We propose the following Specific Aims: 
Specific Aim 1: To examine the effects of pioglitazone on stress-induced relapse risk in a 
laboratory model. 
Hypothesis 1a: Participants receiving pioglitazone will show decreased stress reactivity (heart rate, blood 
pressure, salivary cortisol) compared to those receiving placebo. 
Hypothesis 1b: Participants receiving pioglitazone will show decreased alcohol craving (subjective, 
alcohol demand) compared to those receiving placebo. 
 
Specific Aim 2: To examine the effects of pioglitazone on drinking, stress/anxiety, and alcohol 
craving in the natural environment. 
Hypothesis 2a: Participants receiving pioglitazone will show greater reductions in weekly psychometric 
measures of stress/anxiety compared to those receiving placebo. 
Hypothesis 2b: Participants receiving pioglitazone will show greater reductions in weekly psychometric 
measures of alcohol craving compared to those receiving placebo. 
Hypothesis 2c: Participants receiving pioglitazone will show greater reductions in past week alcohol use 
(heavy drinking days, average drinks/day) compared to those receiving placebo. 
 
There is increasing attention and preclinical evidence supporting the potential role of the PPARγ system as a 
novel target in the treatment of AUD. From a translational perspective, this R21 project is timely and likely to 
advance our understanding of stress as a mechanism of action of pioglitazone effects. Additionally, this project 
will establish the feasibility of a paradigm for assessing medication effects under naturalistic and standardized 
laboratory conditions, thus setting the stage for subsequent R01 projects. 
 
 
IRB NUMBER: HSC-MS-18-0922 
IRB APPROVAL DATE: 10/11/2023 

a value)62
 SIGNIFICANCE 
 
Public Health Impact of AUD. AUD is 1) the 4th leading cause of death in the US (~88,000 
deaths/year), decreasing lifespan by ~30 years; 2) a tremendous economic burden on society (~$249 
billion/year), with the majority of these costs due to binge drinking; and 3) associated with a host of short- and 
long-term negative consequences including violence, legal problems, morbidity, and family problems33–35. 
AUD and the Central Role of Stress. Stress can enhance alcohol reward during initial stages of 
drinking36,37. However, persistent excessive drinking acts as a chronic stressor that 1) shifts brain systems 
beyond normal homeostatic limits into a state of allostasis; 2) which in turn alters physiological and brain 
motivational systems central for regulating alcohol use; and 3) has a negative impact on autoimmune and 
inflammatory responses that can in turn influence alcohol use38–42. Therefore, initial drinking is under 
relatively greater control of positive reinforcing effects of alcohol and impulsive characteristics of the 
individual. However, over time, drinking takes on more compulsive characteristics as it becomes maintained by 
negative reinforcement due to increased withdrawal symptoms, stress-related anxiety, alcohol craving, and 
decreased stress-resiliency and cognitive deficits from neuro-inflammatory damage38,43,44. Despite the 
profound negative impact of stress on AUD, none of the currently approved medications for AUD directly 
target stress or stress-related consequences associated with AUD, underscoring the need for pharmacological 
interventions that target novel biological systems. 
Targeting Stress-Reactivity and AUD through the PPAR System. PPARs are proteins that act as 
ligand-activated transcription factors, which are central to their anti-inflammatory actions45. Several PPAR 
isoforms (α, δ/β, γ) have been identified, all of which are present in the CNS with relatively high activity46–48. 
PPARγ agonists can modulate genes linked to synaptic transmission and neuronal function in stress-related 
brain regions such as the amygdala and hippocampus49,50. A growing number of pre-clinical studies have 
observed promising effects of PPAR agonists on various aspects of drug use (e.g., discrimination, self- 
administration, reinstatement, sensitization) for several drugs of abuse including alcohol28. In alcohol-related 
human studies, expression of PPARδ and PGC-1α, the coactivator of PPARγ, is altered in brains of individuals 
with AUD51. Associations between single nucleotide polymorphisms (SNPs) and several PPAR genes related to 
PPARα and PPARγ have been found for AUD and alcohol withdrawal using human genome wide association 
study (GWAS) data from the Collaborative Study on the Genetics of Alcoholism (COGA)52. 
Currently, only the PPARγ isoform can be targeted in humans. PPARγ is highly expressed in a number of 
brain regions associated with drug reward53 and stress response31,32. Activation of PPARγ mediates 
neuroprotective responses against inflammatory damage, which can attenuate drug affects. Pioglitazone 
(Actos) is a PPARγ agonist and currently FDA-approved for the treatment of diabetes and metabolic disorders. 
Recent human addiction studies have shown pioglitazone to reduce heroin craving and anxiety29 as well as 
nicotine craving30. In regards to pioglitazone’s potential to address stress-related alcohol use, two preclinical 
studies indicate that pioglitazone 1) significantly reduced alcohol drinking in rats; and 2) attenuated stress- 
induced alcohol drinking and alcohol withdrawal symptoms in rats bred to highly prefer alcohol, but did not 
affect cue-induced alcohol drinking. Naltrexone did attenuate cue-induced alcohol drinking, but had no effect 
on stress-induced alcohol drinking, suggesting a unique role for pioglitazone. More recently, our group 
collected preliminary data suggesting attenuation of stress-induced reactivity and weekly psychometric 
measures of stress/anxiety, alcohol craving, and alcohol use among individuals with AUD following 4 weeks of 
treatment with pioglitazone (see Preliminary Data). Currently, there is one registered study (NCT03864146) 
assessing the effects of pioglitazone on alcohol use among Veterans, but that study does not appear to be 
targeting individuals with stress/anxiety in addition to AUD. 
Multi-Dimensional Assessment of Relapse Risk. Drug craving often serves as a proxy of motivation 
to consume drug. Self-report craving measures are ubiquitous in addictions research but have limitations that 
have likely result in equivocal results54. We hope to mitigate these potential limitations by incorporating 
behavioral economic measures (i.e., alcohol demand, delay discounting) that are closely tied to drug use and a 
broader framework of drug addiction. Both delay discounting and drug demand have been associated with 
virtually every aspect of drug use (e.g., initiation, severity, relapse risk, etc.), and multiple meta-analyses have 
cemented the utility of these measures in addictions research55–58. These measures are not correlated, 
supporting a multi-dimensional model in which these measures represent distinct aspects of motivation to use 
alcohol54,59–61. Dr. Yoon (PI) is an expert in utilizing behavioral economic measures in both human laboratory 
and clinical research involving individuals with SUDs. 
Bayesian Statistical Methods in Addictions Research. The current proposal will incorporate 
Bayesian analytical methods in addition to traditional frequentist methods utilizing significance testing. Null 
hypothesis statistical testing under frequentist inference values a rigid focus on dichIoRtBom
NUoM
usBeEvRa:luHaStCio-MnsS-o1f8-0922 
evidence (i.e., exhibiting a p value greater or less than a pre-defined alph 
. IRnBcoAmPPpRaOriVsoAnL, DBAayTeEs:i1a0n/11/2023 

Systolic BP 
Diastolic BP 
Heart Rate 
Salivary Cortisol 
approaches avoid these issues by directly evaluating the probability that an alternative hypothesis exists, given 
the current data and prior evidence for the alternative hypothesis63. The primary limitation of Bayesian 
methods is that they require relatively greater computational power, which has been largely mitigated with 
advances in computer technology. Subsequently, Bayesian methods have been increasingly utilized in clinical 
research. Dr. Suchting (Co-I) is an expert in implementing Bayesian methods in addictions research. 
 
 INNOVATION 
 
The current proposal has a number of innovative features. First, we are targeting a relatively novel 
biological mechanism that has potential to expand treatment options, particularly for those in which stress- 
related process are a central component of their AUD. Second, we are utilizing a multi-dimensional assessment 
of relapse risk that includes stress-related biomarkers, traditional measures of alcohol craving, and behavioral 
economic measures. Third, this study will assess change in stress reactivity and stress-induced alcohol craving 
within a human laboratory model as well as changes in stress/anxiety, alcohol craving, and past 7-day alcohol 
consumption (heavy drinking days, average drinks/day) in the natural environment. Fourth, the current 
proposal utilizes Bayesian statistical methods, which can be particularly useful in evaluating treatment effects 
in relatively small studies, necessitated here by the scope and intent of the NIH R21 mechanism. 
 
 APPROACH 
 
Preliminary Data. Our group has experience safely administering pioglitazone at doses matching the 
current proposal among treatment-seeking individuals with cocaine use disorder (CUD). In a post hoc analysis, 
our group observed decreased alcohol use among individuals with concurrent CUD + AUD receiving 
pioglitazone vs. placebo in a study assessing cocaine craving and white matter integrity among individuals with 
primary CUD64. Directly related to current proposal, Dr. Yoon (PI) recently completed a pilot study assessing 
the effects of 4 weeks of pioglitazone (45 mg) administered in a single-blind manner among treatment-seeking 
individuals with AUD and elevated baseline levels of stress/anxiety (N = 4). Figure 1 below shows changes in 
laboratory stress reactivity measures following a cold-pressor challenge to the stress axis (left panel) and 
weekly psychometric measures of stress/anxiety, craving, depressive symptoms, and alcohol consumption 
(right panel). All participants completed the study with no missed visits. Notably, decreases in all variables of 
interest were systematically observed over 4 weeks, with 3 of 4 participants reporting no drinking by week 4. 
Accordingly, these preliminary data support both feasibility and potential utility of pioglitazone for attenuating 
stress reactivity and alcohol use. 
 
 
0 
20 
 
-25 
0 
 
 
-50 
-20 
 
 
-75 
-40 
 
 
-100 
 
-60 
 
 
-125 
 
-80 
 
 
-150 
BL 
1 
2 
3 
4 
Study Week 
-100 
BL 
1 
2 
3 
4 
Study Week 
Figure 1. Changes in stress reactivity (left panel) and weekly measures of stress/anxiety, 
alcohol craving, depressive symptoms, and alcohol consumption (right panel). 
 
Overall Study Design. To accomplish the project aims, we will utilize a double-blind, mixed-model 
design with a between-groups factor of dose (pioglitazone vs. placebo) and a within-subjects factor of time. We 
will utilize urn-randomization based on gender and severity of alcohol use (AUDIT). A summary of the study 
timeline, procedures, and assessments is shown in Table 1 below. 
 
Table 1. Outline of Study Timeline, Procedures, and Assessments 
 
 
23 
Stress - PSS 
Anxiety - HAM-A 
Craving - PACS 
Depressive symptoms - BDI 
Drinks/week 
Binge episodes/week 
11/2
: 10
TE
AL D
OV
APP
IRB
Consent and Baseline Screening 
8 
-092
7 
S-18
6 
C-M
5 
: HS
4 
BER
3 
NUM
2 
IRB
1 
0 
Study Week 
Procedures and Assessments 
%Change from BL 
%Change from BL 

SCID, ASI, KMSK, TLFB, CIWAA, AUDIT 
X 
Receive Study Medication (Pioglitazone or Placebo) 
Assess Medication Compliance and Adverse Events 
Brief Counseling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Human Laboratory Assessments (Specific Aim 1) 
Stress-Reactivity Assessment (Salivary Cortisol, HR, BP, self-report) 
Alcohol craving (self-report, brief alcohol demand) 
X 
X 
X 
X 
X 
X 
Weekly Assessments (Specific Aim 2) 
Alcohol Use and Craving (TLFB, BrAC, ETG, PACS, DMQ-R) 
Stress and Anxiety (HAM-A, PSS, PCL-5) 
Delay Discounting, Alcohol Demand (purchasing task) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SCID - Structured Clinical Interview for DSM-5, ASI - Addiction Severity Index65; KMSK - Kreek-McHugh- 
Schluger-Kellogg scale66; TLFB - Timeline Followback67; CIWAA - Clinical Institute Withdrawal Assessment for 
Alcohol68; AUDIT – Alcohol Use Identification Test69; BrAC – Breath Alcohol Concentration; ETG – Ethyl 
Glucuronide; PACS – Pennsylvania Alcohol Craving Scale70; DMQ-R – Drinking Motives Questionnaire Revised1,2. 
HR – Heart Rate; BP – Blood Pressure; HAM-A – Hamilton Anxiety Rating Scale71; PSS – Perceived Stress Scale72; 
PCL-5 - PTSD Checklist for DSM-573. 
 
Recruitment. Recruitment strategies will include local advertising in print media, public service 
announcements on radio, and referrals to CNRA in the Houston metropolitan area. Additionally, we will utilize 
the University of Houston SONA system, which provides students credit for participating in various research 
studies. Access to SONA is made possible with the inclusion of Dr. Vujanovic (Consultant). We will also recruit 
from the Department of Psychiatry Recruitment Registry: HSC-MS-23-0768. 
Participants. We will enroll 60 participants to reach a target of N = 50 completers (25/group). 
Participants will consist of otherwise healthy treatment-seeking individuals with AUD exhibiting elevated 
baseline stress/anxiety. All participants will meet the following inclusion and exclusion criteria: 
Inclusion criteria. Be treatment-seeking individuals diagnosed with AUD (DSM-5); be at least 18 years 
old and fluent in English; past month excessive alcohol use (>7 drinks/week for woman, >14 drinks/week for 
men, >3 drinks/occasion for women>4 drinks/occasion for men)35; exhibit baseline measures of either 1) 8-23 
on HAM-A indicative of mild to moderate anxiety, 2) 14-26 on PSS Score indicative of moderate stress, or 3) ≥2 
on DMQ-R questions related to drinking indicating that individuals drink at least “some of the time” to cope; 
and exhibit increased stress reactivity (increased physiological response and/or self-report) at the baseline 
stress reactivity assessment. 
Exclusion criteria. Exhibit severe scores on the HAM-A, PSS, or PTSD checklist (PCL-5) – may be 
enrolled at the discretion of the admitting physician (Dr. Weaver); physical dependence on alcohol (CIWAA > 
10); greater than mild substance use disorder on drugs other than alcohol, nicotine, and marijuana; 
contraindications for taking pioglitazone; medical conditions (e.g., congestive heart failure, clinically 
significant edema, clinically significant liver disease, hypoglycemia, diabetes, history of bladder cancer) 
contraindicating pioglitazone pharmacotherapy or taking contraindicated medications (e.g., CYP2C8 inhibitors 
or inducers, antihyperglycemic medications); be pregnant, nursing, or planning on becoming pregnant during 
the course of the study; females will need to agree to use of barrier methods of contraception due to 
pioglitazone’s effects on plasma concentrations of oral contraceptives; have any other illness, condition, or use 
of medications, which in the opinion of the PI and/or admitting physician would preclude safe and/or 
successful completion of the study. 
Baseline Screening. Participants will receive a comprehensive medical and psychiatric evaluation 
including a medical-history questionnaire, physical examination, laboratory chemistries (e.g., blood chemistry 
screen, complete blood count, urinalysis and serum pregnancy test), and ECG. Clinicians will conduct the 
SCID, the ASI65, the KMSK66 assessment of lifetime substance use interview, and TLFB67. Alcohol 
dependence will be assessed using the SCID and the CIWA-A74. A CIWA-A score > 10 will be exclusionary. 
Alcohol-Related Measures. Assessment of alcohol use will include self-report (TLFB) and BrAC 
(Alco-Sensor FST, Intoximeters, Inc., Saint Louis, MO). The TLFB will be used to assessed the occurrence of 
heavy drinking days (>3 drinks/occasion for women>4 drinks/occasion for men)35 in the past 7 days and 
average drinks/day for the past 7 days. Severity of alcohol use will be assessed using the AUDIT69. Alcohol 
craving will be assessed using a 4-item questionnaire75 during the stress reactivity assessment and the PACS 
at weekly clinic visits. Motivations for drinking will be assessed using the DMQ-R1, with demonstrated utility 
in the general2,76,77 as well as clinical78,79 populations. The DMQ-R consists of 20 questions assessing 
motivations for drinking that are rated on a 1 “almost never/never” to 6 “almost alwIaRyBs/NaUlwMaByEs”Rs: cHaSlCe.-MEST-G18-w09il2l2 
IRB APPROVAL DATE: 10/11/2023 

be assessed using dipcards with a 300 ng/ml cutoff. ETG dipcards show good agreement with traditional 
immunoassays80–82. 
Behavioral Economic Measures. During the stress reactivity assessment, alcohol demand will be 
assessed via the Brief Assessment of Alcohol Demand (BAAD)59. The BAAD is a 3-item questionnaire 
measuring the three most common indices of alcohol demand. A recent meta-analysis has demonstrated 
demand measures to be sensitive to acute experimental manipulations, include small but significant increases 
for stress83. Global changes in alcohol demand and delay discounting will be assessed at baseline and Weeks 4 
and 8 using a purchasing task and computerized delay discounting task developed by Dr. Yoon (PI)84–94. In 
addition to the standard money now vs. later choices, the delay discounting task will present choices between 
alcohol now vs. money later, which more closely models alcohol-related decision making and has also been 
demonstrated by Dr. Yoon to be sensitive to weekly changes in drug use status for cigarettes87. 
Stress and Anxiety Measures. Stress and anxiety levels will be assessed using the HAM-A71, PSS72, 
and the PCL-573. Established norms will be used for the HAM-A and PSS to assess mild to moderate stress and 
anxiety and screen out for cases in which laboratory induced stress may be too aversive. The PCL-5 will be 
administered at baseline and Weeks 4 and 8. 
Study Medication and Compliance. Pioglitazone (Actos®, Takeda Pharmaceuticals U.S.A., Inc.) is 
FDA-approved for the treatment of diabetes mellitus type 2; has anti-inflammatory, neuroprotective, 
antioxidative, and anti-excitotoxic properties95; and extensive research has shown it to be safe and well 
tolerated in human patient populations96,97. The medication schedule is based on previous work from our group 
showing that a daily dose of 45mg (maximum suggested dose) was associated with acceptable levels of 
tolerability, safety, and compliance in a study assessing the effects of pioglitazone on individuals with CUD and 
AUD64. We will follow recommended adult initial dosing at 30 mg/d to reach a maintenance dose of 45 mg/d 
by the end of Week 1, which is within standard titration parameters as per the investigator’s brochure. 
One week’s supply of the study medication will be dispensed. Cell-phone assisted remote observation of 
medication adherence (CAROMA) will be used to assess compliance. Riboflavin will be added to medication 
capsules and urine ultraviolet fluorescent tests will be conducted at weekly clinic visits to also assess 
compliance. Participants will receive $10 at each clinic visit based on self-report, CAROMA, and riboflavin 
measures all being consistent with medication compliance. For safety purposes, blood will be drawn every 2 
weeks for liver function testing as is standard for other Pioglitazone protocols at the CNRA. 
Assessment of Stress Reactivity. At baseline and Weeks 4 and 8, stress reactivity will be assessed using 
a modified cold-pressor task (CPT). The CPT is widely used as a stress-inducer in human 
laboratory studies and elicits moderate activation of the sympathetic nervous system and limited activation of 
the HPA-axis, which are two major stress systems in the body98–101. HPA-axis activation during the CPT can be 
increased by incorporating a social evaluative component. These will include 1) a study member dressed in a 
white labcoat and taking notes on a clipboard; and 2) a webcam and 
monitor showing the participant’s face. Participants will be informed that 
their facial expressions will be assessed during the CPT. The addition of 
these social components during the CPT has been demonstrated to 
selectively activate the HPA-axis and significantly increase salivary cortisol 
levels100. During the CPT, participants will submerge their dominant arm in 
an ice-water bath for up to 2 minutes. Physiological measures of stress 
reactivity will include HR, BP, and salivary cortisol consistent with previous 
studies from our group102,103. HR and BP will be will be assessed using 
standard laboratory equipment. Saliva samples will be collected in swabs 
using the Cortisol-Salivette® system (Sarstedt) and measured using the 
Cortisol ELISA Kit (Enzo Life Sciences), per manufacture instructions, 
Table 2. Time Course for 
Assessing Stress-Induced 
Relapse Risk 
Time 
(pm) 
Study 
Procedures 
3:00 
Assess Craving, BAAD, 
Stress, Cortisol, HR, BP 
3:15 
Cold Pressor Task 
3:20 
Assess Craving, BAAD, 
Stress, HR, BP 
3:45 
Assess Craving, BAAD, 
Stress, Cortisol, HR, BP 
detailed in Suchting et al (2019)4. Alcohol craving will be assessed using a 4-item questionnaire75 as well as the 
BAAD. Stress will be assessed using a single-item VAS question. 
Brief Counseling. At baseline, all participants will receive the NIAAA booklet “Rethinking Drinking: 
Alcohol and Your Health” providing research-based information related to alcohol use 
(RethinkingDrinking.niaaa.nih.gov). Study therapists will go over the booklet with the participant at the initial 
visit and at subsequent weekly visits using motivational interviewing techniques. At each visit, participants will 
also be assessed for recent alcohol use (self-report, ETG, BrAC), alcohol craving (PACS), and stress/anxiety 
(HAM-A, PSS). At the end of the study, referrals to local alcohol treatment services will be provided as needed. 
Participant Payment & Compensation. Participants will receive $50 for completing the baseline 
screening, $25/visit for attending study visits (9 visits), $25/assessment for compleItRinBgNsUtrMesBsErRe:aHctSivCi-tMy S-18-0922 
IRB APPROVAL DATE: 10/11/2023 

articipants
xiety (pri 
assessments (3 assessments), $10/week for medication compliance (8 weeks), and $100 for completing the 
study ($530 total). Participants will also receive $5 compensation for busfare/parking at each study visit. 
 
 DATA ANALYTIC STRATEGY 
 
Descriptive Statistics & Confounding Variables Descriptive statistics will evaluate measures of 
central tendency (continuous) and frequencies (categorical) for study-related variables. General variable 
relationships will be evaluated using correlation analyses. Preliminary analyses will inspect relationships 
between sample characteristics (e.g., demographics), predictor variables (e.g., inflammatory markers), and 
specified outcome variables (e.g., resilience measures) via traditional statistical tests (e.g., chi-square, Mann- 
Whitney-Wilcoxon, Kruskal-Wallis, and t-tests). Sample characteristic variables demonstrating a relationship 
with both the predictor and outcome variables in a given model will meet criteria as a potential 
confounder104,105 and included as a covariate in such models for hypothesis testing and explored as potential 
moderators of treatment group effects on experimental outcomes. 
Inferential Paradigm Following recommendations in the literature106–108, analyses will utilize parallel 
frequentist and Bayesian statistical inference. Frequentist results yield the probability of the data (or data more 
extreme), given the null hypothesis, whereas Bayesian results directly yield the probability of an alternative 
hypothesis109. If possible, Bayesian analyses will incorporate informative priors as they develop in the 
literature; otherwise, weakly informative priors will be incorporated as a default. Sensitivity analyses using 
optimistic and pessimistic, skeptical priors will evaluate prior assumptions110. Assessing the convergence of 
Bayesian analyses on the posterior distributions via Monte-Carlo Markov chain (MCMC) will use diagnostic 
evidence including effective sample size and scale reduction factors. Evaluation of posterior distributions will 
permit statements regarding the probability that effects of varying magnitudes exist, given the data. Statistical 
analyses will use the most up-to-date stable release version of the R statistical computing environment111 using 
packages rstan111 and brms112. 
Statistical Modeling Analyses will primarily use generalized linear modeling (GLM). Continuous, count, 
and dichotomous outcome variables will utilize normal, Poisson/negative binomial, and binomial distribution 
families respectively, with identity, log, and logit link functions as appropriate. Evaluation of distributional 
assumptions will use residual plots, formal statistical tests, and posterior predictive checking. Violations of 
assumptions will be addressed via transformation, robust estimation, stratification, and/or coefficient scaling 
where appropriate. 
Missingness & Multiple Comparisons Missing data will be addressed via maximum likelihood, 
explicit modeling of missingness, and/or imputation where appropriate. Each approach is robust to ignorable 
missingness (i.e. MCAR and MAR). Sensitivity analyses will permit evaluation of the robustness of findings to 
missing data assumptions. While Bayesian analyses are not influenced by traditional concerns of multiplicity, 
for the frequentist analyses, all primary outcome variables (those specified by name in the hypothesis 
statements below) will be evaluated at the α = 0.05 statistical significance level. Secondary analyses will 
examine additional predictor and outcome variables (e.g., other inflammatory markers collected by assays); 
these and any otherwise post hoc analyses will employ false discovery rate (FDR) to control for Type I error. 
Specific Analyses 
Specific Aim 1: To examine the effects of pioglitazone on stress-induced relapse risk in a 
laboratory model. Hypothesis 1a: Participants receiving pioglitazone will show decreased stress 
reactivity (heart rate, blood pressure, salivary cortisol) compared to those receiving placebo. Hypothesis 
1b: Participants receiving pioglitazone will show decreased alcohol craving (subjective, alcohol demand) 
compared to those receiving placebo. 
For hypothesis 1a, GLMM will model each stress reactivity outcomes (primary: heart rate, blood pressure, 
and salivary cortisol) as a function of the main effects and higher-order interactions between time (baseline 
to Week 8), treatment (pioglitazone vs. placebo), and CPT measurement point (pre-CPT vs. post-CPT). 
Follow-up analyses will examine lower-order interactions longitudinally as well as cross-sectional changes 
from pre- to post-CPT at each time point. Variable relationships and analyses for hypothesis 1b will follow 
the patterns stated above for Hypothesis 1a, with craving in place of stress reactivity. 
 
Specific Aim 2: To examine the effects of pioglitazone on drinking, stress/anxiety, and 
alcohol craving in the natural environment. Hypothesis 2a:  P 
rIReBceNivUinMgBpEiRo:gHliStCaz-MonSe-1w8-i0l9l 22 
show greater reductions in weekly psychometric measures of stress/an 
mIaRrBy AmPePaRsOuVreAsL: DPASSTEa:n1d0/11/2023 

HAM-A) compared to those receiving placebo. Hypothesis 2b: Participants receiving pioglitazone will 
show greater reductions in weekly psychometric measures of alcohol craving (primary measures: PACS) 
compared to those receiving placebo. Hypothesis 2c: Participants receiving pioglitazone will show greater 
reductions in past week alcohol use (primary measures: heavy drinking days as defined by >3 
drinks/occasion for women and >4 drinks/occasion for men, average drinks/day) compared to those 
receiving placebo. 
For all hypotheses, GLMM will model primary outcome measures as a function of the main effects and 
interaction between treatment and time. 
 
Sample Size and Power Considerations 
Frequentist Analyses. Power for Specific Aim 1 is based on the rate at which we may detect the three- 
way interaction between time, treatment, and CPT measurement point for a given measure of stress reactivity 
(transformed for normality) across k = 1000 Monte Carlo simulations (executed via SAS 9.4). Calculations 
assume the following conditions: α = 0.05, an autocorrelation of r = 0.50 between consecutive observations 
(with a decay of r = -0.10 for subsequent observations), and a small correlation of r = 0.05 for observations 
occurring at the same time point across groups. Based on these assumptions, the different sample sizes 
(pragmatic and pessimistic) stipulated in Table 3 each provide power to detect small-to-moderate effect sizes 
(treatment group differences expressed as Cohen’s D, with effects unfolding in linear fashion over time). Power 
for Specific Aim 2 is based on evaluating reductions in drinks per week. Estimates are derived using G*Power 
3.1.9.2. Assuming α = 0.05 (two-tailed) and an average baseline of drinks/week across participants (calculated 
as an average from 14 and 7 drinks/week for a 3:1 ratio of males to females, respectively), the different sample 
sizes (pragmatic and pessimistic) stipulated in Table 3 each provide power to detect varying decreases in 
alcohol consumption. 
Bayesian Analyses. The Bayesian analyses in the current proposal will provide probabilistic estimates of 
effects for all hypotheses irrespective of statistical power. Moreover, the MCMC approaches utilized in Bayesian 
analyses do not rely on large sample size assumptions. Bayesian analyses will focus on posterior probabilities ≥ 
0.75 (equivalent to a Bayes factor = 0.33 or 3.0) that parameter estimates are greater or less than zero to 
emphasize the value in discerning model effects. 
 
Table 3. Power estimates for Aims 1 and 2 given different sample and effect sizes. 
N 
(N/group) 
SA1: Group Difference (Cohen’s D) 
SA2: % Decreased Consumption 
D = 0.50 
D = 0.40 
D = 0.30 
-12.0% 
-11.0% 
-10.0% 
50 (25/25) 
100.0% 
97.8% 
84.6% 
97.8% 
95.2% 
90.8% 
40 (20/20) 
99.8% 
95.0% 
71.8% 
88.6% 
82.5% 
74.6% 
Cohen’s D for observed within-subject effects sizes from our Preliminary Data are as follows: HR (0.8), BP 
(systolic - 0.5, diastolic - 1.6), cortisol (0.13), PSS (2.1), HAM-A (1.3), BDI (1.2), PACS (1.5), Drinks/week (1.3), 
Heavy drinking (0.8). Note that Table 3 effect sizes represent between group differences unfolding over time. 
 
 STUDY TIMELINE 
 
The time frame illustrated in Table 4 below is based on conservative estimates. We will continuously 
monitor our procedures and implement measure to enhance progress as indicated. Our goal is to enroll 60 
subjects to achieve 25 completers/group. However, we will continue to enroll subjects based on available 
resources and subject attrition. Pre-award preparations following pre-award requests (just-in-time (JIT)) will 
include submitting an initial IRB protocol. Startup will include hiring and training of study staff. Over the 
course of the study, preliminary and final results will be presented at appropriate scientific conferences (e.g., 
Research Society on Alcoholism, College on Problems of Drug Dependence, Research Society on Alcoholism, 
etc.). 
Table 4. Study Timeline. 
 
 
 
 
23 
Year 1 
Year 2 
Month 
Month 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Pre-award prep 
Startup 
IRB NUMBE : H C-MS-18-092
Phone screens: 250 
IRB APPROVAL DAT : 10 11/2

his inform
Intake evaluations: 100 
Enrollment and randomization: 60 (~3-4 subjects/month) 
Completion of protocol (~3-4 subjects/month) 
Data cleaning & analysis, write-up 
paper/grant renewal preparation 
 
 PROTECTION OF HUMAN SUBJECTS 
 
E.1. 
Risk to the Subjects 
E.1.1. Human Subjects Involvement and Characteristics 
The 2-year project will enroll male and female individuals (18 and older) regular alcohol users with past month 
excessive use of alcohol. Research data will be collected at screening, baseline, and weekly study visits. 
 
This study is funded by the National Institute on Alcohol and Alcoholism (NIAAA). All studies funded by 
NIAAA, including this study, now submit data to the National Institute of Mental Health Data Archive (NDA) 
at the National Institutes of Health (NIH). All subject data will be de-identified by using a computer-generated 
global unique identifier (GUID) within the NDA database. 
 
The single study site is the Center for Neurobehavioral Research on Addiction (CNRA) at the University of 
Texas McGovern Medical School, Houston. The CNRA is centrally located in a large U.S. metropolitan area 
known to have an adequate and representative alcohol-using population [see Facilities and Other Resources]. 
Moreover, the site has demonstrated its ability to recruit and retain the appropriate population using various 
recruitment strategies. 
 
We plan on recruiting 4 participants/month over the course of 20 months for a total of 80 enrolled 
participants. We estimate that 60 participants (75%) will complete the study, based on previous studies from 
our group. Recruitment strategies will include local advertising in print media, public service announcements 
on radio, and referrals to CNRA in the Houston metropolitan area. Additionally, we will utilize the SONA 
system, which provides University of Houston students credit for participating in various research studies. 
Potential participants will complete a brief phone screen to assess initial eligibility and subsequently invited to 
undergo a comprehensive baseline screening following informed consent. The baseline screening will include a 
full medical evaluation by the CNRA Medical Director (Dr. Weaver. Co-I). All participants will meet the 
following selection criteria. 
 
Inclusion criteria. Be treatment-seeking individuals diagnosed with AUD (DSM-5); be at least 18 years 
old and fluent in English; past month excessive alcohol use (>7 drinks/week for woman, >14 drinks/week for 
men, >3 drinks/occasion for women>4 drinks/occasion for men)35; exhibit baseline measures of either 1) 8-23 
on HAM-A indicative of mild to moderate anxiety, 2) 14-26 on PSS Score indicative of moderate stress, or 3) ≥2 
on DMQ-R questions related to drinking indicating that individuals drink at least “some of the time” to cope; 
and exhibit increased stress reactivity (increased physiological response and/or self-report) at the baseline 
stress reactivity assessment. 
Exclusion criteria. Exhibit severe scores on the HAM-A, PSS, or PTSD checklist (PCL-5) – may be 
enrolled at the discretion of the admitting physician (Dr. Weaver); physical dependence on alcohol (CIWAA > 
10); greater than mild substance use disorder on drugs other than alcohol, nicotine, and marijuana; 
contraindications for taking pioglitazone; medical conditions (e.g., congestive heart failure, clinically 
significant edema, clinically significant liver disease, hypoglycemia, diabetes, history of bladder cancer) 
contraindicating pioglitazone pharmacotherapy or taking contraindicated medications (e.g., CYP2C8 inhibitors 
or inducers, antihyperglycemic medications); be pregnant, nursing, or planning on becoming pregnant during 
the course of the study; females will need to agree to use of barrier methods of contraception due to 
pioglitazone’s effects on plasma concentrations of oral contraceptives; have any other illness, condition, or use 
of medications, which in the opinion of the PI and/or admitting physician would preclude safe and/or 
successful completion of the study. 
 
E.1.2. Sources of Materials 
We will obtain information about subjects from structured interview evaluations, phIRysBicNaUl eMxBaEmRi:nHaStiCo-nMsS, -s1e8l-f0-922 
report measures, biological samples, and behavioral laboratory tasks.  T 
atIiRoBnAwPiPllRbOeVcAoLlleDcAteTdE:a1t0/11/2023 

specified time points during the study. The biological specimens obtained from all subjects will include urine, 
blood, salivary cortisol, and breath samples for alcohol detection. All materials will be obtained for the specific 
purposes of this research. 
 
E.1.3. Potential Risks 
Medication. Pioglitazone (trade name Actos) is approved by the FDA for the treatment of type II diabetes. 
According to the prescribing information for Actos “Over 8500 patients with type 2 diabetes have been treated 
with ACTOS in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 
diabetes and macrovascular disease treated with ACTOS in the PROactive clinical trial. In these trials, over 
6000 patients have been treated with ACTOS for 6 months or longer, over 4500 patients have been treated 
with ACTOS for one year or longer, and over 3000 patients have been treated with ACTOS for at least 2 years.” 
 
In addition, several studies have taken place in non-diabetic patients. Sixty non-diabetic patients with 
hypertension were treated with pioglitazone or placebo in one trial, finding a significant reduction in diastolic 
blood pressure in the pioglitazone treated group113. 
 
Another larger study in non-diabetic hypertensive patients found a significant reduction in biomarkers of 
insulin resistance and chronic systemic inflammation in pioglitazone treated patients114. An additional pilot 
study administered pioglitazone to 29 non-diabetic patients with Alzheimer’s disease at a dose up to 45mg 
daily for 18 months. No adverse events leading to treatment discontinuation were seen in this trial. Peripheral 
edema was the principal side effect noted in pioglitazone treated subjects, but this side effect was not severe 
enough to lead to medication discontinuation115. 
 
Common adverse events from clinical trials that occurred more frequently than placebo include upper 
respiratory tract infections, edema, headache, sinusitis, myalgia, and pharyngitis. 
 
Hypoglycemia: Patients treated with insulin or other antidiabetic medication in addition to pioglitazone may be 
at increased risk of hypoglycemia. Due to this risk subjects with diabetes will be excluded. 
 
The most significant potential side effect of pioglitazone is exacerbation of congestive heart failure. Due to this 
potential side effect, all subjects will be carefully screened for congestive heart failure (CHF) using 
Framingham criteria and no subjects with CHF will be enrolled, and weight will be monitored closely for 
increased fluid retention. Also, EKGs will be repeated every two weeks to monitor for changes. 
 
Hepatic effects: Although there was no evidence of drug induced hepatotoxicity from clinical trials, post- 
marketing reports of fatal and non-fatal hepatic failure have been made in patients taking pioglitazone for 
diabetes. Due to this risk, liver function tests will be performed every two weeks during the trial. 
Urinary Bladder Tumors: Tumors were observed in the urinary bladder of male rats in a two-year 
carcinogenicity study (https://general.takedapharm.com/actoplusmetpi/). In clinical studies, two 3-year trials in 
which pioglitazone was compared to placebo or glyburide, according the prescribing information “there were 
16/3656 (0.44%) reports of bladder cancer in patients taking ACTOS compared to 5/3679 (0.14%) in patients 
not taking ACTOS. After excluding patients in whom exposure to study drug was less than one year at the time 
of diagnosis of bladder cancer, there were six (0.16%) cases on ACTOS and two (0.05%) cases on placebo. 
There are too few events of bladder cancer to establish causality.” 
 
Fractures: In female patients with diabetes treated for a year with pioglitazone there was a higher rate of bone 
fractures (5.1%) compared to placebo (2.5%). There was no increase in fractures in male patients. 
 
Laboratory Values: Clinical trials showed a slight reduction in hemoglobin and hematocrit (2-4%) over 12 
weeks of treatment, likely related to increased plasma volume and not associated with any clinically significant 
hematologic effects. 
IRB NUMBER: HSC-MS-18-0922 
IRB APPROVAL DATE: 10/11/2023 

Ovulation: Pioglitazone can increase ovulation in non-postmenopausal women. In addition, other medications 
in this same class have reduced the plasma concentrations of oral contraceptives. Because of these facts, female 
subjects must agree to an effective barrier method of contraception. 
 
Pregnancy: Pioglitazone is pregnancy Category C. There are no known adverse events of pioglitazone during 
pregnancy but there are inadequate studies in humans. Animal studies using doses 10 to 40 times the 
maximum recommended human dose showed increased rates of post-implantation loss, delayed development, 
reduced fetal weights, and delayed parturition. Due to these issues all female subjects must agree to an effective 
barrier method of contraception. 
 
Safety data from our pilot trial suggest a highly favorable risk/benefit profile for pioglitazone. Thirty men and 
women with CUD received randomly assigned treatment of pioglitazone (n=15) or placebo (n=15) in double- 
blind fashion for 12 weeks. Safety and tolerability were assessed via a weekly side effects questionnaire 
composed of 38 common symptoms, along with nurse evaluation of any adverse or serious adverse events. 
The most frequent side effects reported by at least 10% of participants included not sleeping 
well, diarrhea, stomach pain, cough, and increased urination. All were rated mild with none 
occurring significantly more frequently in the pioglitazone group. One participant in the placebo group 
experienced a serious adverse event (coronary artery vasospasm) that was diagnosed as cocaine-induced and 
required an emergency department visit. 
 
Blood draw: The principal risk is hematoma at the venipuncture site, which is not serious and disappears 
after several days. CNRA phlebotomists drawing blood will are trained in venipuncture techniques to minimize 
extravasation. 
 
Stress Reactivity: Cold pressor task. Individuals with cardiovascular disorders and neurological 
disorders should not participate in the cold-pressor task due to cardiovascular change induced by the testing. 
This information will be obtained during medical screening. Due to individual variation in pain and cold 
sensitivity, for some subjects the cold water may become too painful to sustain immersion for 120 seconds. 
There are no lasting effects from placing the hand and wrist in ice water (~0° Celsius) for 120 seconds. 
 
Psychological. Items on certain questionnaires and interviews might be perceived as psychologically 
discomforting to some subjects. While subjects may be uncomfortable reporting these issues, the risks of 
serious sequelae are extremely low. 
 
Alternative Treatments. Participants seeking treatment will be referred to appropriate treatment options. 
 
E.2. 
Adequacy of Protection against Risks 
E.2.1. Recruitment and Informed Consent 
Participants will be self-referred in response to various study advertisements via newspaper and radio. 
Individuals who call for information will be given a brief description of the study. Those interested will then be 
asked to answer questions about their current substance use. A trained research assistant will conduct this 
telephone-screening interview. Eligible subjects will be scheduled for an in-person intake visit at which time a 
research staff member will present the informed consent form. The consent form will detail the requirements 
of study participation (e.g., # of visits, type of data collected, time commitment, etc.). 
 
Subjects will be told that the purpose of the study is to evaluate a medication’s effect on their alcohol use in 
their natural environment and following exposure to an acute stressor. Information about each study 
procedure will be explained. Subjects will be informed that they will attend weekly clinic sessions and to take 
their medication. Other information on the consent form will include a full description of study requirements, 
reimbursement, risks, benefits, alternatives, and the role of the local IRB. All questions will be answered 
before written consent is requested. 
 
E.2.2. Protection Against Risk 
IRB NUMBER: HSC-MS-18-0922 
IRB APPROVAL DATE: 10/11/2023 

trial data and 
Thorough screening of all subjects including history and physical examination, serum chemistry and 
hematology, EKG, urinalysis and Urine Drug Screen as well as structured psychiatric interviews will be 
completed on all subjects. Exclusion criteria include subjects at greatest risk of side effects of pioglitazone, 
including those with congestive heart failure, significant liver disease, edema, and diabetes, as well as risks of 
alcohol use (pregnant women). Monitoring of weight to capture potential fluid retention will occur at each visit. 
Weekly assessment for edema and urine pregnancy will occur. Twice monthly serum chemistry and hematology 
will take place to monitor liver functions and hemoglobin/hematocrit. In addition twice monthly EKGs will be 
done. Female subjects must agree to use an effective barrier method of birth control to minimize risk of 
pregnancy. 
 
Confidentiality will be protected in several ways. All information collected solely for research purpose will be 
kept in locked, restricted access files. Subject records will be coded and filed by a number code. Subject 
identities will not be revealed in any publication of the data. Individual subject information will be transferred 
to outside sources only with the express written request of the subject. Subjects will receive a copy of their 
signed consent form. 
 
E.3. 
Potential Benefits of the Proposed Research to the Subject and Others 
There are no potential benefits for participants. However, knowledge gained from the current proposal may 
benefit future individuals with AUD. 
 
E.4. 
Importance of the Knowledge to be Gained 
Results from the current proposal may help develop novel pharmacotherapies for AUD based on mechanisms 
targeting PPAR. AUD is a public health issue with substantially negative effects on health and society. Results 
from the current proposal will help inform future medication development efforts. 
 
The above stated risks are relatively mild in degree and procedures have been designed to minimize their 
probability. We believe this protocol has an extremely favorable risk/benefit ratio. The clinical research at the 
CNRA has an excellent track record in conducting controlled trials with the utmost attention to safety. 
 
 
 DATA SAFETY MONITORING PLAN 
 
This plan describes the general data and safety monitoring procedures for the proposed study. A detailed DSM 
plan will be submitted for approval prior to starting the study. 
 
1. 
The Principal Investigators (Yoon, Lane) will be responsible for knowing the policies of the local IRB. In 
this capacity, they will maintain accurate documentation of IRB correspondence and reports and oversee the 
handling of all possible study-related adverse events. The CNRA has longstanding data collection and safety 
monitoring system in place that will be available for the proposed study. This includes staff training, manual 
driven processes, weekly audit of data collection/entry, medical screening with results reviewed by on-site 
nurse and physician, use of standardized assessments, continued medical monitoring during treatment, use of 
a certified (CLIA) analytical laboratory to perform urine toxicology testing, procedures to monitor medication 
compliance (e.g., riboflavin), collaboration with the statistician who oversees data analysis and system 
management. The PI will assure that the above systems are in place and functioning properly for the duration 
of the study. 
 
2. 
A DSM Board will be formed to provide additional, independent oversight of data related to patient 
safety. Membership will include Drs. Jan Blalock (UT-MDA Cancer Center), Edward Fann (Baylor College of 
Medicine-Psychiatry), Daryl Ishaq Shorter (Baylor College of Medicine), and Claudia Pedrozo (UTHealth). 
Selected individuals have relevant expertise and experience in monitoring clinical trials. This committee will 
perform the following activities: (a) review the research protocol and plans for data and safety monitoring; (b) 
evaluate study progress, including data quality, participant recruitment rates, retention rates, outcome and 
adverse experience data, and risk versus benefit profile; (c) make recommendationsIRtoBtNerUmMiBnEatRe: tHhSeCt-rMiaSl-18-0922 
because of safety concerns; and (d) protect the confidentiality of the 
thIReBreAsPuPltRsOoVf AmLoDnAitToEri:n1g0./11/2023 

3. 
Adverse events (AE) will be reported to the local IRB on an annual basis. Serious adverse events will be 
reported immediately (verbally within 24 hours) to the IRB, the DSMB, and to the NIDA. A written report will 
follow as soon as possible but in no more than three days. The written report will be in the format required by 
the IRB and will contain information regarding the date of the AE, description of the AE, severity rating 
(Grade 1 to 4), assessment of cause, whether the AE indicates an increased risk for current or future subjects, 
and whether changes to the informed consent form are necessary. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB NUMBER: HSC-MS-18-0922 
IRB APPROVAL DATE: 10/11/2023 

novic AA. P
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