AlcoholismPhase 2APPEALNCT03060772
A Study of Pleiotropic Pioglitazone Effects on the Alcoholic Lung (APPEAL Study)
A Phase 2 study testing Pioglitazone in people with Alcoholism, run by Emory University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 60 yearsHealthy volunteers can take part
- Conditions the study is for
- Alcoholism
- What is being tested?
- Pioglitazone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 50 participants
- Where
- 1 siteUnited States
- Study dates
- 3 Jan 2018to 28 Jan 2020
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Active alcohol use disorder, with last alcoholic drink within 8 days of randomization (for those in the alcohol use disorder arms)
Who cannot join
- 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
Show all 17Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the 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.
- Conditions
- Alcoholism
- Being tested
- Pioglitazone
- Keywords
- Pulmonary Medicine, Oxidative Stress, Pioglitazone, Immunology, Addictive/Compulsive Behavior
- Medical subject headings
- Alcoholism, Compulsive Behavior
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PioglitazoneDrug
Also called Actos
Participants will take 30 mg of pioglitazone once daily for a total of two to four weeks for those randomized to therapy, until the next bronchoscopy is performed. Participants will receive 14 to 28 tablets of active pioglitazone, which is enough to complete the minimum 14-day course of therapy.
| Study group | Role | What they receive |
|---|---|---|
| Alcohol use disorder - Pioglitazone Treatment | Experimental | Participants with alcohol use disorder randomized to this group will receive pioglitazone. Study procedures include a bronchoscopy at baseline and an additional bronchoscopy after taking the study medication for 2 to 4 weeks. Receives: Drug: Pioglitazone |
| Alcohol use disorder - No Pioglitazone | No intervention | Participants with alcohol use disorder randomized to this group will receive their usual care but will not receive pioglitazone. Study procedures include a bronchoscopy at baseline and an additional bronchoscopy 2 to 4 weeks later. |
| Healthy controls without alcohol use disorder | No intervention | Healthy individuals who do not have alcohol use disorder will be enrolled will serve as a control group. Healthy controls will be a matched to participants receiving the treatment based on age, gender, and smoking status. This group will have a single bronchoscopy. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in phagocytic index
The change in phagocytic index will be determined between the alcohol use disorder study arms to examine the effect of PIO treatment. Phagocytic index of the alveolar macrophage is the rate at which particles are cleared from a culture. The phagocytic index is a well-established marker of immune function and its improvement with pioglitazone (PIO) treatment would indicate reversal of the alcoholic lung phenotype. The phagocytic index will be measured in bronchoalveolar lavage (BAL) fluids.
Measured: Baseline, After 2-4 weeks
Secondary outcomes (8)
Change in nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase)
The change in nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) will be determined between the alcohol use disorder study arms to examine the effect of PIO treatment. Nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) is an enzyme complex. NADPH oxidases are the primary sources of oxidative stress in the alveolar macrophage. Chronic alcohol consumption causes pulmonary oxidative stress via increased expression and activity of NADPH oxidases. NADPH oxidases will be measured in bronchoalveolar lavage (BAL) fluids.
Measured: Baseline, After 2-4 weeks
Change in alveolar macrophage oxidative stress
The change in alveolar macrophage oxidative stress will be determined between the alcohol use disorder study arms to examine the effect of PIO treatment. The alveolar macrophage plays a crucial role in lung immunity by protecting the individual from developing respiratory infections such as pneumonia. Alcohol-induced oxidative stress impairs the ability of the alveolar macrophage to function normally. A decrease in alveolar oxidative stress with pioglitazone treatment would indicate that the treatment is having a positive impact. This outcome will be measured in bronchoalveolar lavage (BAL) fluids.
Measured: Baseline, After 2-4 weeks
Change in redox couple glutathione/glutathione disulfide (GSH/GSSG)
The change in redox couple glutathione/glutathione disulfide (GSH/GSSG) will be determined between the alcohol use disorder study arms to examine the effect of PIO treatment. Glutathione (GSH)/glutathione disulfide (GSSG) is a redox (a chemical reaction) which is frequently measured as an indicator of oxidative stress. The antioxidant GSH reduces to GSSG and in a healthy state there is greater than 90% GSH to less than 10% GSSG. Chronic alcohol consumption causes pulmonary oxidative stress via decreased levels of GSH. GSH and GSSG will be measured in bronchoalveolar lavage (BAL) and exhaled breath condensate (EBC) fluids.
Measured: Baseline, After 2-4 weeks
Change in cysteine/cystine (Cys/CySS) redox potential
The change in cysteine/cystine (Cys/CySS) redox potential will be determined between the alcohol use disorder study arms to examine the effect of PIO treatment. Cysteine (Cys)/cystine (CySS) is a redox (a chemical reaction) regulating a variety of biological processes. CySS is the oxidized form of Cys and the ratio is sensitive to alcohol abuse, among other environmental exposures. Cys and CySS will be measured in bronchoalveolar lavage (BAL) and exhaled breath condensate (EBC) fluids.
Measured: Baseline, After 2-4 weeks
Comparison of nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase)
Nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) will be compared between the PIO treatment arm and the healthy control arm to determine if PIO treatment leads to normal function. Nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) is an enzyme complex. NADPH oxidases are the primary sources of oxidative stress in the alveolar macrophage. Chronic alcohol consumption causes pulmonary oxidative stress via increased expression and activity of NADPH oxidases. NADPH oxidases will be measured in bronchoalveolar lavage (BAL) fluids.
Measured: Baseline (control group), After 2-4 weeks (treatment group)
Comparison of alveolar macrophage oxidative stress
Alveolar macrophage oxidative stress will be compared between the PIO treatment arm and the healthy control arm to determine if PIO treatment leads to normal function. The alveolar macrophage plays a crucial role in lung immunity by protecting the individual from developing respiratory infections such as pneumonia. Alcohol-induced oxidative stress impairs the ability of the alveolar macrophage to function normally. A decrease in alveolar oxidative stress with pioglitazone treatment would indicate that the treatment is having a positive impact. This outcome will be measured in bronchoalveolar lavage (BAL) fluids.
Measured: Baseline (control group), After 2-4 weeks (treatment group)
Comparison of redox couple glutathione/glutathione disulfide (GSH/GSSG)
Redox couple glutathione/glutathione disulfide (GSH/GSSG) will be compared between the PIO treatment arm and the healthy control arm to determine if PIO treatment leads to normal function. Glutathione (GSH)/glutathione disulfide (GSSG) is a redox (a chemical reaction) which is frequently measured as an indicator of oxidative stress. The antioxidant GSH reduces to GSSG and in a healthy state there is greater than 90% GSH to less than 10% GSSG. Chronic alcohol consumption causes pulmonary oxidative stress via decreased levels of GSH. GSH and GSSG will be measured in bronchoalveolar lavage (BAL) and exhaled breath condensate (EBC) fluids.
Measured: Baseline (control group), After 2-4 weeks (treatment group)
Comparison of cysteine/cystine (Cys/CySS) redox potential
Cysteine/cystine (Cys/CySS) redox potential will be compared between the PIO treatment arm and the healthy control arm to determine if PIO treatment leads to normal function. Cysteine (Cys)/cystine (CySS) is a redox (a chemical reaction) regulating a variety of biological processes. CySS is the oxidized form of Cys and the ratio is sensitive to alcohol abuse, among other environmental exposures. Cys and CySS will be measured in bronchoalveolar lavage (BAL) and exhaled breath condensate (EBC) fluids.
Measured: Baseline (control group), After 2-4 weeks (treatment group)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Feb 2017
- Study start3 Jan 2018
- Primary completion28 Jan 2020
- Study completion28 Jan 2020
Why it stopped: Study was suspended in 2020 due to COVID-19 pandemic as a result of recruitment challenges and the inability to conduct all study procedures (e.g., bronchoscopy) per protocol. In late 2021 the decision was made to not re-open the study.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for AlcoholismStudies of the same condition, open and under way.
- More trials run by Emory UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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.
- Masking
- None (open label)
- Enrolment
- 50 participants (actual)
Sponsor and investigators
- Lead sponsor
- Emory University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Alcohol Abuse and Alcoholism (NIAAA)
- Responsible party
- Principal investigator, David M. Guidot, Emory University
- Investigators
- David Guidot, MD, Principal investigator, Emory University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03060772
- Sponsor's protocol ID
- IRB00071908
- Other IDs
- 1R01AA025857
- Acronym
- APPEAL
- Status last verified
- Feb 2023
- First submitted
- 19 Feb 2017
- Last updated
- 14 Feb 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Study of Pleiotropic Pioglitazone Effects on the Alcoholic Lung (APPEAL Study)
- ClinicalTrials.gov ID
- NCT03060772
- Acronym / sponsor ID
- APPEAL / IRB00071908
- Conditions
- Alcoholism
- Keywords
- Pulmonary Medicine, Oxidative Stress, Pioglitazone, Immunology, Addictive/Compulsive Behavior
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Study was suspended in 2020 due to COVID-19 pandemic as a result of recruitment challenges and the inability to conduct all study procedures (e.g., bronchoscopy) per protocol. In late 2021 the decision was made to not re-open the study.
- Enrolment
- 50 participants (actual)
- Lead sponsor
- Emory UniversityUniversity, hospital or other
- Collaborators
- National Institute on Alcohol Abuse and Alcoholism (NIAAA)
- Study start
- 3 Jan 2018 (actual)
- Primary completion
- 28 Jan 2020 (actual)
- Study completion
- 28 Jan 2020 (actual)
- First posted
- 23 Feb 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- 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.
| Arm | Type | Receives |
|---|---|---|
| Alcohol use disorder - Pioglitazone Treatment | Experimental | Drug: PioglitazoneParticipants with alcohol use disorder randomized to this group will receive pioglitazone. Study procedures include a bronchoscopy at baseline and an additional bronchoscopy after taking the study medication for 2 to 4 weeks. |
| Alcohol use disorder - No Pioglitazone | No intervention | –Participants with alcohol use disorder randomized to this group will receive their usual care but will not receive pioglitazone. Study procedures include a bronchoscopy at baseline and an additional bronchoscopy 2 to 4 weeks later. |
| Healthy controls without alcohol use disorder | No intervention | –Healthy individuals who do not have alcohol use disorder will be enrolled will serve as a control group. Healthy controls will be a matched to participants receiving the treatment based on age, gender, and smoking status. This group will have a single bronchoscopy. |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (1 listed)
- Active alcohol use disorder, with last alcoholic drink within 8 days of randomization (for those in the alcohol use disorder arms)
Key exclusion criteria (17 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PioglitazoneAlso: ActosParticipants will take 30 mg of pioglitazone once daily for a total of two to four weeks for those randomized to therapy, until the next bronchoscopy is performed. Participants will receive 14 to 28 tablets of active pioglitazone, which is enough to complete the minimum 14-day course of therapy. | Drug | Alcohol use disorder - Pioglitazone Treatment |
Primary outcome
Change in phagocytic index
Time frame: Baseline, After 2-4 weeks
The change in phagocytic index will be determined between the alcohol use disorder study arms to examine the effect of PIO treatment. Phagocytic index of the alveolar macrophage is the rate at which particles are cleared from a culture. The phagocytic index is a well-established marker of immune function and its improvement with pioglitazone (PIO) treatment would indicate reversal of the alcoholic lung phenotype. The phagocytic index will be measured in bronchoalveolar lavage (BAL) fluids.
8 secondary outcomes
Change in nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase)
Time frame: Baseline, After 2-4 weeks
Change in alveolar macrophage oxidative stress
Time frame: Baseline, After 2-4 weeks
Change in redox couple glutathione/glutathione disulfide (GSH/GSSG)
Time frame: Baseline, After 2-4 weeks
Change in cysteine/cystine (Cys/CySS) redox potential
Time frame: Baseline, After 2-4 weeks
Comparison of nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase)
Time frame: Baseline (control group), After 2-4 weeks (treatment group)
Comparison of alveolar macrophage oxidative stress
Time frame: Baseline (control group), After 2-4 weeks (treatment group)
Comparison of redox couple glutathione/glutathione disulfide (GSH/GSSG)
Time frame: Baseline (control group), After 2-4 weeks (treatment group)
Comparison of cysteine/cystine (Cys/CySS) redox potential
Time frame: Baseline (control group), After 2-4 weeks (treatment group)
Results and safety
The study was stopped early (reason given: Study was suspended in 2020 due to COVID-19 pandemic as a result of recruitment challenges and the inability to conduct all study procedures (e.g., bronchoscopy) per protocol. In late 2021 the decision was made to not re-open the study.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Feb 2023.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David Guidot, MD principal investigator
Emory University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Pioglitazone in people with Alcoholism, run by Emory University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 14 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Study was suspended in 2020 due to COVID-19 pandemic as a result of recruitment challenges and the inability to conduct all study procedures (e.g., bronchoscopy) per protocol. In late 2021 the decision was made to not re-open the study.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in phagocytic index (time frame: Baseline, After 2-4 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Feb 2023.