Clinical trial NCT03060772: A Study of Pleiotropic Pioglitazone Effects on the Alcoholic Lung (APPEAL Study)
Official title: A Study of Pleiotropic Pioglitazone Effects on the Alcoholic Lung (APPEAL Study)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Alcoholism
Keywords: Pulmonary Medicine
Oxidative Stress
Pioglitazone
Immunology
Addictive/Compulsive Behavior
Lead sponsor: Emory University
Sponsor class: OTHER
Collaborators: name: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
First posted: 2017-02-23
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Individuals with alcohol use disorder will be randomized to receive the study medication, pioglitazone, or no medication (12 in each group). A third group of healthy individuals who do not have an alcohol use disorder will also be enrolled to serve as an additional comparison group.
Primary purpose: TREATMENT

Brief summary: This study is a single center, open-label, randomized clinical trial to determine the effect of pioglitazone (PIO) treatment on alveolar macrophage immune function, redox stress, and NADPH oxidase expression in outpatient alcoholic subjects. The researchers will recruit a cohort of otherwise healthy patients with an alcoholic use disorder from the Substance Abuse Treatment Program at the Atlanta Veterans Affairs (VA) Medical Center and randomize them to receive the usual treatment for two to four weeks or to the usual treatment plus PIO treatment for two to four weeks. There will also be a healthy control group (matched on age, gender, and smoking status) that will receive no treatment. To measure the effect of pioglitazone, participants will undergo a bronchoscopy before taking the study drug and then again 2-4 weeks later to look for changes. The bronchoscopy will allow researchers to obtain fluid from the lungs to see how well their immune cells respond to bacteria by determining phagocytic capacity.

Detailed description: Alcohol abuse is a major burden on society and an enormous problem in the veteran population. Many people are aware that chronic alcohol ingestion can cause serious health problems like liver injury and brain damage but chronic alcohol consumption can also hurt the lungs. People who regularly drink more than the daily maximum levels recommended by the Centers for Disease Control and Prevention (CDC) (1 drink per day for women or 2 drinks per day for men) are more likely to suffer from pneumonia and acute lung injuries.

The primary goal of this clinical research study is to determine if a Food and Drug Administration (FDA) approved diabetes drug, called pioglitazone, can improve the lung immune defenses in otherwise healthy alcoholics. There is strong evidence from experimental animal models that pioglitazone preserves lung health even during daily alcohol ingestion.

This National Institutes of Health (NIH) funded project will recruit veterans who are patients at the Atlanta VA Hospital. Half of the participants will be randomly assigned to receive pioglitazone and half will be assigned to receive no treatment. Participants assigned to pioglitazone will take the pill once per day for two to four weeks. To measure the effect of pioglitazone, participants will undergo a procedure called a bronchoscopy before taking the study drug and then again 2-4 weeks later to look for changes. The bronchoscopy will allow researchers to obtain fluid from the lungs to see how well their immune cells respond to bacteria (by determining phagocytic capacity). The researchers also plan to enroll 12 healthy veteran patients who do not drink. These participants will undergo a one-time bronchoscopy and no other visits will be required of them.

The findings from this study will guide future, larger scale clinical trials to determine if pioglitazone can be used in the clinical setting to improve outcomes in alcoholics who develop pneumonia or acute lung injury.

Eligibility criteria: Inclusion Criteria:

* Active alcohol use disorder, with last alcoholic drink within 8 days of randomization (for those in the alcohol use disorder arms)

Exclusion Criteria:

* History of diabetes
* History of heart failure
* History of cirrhosis of the liver
* Elevation of liver enzymes greater than 2.5 times upper limit of normal
* History of bladder cancer
* Primary substance of abuse is something other than alcohol
* Current abnormal chest x-ray or other evidence of significant lung disease
* HIV-positive
* Renal impairment, defined as glomerular filtration rate (GFR) \<60
* Current pregnancy or planning to become pregnant in the next 6 months
* Currently on pioglitazone treatment for another reason
* Contraindication to treatment with pioglitazone
* Any active and uncontrolled medical problem that may negatively impact the study results
* Currently on an oral steroid or inhaled corticosteroid
* History of profound psychiatric problems, poor compliance, or other psycho-social issues that may negatively impact participation
* Inability to give informed consent (i.e., limited cognitive capacity)
* Non-English speaking

Primary outcomes:
measure: Change in phagocytic index
timeFrame: Baseline, After 2-4 weeks
Secondary outcomes:
measure: Change in nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase)
timeFrame: Baseline, After 2-4 weeks
measure: Change in alveolar macrophage oxidative stress
timeFrame: Baseline, After 2-4 weeks
measure: Change in redox couple glutathione/glutathione disulfide (GSH/GSSG)
timeFrame: Baseline, After 2-4 weeks
measure: Change in cysteine/cystine (Cys/CySS) redox potential
timeFrame: Baseline, After 2-4 weeks
measure: Comparison of nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase)
timeFrame: Baseline (control group), After 2-4 weeks (treatment group)
measure: Comparison of alveolar macrophage oxidative stress
timeFrame: Baseline (control group), After 2-4 weeks (treatment group)
measure: Comparison of redox couple glutathione/glutathione disulfide (GSH/GSSG)
timeFrame: Baseline (control group), After 2-4 weeks (treatment group)
measure: Comparison of cysteine/cystine (Cys/CySS) redox potential
timeFrame: Baseline (control group), After 2-4 weeks (treatment group)
Other outcomes:
Locations:
city: Decatur
country: United States
facility: Atlanta VA Medical Center
state: Georgia
Study officials:
affiliation: Emory University
name: David Guidot, MD
role: PRINCIPAL_INVESTIGATOR
References: