Clinical trial NCT03860753
Conditions: Alcohol Use Disorder
Keywords: Alcohol Pioglitazone Stress Anxiety
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2019-03-01; Completion date: 2019-08-23
Enrollment: 4 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the effect of pioglitazone on stress- and alcohol-related measures in treatment-seeking individuals with alcohol use disorder (AUD) and elevated levels of stress and anxiety.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Pioglitazone intervention 2: Placebo
Intervention descriptions: intervention 1: For the current trial we will follow recommended adult initial dosing at 30 mg/d to reach maintenance dose of 45 mg/d by week 2, which is within standard titration parameters as per the investigator's brochure. intervention 2: Pill capsules will look same as that of active drug.

Protocol documents:
Prot_SAP_000.pdf: 
IRB APPROVAL DATE: 05/08/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Effects of Pioglitazone on Stress Reactivity and Alcohol Craving 
 
NCT03860753 
 
Version Date: 05/08/2019  
 


IRB APPROVAL DATE: 05/08/2019 
 
ABSTRACT 
Alcohol use disorder (AUD) is associated with significant negative health, social, and economic costs. 
Alcohol activates the hypothalamic-pituitary-adrenocortical (HPA)-axis, and stress can increase the reward 
value of drinking. Continued excessive drinking results in behavioral changes marked by increased compulsive 
drinking, stress reactivity, and neuro-inflammation8. FDA-approved pharmacotherapies for AUD (e.g., 
naltrexone, acamprosate, disulfiram) are effective in less than a third of treated individuals9. Importantly, 
none of the currently approved medications for AUD directly address stress reactivity, underscoring the need 
to develop novel pharmacotherapies targeting stress-related processes associated with AUD. 
A promising pharmacological target for addressing AUD and stress reactivity is the family of peroxisome 
proliferator-activated receptors (PPARs), proteins that act as ligand-activated transcription factors that exhibit 
both anti-inflammatory and neuro-protective responses in the brain10. A growing number of pre-clinical 
models have shown promising effects of PPAR agonists on drug-related outcomes11. For example, 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 alcohol12,13. 
An important innovation of the current study will be to translate these results for the first time to humans with 
AUD. 
The primary purpose of the current proposal is to obtain preliminary data to increase the likelihood of 
funding for a future NIH grant, while balancing the feasibility of completing the current proposal. To that end, 
we will utilize a within-subject, repeated measures design to assess the feasibility of administering pioglitazone 
for four weeks to non-treatment and treatment-seeking individuals with AUD and elevated levels of 
stress/anxiety (N=20). Participants will undergo pre- and post-treatment human laboratory assessment of 
stress-reactivity and stress-induced alcohol craving. During treatment, changes in alcohol use, stress/anxiety, 
and alcohol craving will be assessed in the natural environment. The study design features 1) rigorous 
monitoring of medication compliance (Medication Event Monitoring System (MEMs)) and alcohol use (urinary 
ethyl glucuronide (ETG)); 2) biological assessment of stress reactivity (salivary cortisol, blood pressure, and 
heart rate); and 3) a multi-dimensional assessment of stress-induced alcohol craving incorporating both 
traditional measures of alcohol craving in addition to relatively novel behavioral economic measures (delay 
discounting, alcohol demand). Taking these measures together, we hope to present a robust and 
comprehensive characterization of pioglitazone on alcohol use, stress reactivity, and stress-induced alcohol 
craving. 
 
SPECIFIC AIMS 
 
Specific Aim 1: To assess pre- to post-treatment reductions in stress reactivity (self-report, salivary cortisol, 
heart rate, blood pressure) and stress-induced alcohol craving (self-report, alcohol demand) in the human 
laboratory setting. 
Hypothesis 1: We will observe pre- to post- treatment reductions in stress reactivity and stress-induced 
alcohol craving. 
 
Specific Aim 2: To assess changes in alcohol drinking (drinks per day, heavy drinking days), stress/anxiety 
(PSS, HAMA, PCL-5), and alcohol craving (PACS, delay discounting, alcohol demand) during treatment in the 
natural environmental setting. 
Hypothesis 2: We will observe decreased alcohol drinking, stress/anxiety, and alcohol craving over the 
course of treatment. 
 
There is increasing attention and evidence supporting the potential role of the PPARγ system as a novel target 
in the treatment of AUD. From a translational perspective, this study is timely and likely to advance our 
understanding of stress as a mechanism of action of pioglitazone effects. 
IRB NUMBER: HSC-MS-18-0922 


IRB APPROVAL DATE: 05/08/2019 
 
BACKGROUND AND RATIONALE 
 
Public Health Impact of AUD. AUD is 1) the 4th leading cause of death in the US (~88,000 
deaths/year), decreasing lifespan by approximately 30 years; 2) a tremendous economic burden on society 
(~$249 billion/year); and 3) associated with a host of short- and long-term negative consequences including 
violence, legal problems, morbidity, and family problems14–16. 
 
AUD and the Central Role of Stress. Persistent excessive drinking is 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 negative impact on autoimmune 
and inflammatory responses that can in turn influence alcohol use17–21. Whereas initial drinking is influenced 
by the positive reinforcing effects of alcohol and impulsivity, continued drinking adopts compulsive 
characteristics maintained increasingly by negative reinforcement (e.g., alcohol withdrawal symptoms, stress- 
related anxiety, alcohol craving) as well as decreased stress-resiliency and cognitive deficits from neuro- 
inflammatory damage17,22,23. Despite the profound negative impact of stress on AUD, none of currently 
approved medications for AUD directly target stress or stress-related consequences associated with AUD. 
 
Novelty and Promise of the PPAR System. PPARs are proteins that act as ligand-activated 
transcription factors, which is central to their anti-inflammatory actions24 . Pre-clinical studies highlight the 
potential of PPAR agonists on various aspects of drug use (e.g., discrimination, self-administration, 
reinstatement, sensitization) for several drugs of abuse including alcohol11. In human studies, expression of 
PPAR has been shown to be altered among individuals with AUD in genome-wide association studies (GWAS) 
25 26 studies. In a recent study by our group, post hoc analyses revealed significantly decreased alcohol use 
among individuals with concurrent cocaine use disorder (CUD) and AUD receiving the PPARγ agonist 
pioglitazone, compared to placebo, in a study assessing cocaine craving and white matter integrity.27. 
Currently, only the PPAR gamma (PPARγ) isoform can be targeted in humans. PPARγ is highly expressed 
in a number of brain regions associated with drug reward28 and stress response12,13. Activation of PPARγ 
mediates neuroprotective responses against inflammatory damage, which can attenuate drug affects29– 32. The 
PPARγ agonist Pioglitazone (Actos) is FDA-approved for the treatment of diabetes and metabolic disorders. In 
preclinical studies, pioglitazone protects against 1) alcohol-induced neuronal and cognitive damage in a model 
of binge-drinking33; and 2) neuro-inflammation and neurodevelopmental toxicity in a model of fetal alcohol 
spectrum disorder34 . Directly relevant to the current study, 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 alcohol12,13. 
 
Multi-Dimensional Assessment of Alcohol-Induced Craving. Self-report measures of drug craving 
are ubiquitous and often serves as a proxy of motivation to consume drug but have limitations that have likely 
resulted in equivocal results in human laboratory studies35. Behavioral economic measures (i.e., delay 
discounting, alcohol demand) may help mitigate these issues and are both closely associated with drug use and 
directly tied to a broader framework of drug addiction. Delay discounting is a relatively stable, trait-like 
measure that assesses the decrease in value of a reward as a function to delay of its receipt, and also serves as a 
measure of impulsivity. Delay discounting has an extensive literature revealing associations with virtually every 
aspect of drug use including initiation, severity, and relapse risk36–38. Alcohol demand assesses how much 
alcohol an individual is willing to consume as a function of increasing price, serving as 1) a robust 
characterization of the reward value of alcohol and therefore craving; and 2) a proxy of compulsive drug use 
(i.e., consuming alcohol despite increasing aversive consequences). Drug demand can be easily and quickly 
assessed through purchasing tasks, which have very strong reliability, predictive validity, and are sensitive to 
state-dependent changes in demand under conditions of withdrawal, cue exposure, environmental stressors, 
IRB NUMBER: HSC-MS-18-0922 


IRB APPROVAL DATE: 05/08/2019 
 
and predict alcohol treatment response39–42. Delay discounting and alcohol demand are poorly correlated with 
each other, supporting a multi-dimensional model in which these measures represent distinct aspects of 
motivation to use alcohol42–48. In the current proposal, we will assess changes in both delay discounting and 
alcohol demand over Study Weeks 0 to 4 and alcohol demand will be used to assess state-dependent changes 
during the human laboratory stress-reactivity assessment. 
 
METHODS 
 
Research team. The research team will consist of Dr. Yoon (PI) and a number of collaborators from 
UTHealth and Brown University. Dr. Yoon (PI) is an experienced addiction researcher and an expert in 
assessing behavioral economic measures in addiction research, which is pertinent to the current project. Drs. 
Weaver (CNRA Medical Director) and Lin (Addictions Psychiatrist) will provide medical guidance and ensure 
participant safety over the course of the study. Dr. Lane is Professor and Vice Chair for Research and directs 
the Behavioral Laboratory at the CNRA with expertise in medication development trials as well as alcohol 
studies. Dr. Suchting is a biostatistician and data scientist with expertise in experimental design and statistical 
modeling, including the type of generalized linear modeling that will be utilized by the present research. From 
Brown University, Dr. Haas-Koffler (Co-I) is serving as a consultant on this project and is an expert in stress 
and alcohol research1–7. Additionally, our group has a history of collaborating with the Laboratory of 
Biomarkers located in the BBSB for analyzing biological samples, such as salivary cortisol in the current 
protocol. We will work with Dr. Fries to ensure that samples are collected and analyzed appropriately. 
 
Overall study design. We will utilize a within-subject, repeated measures design. Participants will 
receive pioglitazone or placebo for four weeks. A summary of the study timeline, procedures, and assessments 
is shown in the following Table. 
Table 1. Outline of Study Timeline, Procedures, and Assessments 
Study Week 
Procedures and Assessments 
0 
1 
2 
3 
4 
Consent and Baseline Screening 
SCID, ASI, KMSK, TLFB, CIWAA, AUDIT 
X 
Receive Study Medication (Pioglitazone or Placebo) 
Assess Medication Compliance and Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Human Laboratory Procedures (Specific Aim 1) 
Stress-Reactivity Assessment (Salivary Cortisol, HR, BP, Craving) 
Alcohol Demand, Alcohol Ladder 
X 
X 
X 
X 
Natural Environment Procedures (Specific Aim 2) 
Alcohol Use and Craving (Self-Report, BrAC, ETG, PACS) 
Stress and Anxiety (HAM-A, PSS, BDI-II, PCL-5) 
Delay Discounting, Alcohol Demand 
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 Index49; KMSK - Kreek-McHugh-Schluger- 
Kellogg scale50; TLFB - Timeline Followback51; CIWAA - Clinical Institute Withdrawal Assessment for Alcohol52; 
AUDIT – Alcohol Use Identification Test53; BrAC – Breath Alcohol Concentration; ETG – Ethyl Glucuronide; PACS 
– Pennsylvania Alcohol Craving Scale54; HR – Heart Rate; BP – Blood Pressure; HAM-A – Hamilton Anxiety Rating 
Scale55; PSS – Perceived Stress Scale56; PCL-5 - PTSD Checklist for DSM-5; BDI-II – Beck Depression Inventory - 
II. 
 
Participants, Recruitment, and Setting. Participants (N=20) will consist of non-treatment and 
treatment-seeking individuals diagnosed with AUD (DSM-5) between 21 to 40 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)14; baseline HAM-A or PSS Score indicative of mild to moderate anxiety 
(score 8 to 23) or moderate stress (score 14 to 26), respectively; and increase in alcoIhRoBl NcrUaMviBnEgRfo: HlloSwC-iMngS-t1h8e-0922 


IRB NUMBER: HSC-MS-18-0922 
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baseline stress reactivity assessment. Individuals will be excluded for exhibiting severe scores on the HAM-A, 
PSS, BDI-II, or PTSD checklist (PCL-5) at the discretion of the admitting physician (Dr. Weaver); physical 
dependence on alcohol; greater than mild substance use disorder on drugs other than alcohol, nicotine, and 
marijuana; contraindications for taking pioglitazone; medical conditions contraindicating pioglitazone 
pharmacotherapy or taking contraindicated medications; be pregnant, nursing, or planning on becoming 
pregnant during the course of the study; 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. 
Recruitment strategies will include local advertising in print media, public service announcements on radio, 
and referrals to CNRA in the Houston metropolitan area. 
 
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 urine pregnancy test), and ECG.  Clinicians will conduct the 
SCID, the ASI ASI49, the KMSK50 assessment of lifetime substance use interview, and TLFB51. Alcohol 
dependence will be assessed using the SCID and the CIWAA52. 
 
Alcohol-Related Measures. Assessment of alcohol use will include self-report (TLFB), BrAC (Alco- 
Sensor FST, Intoximeters, Inc., Saint Louis, MO). Severity of alcohol use will be assessed using the AUDIT53. 
Motivation to quit will be assessed using the Alcohol Ladder questionnaire. Alcohol craving will be 
assessed using a 5-item questionnaire57. ETG will be assessed using dipcards with a 300 ng/ml cutoff. ETG 
dipcards show good agreement with traditional immunoassays58–60. 
 
Behavioral Economic Measures. Alcohol demand will be assessed via the Brief Assessment of 
Alcohol Demand (BAAD)42, a 3-item questionnaire measuring the three most common indices of alcohol 
demand. Delay discounting will be assessed for both money and alcohol using a computerized task at weekly 
clinic visits developed by Dr. Yoon (PI)61,62,71,63–70. 
 
Stress and Anxiety Measures. Stress and anxiety levels will be assessed using the HAM-A55, PSS56, 
BDI-II, and the PCL-5. Established norms will be used for the HAM-A and PSS to assess mild to moderate 
stress and anxiety and screen out for cases of severe stress and anxiety. 
 
Stress Reactivity Measures. HR and BP 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. 
 
Study Medication. 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 properties72; and extensive research has shown it to be safe in human patient populations73,74 . The 
medication schedule is based on previous work from our group showing that a daily dose of 45mg was 
associated with acceptable levels of tolerability, safety, and compliance in a study assessing the effects of 
pioglitazone on individuals with CUD and AUD27. Our pilot trial used a conservative 2-week dose titration 
schedule (i.e., Week 1: 15 mg/d; Week 2: 30 mg/d), with no adverse effects reported or observed. For the 
current trial we will follow recommended adult initial dosing at 30 mg/d to reach maintenance dose of 45 mg/d 
by week 2, which is within standard titration parameters as per the investigator’s brochure. 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 


IRB NUMBER: HSC-MS-18-0922 
IRB APPROVAL DATE: 05/08/2019 
 
women). Monitoring of weight to capture potential fluid retention will occur at each visit along with an adverse 
event assessment to include assessment for edema. Blood will be drawn at the end of the study for liver 
function testing. Female subjects must agree to use an effective barrier method of birth control and urine 
pregnancy tests will be performed at each visit to minimize risk of pregnancy. 
 
Medication Compliance. One week supplies of the study medication will be dispensed with a 
Medication Event Monitoring System (MEMS) cap to record the number of bottle openings and date/time of 
each opening. Riboflavin will be added to medication capsules and urine ultraviolet fluorescent tests will be 
conducted at weekly clinic visits to assess compliance. Participants will receive $10 at each clinic visit in which 
results from self-report, MEMS, and riboflavin are all consistent with medication compliance. 
 
 
Human Laboratory Procedures (Specific Aim 1). On Study Weeks 0 and 4, participants will engage 
in the 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 body75–78. HPA-axis activation during the CPT can be increased by 
incorporating a social evaluative component. Specifically, a study 
member of the opposite sex of the study participant will dress in a 
white labcoat and be physically present during the CPT. Additionally, 
participants will be videotaped and informed that their facial 
expressions will be assessed during the CPT. The addition of the social 
component during the CPT has been demonstrated to selectively 
activate the HPA-axis and significantly increase salivary cortisol 
levels77. During the CPT, participants will submerge their dominant 
arm in an ice-water bath for up to 2 minutes. Stress levels will be 
assessed using subjective and physiological measures HR, BP, and 
salivary cortisol consistent with previous studies from our group79,80. 
Alcohol craving will be assessed using a 4-item questionnaire57. 
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 
 
Natural Environment Procedures (Specific Aim 2). At Study Week 0, all participants will receive a 
pamphlet copy of the “Rethinking Drinking: Alcohol and Your Health” providing research-based information 
related to alcohol use (RethinkingDrinking.niaaa.nih.gov). Research staff will go over the pamphlet’s 
information with the participant at the initial visit and subsequent visits as necessary. At each study visit, 
participants will receive study medication for the week and assessed for adverse events and medication 
compliance. 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, participants will be referred 
to local alcohol treatment services as needed. 
 
Participant Payment & Compensation. Participants will receive be able to receive $300 for 
completing the study ($50 for completing baseline screening; $25 for each visit ($100); $25 for stress reactivity 
assessments ($50); and $100 completion bonus). Additionally, participants will potentially receive $10/week 
(up to $40) for demonstrating medication compliance. Participants will also receive parking/bus fare 
compensation at each visit worth $5. 
 
DATA ANALYSIS PLAN 
General Data Analytic Strategy. Analyses will proceed in parallel using frequentist and Bayesian 
statistical inference. Frequentist analyses will examine relationships between predictors and outcomes using 
traditional measures of effect size and statistical significance (i.e., regression coefficients, standard errors, 


IRB NUMBER: HSC-MS-18-0922 
IRB APPROVAL DATE: 05/08/2019 
 
confidence intervals, and p-values), while Bayesian analyses will measure uncertainty in model parameter 
estimates via posterior distributions and directly evaluate the probability of the alternative hypothesis. 
 
Specific Aim 1: assess pre- to post-treatment reductions in stress reactivity (self-report, salivary cortisol, 
heart rate, blood pressure) and stress-induced alcohol craving (self-report, alcohol demand) in the human 
laboratory setting. 
Hypothesis 1: We will observe pre- to post- treatment reductions in stress reactivity and stress-induced 
alcohol craving. Generalized linear mixed modeling will be used to evaluate each outcome as a function of 
time (pre-test and post-test) in unique models. 
 
Specific Aim 2: Demonstrate reduced alcohol drinking (drinks per day, heavy drinking days), stress/anxiety 
(PSS, HAMA, PCL-5), and alcohol craving (PACS, delay discounting, alcohol demand) during treatment in the 
natural environmental setting. 
Hypothesis 2: We will observe decreased alcohol drinking, stress/anxiety, and alcohol craving over the 
course of treatment. Generalized linear mixed modeling will be used to evaluate each outcome as a function 
of time in unique models. Alcohol consumption will be modeled via drinks per drinking day, such that the 
number of positive drinking episodes a participant experienced in a week will be included as a count outcome 
(i.e., Poisson-distributed) and the number of drinking days in a week will be controlled for as an off-set 
covariate. 
 
Power/Sample Size Considerations. The frequentist framework using null hypothesis statistical 
testing can provide some understanding of changes over time for each outcome. However, in evaluating a small 
within-subjects pilot trial of N = 20 participants, Bayesian statistical inference provides a superior framework 
for deriving evidence regarding the magnitude and direction of change over time for each model. The posterior 
probability of each effect would then be useful to inform effect sizes for power calculations and/or prior 
distributions in future research. As due diligence, however, a conventional frequentist power analysis follows. 
For the current proposal, power estimates are calculated using G*Power 3.1.9.2 and focus on reduction in 
alcohol consumption. Assuming alpha = 0.05 (one-tailed), an average baseline rate of 10.5 drinks/week across 
all participants (averaged between 14 and 7 drinks/week for male and female participants, respectively), a 
sample size of N = 20 participants provides 80% power to detect a 20% decrease in alcohol consumption over 
five weeks. 


IRB APPROVAL DATE: 05/08/2019 
 
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