Pioglitazone for Lung Cancer Chemoprevention

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT00780234
• Collaborator: (none)
• Enrollment: 92
• Locations: 2
• Arms: 2
• Actual Duration (Months): 96
• Patients Per Site: 46
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This is a chemoprevention trial evaluating the diabetic agent pioglitazone. Non-diabetic subjects at risk for lung cancer (based on smoking history, lung function testing, and atypical cells in a sputum sample) receive either placebo or pioglitazone and have chest computerized tomography (CAT) scans and examinations of their airways with a bronchoscope at the start of the trial and after 6 months on treatment. Compensation will be provided to the subject after completing the trial.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer; Endobronchial Dysplasia	Procedure: fluorescence bronchoscopy; Procedure: quantitative high resolution CT scan; Drug: PIOGLITAZONE VS. PLACEBO 30 mg	Phase 2

Detailed Description

This trial evaluates the oral peroxisome proliferator-activated receptor gamma (PPARgamma) agonist pioglitazone in a double-blind placebo controlled trial. The high risk current and former smokers qualify based on tobacco exposure, airflow limitation on lung function testing, and sputum cytologic atypia. Subjects have a quantitative high resolution thoracic CT scan and a fluorescent bronchoscopy at study entry and after 6 months on drug or placebo. Biologic samples are collected at both time points. The primary outcome is endobronchial histology and determining if pioglitazone can retard progression. Secondary endpoints related to the PPAR gamma signaling pathway will also be analyzed.

Study Design

• Study Type: Interventional
• Actual Enrollment: 92 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Pioglitazone for Lung Cancer Chemoprevention
• Actual Study Start Date: Aug 1, 2009
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Aug 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1: pioglitazone Current or former smokers receive 6 months of treatment with pioglitazone	Procedure: fluorescence bronchoscopy; examination of the central airways with a bronchoscope. Both white light and fluorescent light will be used.; Procedure: quantitative high resolution CT scan; High resolution CT scan of the chest; Drug: PIOGLITAZONE VS. PLACEBO 30 mg; Patients will be randomized to receive either pioglitazone or placebo. Pioglitazone hydrochloride, a thiazolidinedione antidiabetic agent and a potent peroxisome proliferator- activated receptor-gamma agonist. It is FDA approved for the treatment of Type II diabetes. It has been previously administered to non-diabetic subjects. The most common side effect of pioglitazone is fluid retention and modest weight gain. There is a potential risk that pioglitazone may cause an elevation in liver enzymes and more serious hepatotoxicity (rare). There is risk of edema and weight gain associated with pioglitazone therapy. 5% experienced peripheral edema in clinical trials. fluid retention may result in new onset heart failure or exacerbation of existing heart failure. Small risk of hypoglycemia, anemia, myalgia, bone fracture, headache, and macular retinal edema exists. There is insufficient information to confirm its safety in Pregnancy/Breastfeeding. Bladder cancer is more serious but rare.
Placebo Comparator: Arm 2: placebo Current or former smokers receive 6 months of treatment with placebo	Procedure: fluorescence bronchoscopy; examination of the central airways with a bronchoscope. Both white light and fluorescent light will be used.; Procedure: quantitative high resolution CT scan; High resolution CT scan of the chest

Outcome Measures

Primary Outcome Measures

1. 6-month Histology Score [6 months]

   Biopsies were classified into one of the following 8 World Health Organization defined categories to classify the endobronchial lesion and assign a score according to the following scale: 1 = normal bronchial epithelium; 2 = reserve cell hyperplasia; 3 = squamous metaplasia without atypia; 4 = mild dysplasia; 5 = moderate dysplasia; 6 = severe dysplasia; 7 = carcinoma in situ (CIS); and 8 = invasive carcinoma. 1 represents the best outcome and 8 represents the worst outcome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Current or former smoker (at least 10 pack years);

• One or more of the following:

• Mild or worse sputum atypia

• Airflow Limitation (FEV1/FVC<70% predicted)

• Biopsy proven airway dysplasia

Exclusion Criteria:

• myocardial infarction (MI) with ejection fraction < 50%;

• severe/unstable angina;

• history of coronary or peripheral arterial bypass grafting;

• New York Heart Association (NYHA) class III or IV congestive heart failure;

• hypoxemia (less than POX 90 with supplemental oxygen); Diabetes type I or II; severe COPD (GOLD stage III or IV); clinically significant edema requiring diuretic therapy;

• life expectancy < 6 months; history of bladder cancer

• pregnant or breast feeding; inability to give informed consent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Eastern Colorado Health Care System, Denver, CO	Denver	Colorado	United States	80220
2	Tennessee Valley Healthcare System Nashville Campus, Nashville, TN	Nashville	Tennessee	United States	37212-2637

Sponsors and Collaborators

• VA Office of Research and Development

Investigators

• Principal Investigator: Robert L. Keith, MD, VA Eastern Colorado Health Care System, Denver, CO

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Oral iloprost improves endobronchial dysplasia in former smokers

Publications

None provided.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT00780234
• Other Study ID Numbers: CLIN-005-08S
• First Posted: Oct 27, 2008
• Last Update Posted: Apr 11, 2019
• Last Verified: Apr 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by VA Office of Research and Development: chemoprevention; lung cancer; pioglitazone
• Additional relevant MeSH terms: Lung Neoplasms; Pioglitazone

Study Results

Participant Flow

Recruitment Details	243 subjects were consented to provide a pre-screening sputum cytology specimen, and of those, 92 enrolled onto full trial.
Pre-assignment Detail	243 subjects were consented to provide a pre-screening sputum cytology specimen, and of those, 92 enrolled onto full trial.

Arm/Group Title	Arm 1: Pioglitazone	Arm 2: Placebo
Arm/Group Description	Current or former smokers receive 6 months of treatment with pioglitazone. fluorescence bronchoscopy: examination of the central airways with a bronchoscope. Both white light and fluorescent light. quantitative high resolution CT scan: High resolution chest CT scan PIOGLITAZONE VS. PLACEBO 30 mg: Patients will be randomized to receive either pioglitazone or placebo. Pioglitazone hydrochloride, a thiazolidinedione antidiabetic agent and a potent peroxisome proliferator- activated receptor-gamma agonist.	Current or former smokers receive 6 months of treatment with placebo fluorescence bronchoscopy: examination of the central airways with a bronchoscope. Both white light and fluorescent light will be used. quantitative high resolution CT scan: High resolution CT scan of the chest
Period Title: Overall Study
STARTED	47	45
COMPLETED	39	37
NOT COMPLETED	8	8

Baseline Characteristics

Arm/Group Title	Arm 1: Pioglitazone	Arm 2: Placebo	Total
Arm/Group Description	Current or former smokers receive 6 months of treatment with pioglitazone fluorescence bronchoscopy: examination of the central airways with a bronchoscope. Both white light and fluorescent light will be used. quantitative high resolution CT scan: High resolution CT scan of the chest PIOGLITAZONE VS. PLACEBO 30 mg: Patients will be randomized to receive either pioglitazone or placebo. Pioglitazone hydrochloride, a thiazolidinedione antidiabetic agent and a potent peroxisome proliferator- activated receptor-gamma agonist. It is FDA approved for the treatment of Type II diabetes. It has been previously administered to non-diabetic subjects. The most common side effect of pioglitazone is fluid retention and modest weight gain. There is a potential risk that pioglitazone may cause an elevation in liver enzymes and more serious hepatotoxicity (rare). There is risk of edema and weight gain associated with pioglitazone therapy. 5% experienced peripheral edema in clinical trials.	Current or former smokers receive 6 months of treatment with placebo fluorescence bronchoscopy: examination of the central airways with a bronchoscope. Both white light and fluorescent light will be used. quantitative high resolution CT scan: High resolution CT scan of the chest	Total of all reporting groups
Overall Participants	47	45	92
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.6 (9.6)	62.6 (8.2)	60.5 (9.1)
Sex: Female, Male (Count of Participants)
Female	8 17%	7 15.6%	15 16.3%
Male	39 83%	38 84.4%	77 83.7%
Race/Ethnicity, Customized (Count of Participants)
Hispanic	4 8.5%	2 4.4%	6 6.5%
Non-Hispanic White	41 87.2%	36 80%	77 83.7%
Non-Hispanic Black	2 4.3%	6 13.3%	8 8.7%
Non-Hispanic American Indian	0 0%	1 2.2%	1 1.1%

Outcome Measures

1. Primary Outcome

Title	6-month Histology Score
Description	Biopsies were classified into one of the following 8 World Health Organization defined categories to classify the endobronchial lesion and assign a score according to the following scale: 1 = normal bronchial epithelium; 2 = reserve cell hyperplasia; 3 = squamous metaplasia without atypia; 4 = mild dysplasia; 5 = moderate dysplasia; 6 = severe dysplasia; 7 = carcinoma in situ (CIS); and 8 = invasive carcinoma. 1 represents the best outcome and 8 represents the worst outcome.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Although 76 subjects had a 6-month bronchoscopy (39 pioglitazone, 37 placebo), only 64 subjects (34 pioglitazone, 30 placebo) had matched biopsy pairs with non-normal tissue at baseline. Of these 64, 29 were former smokers (15 pioglitazone, 14 placebo), which was the a priori group for the primary analysis.

Arm/Group Title	Arm 1: Pioglitazone	Arm 2: Placebo
Arm/Group Description	Current or former smokers receive 6 months of treatment with pioglitazone fluorescence bronchoscopy: examination of the central airways with a bronchoscope. Both white light and fluorescent light will be used. quantitative high resolution CT scan: High resolution CT scan of the chest PIOGLITAZONE VS. PLACEBO 30 mg: Patients will be randomized to receive either pioglitazone or placebo. Pioglitazone hydrochloride, a thiazolidinedione antidiabetic agent and a potent peroxisome proliferator- activated receptor-gamma agonist. It is FDA approved for the treatment of Type II diabetes. It has been previously administered to non-diabetic subjects. The most common side effect of pioglitazone is fluid retention and modest weight gain. There is a potential risk that pioglitazone may cause an elevation in liver enzymes and more serious hepatotoxicity (rare). There is risk of edema and weight gain associated with pioglitazone therapy. 5% experienced peripheral edema in clinical trials.	Current or former smokers receive 6 months of treatment with placebo fluorescence bronchoscopy: examination of the central airways with a bronchoscope. Both white light and fluorescent light will be used. quantitative high resolution CT scan: High resolution CT scan of the chest
Measure Participants	15	14
Mean (Standard Deviation) [Units on a scale]	3.07 (2.02)	3.71 (2.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Pioglitazone, Arm 2: Placebo
	Comments	The hypotheses tested were: H0: α1 = 0 vs H1: α1 ~= 0
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.53
	Comments
	Method	Regression, Linear
	Comments	The estimates of treatment effect were adjusted for baseline histology values.
Method of Estimation	Estimation Parameter	Regression model parameter (α1)
	Estimated Value	-0.40
	Confidence Interval	(2-Sided) 95%; -1.68 to 0.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.63
	Estimation Comments
Other Statistical Analysis		The hypothesis test was a 2-sided t-test of the effect of group (i.e. the difference between the pioglitazone and placebo groups). The general form of the model is Y = α0 + α1GROUP + α2BASELINE. Y represents the 6-month value of the dependent variable (summary of the histology), GROUP represents a classification variable for the treatment group (1=pioglitazone, 2=placebo), BASELINE represents the value of the outcome measure at baseline, and α0, α1 and α2 represent the parameter estimates from the general linear model. The test of the difference between groups will be the formal test of significance of the α1 parameter.

Adverse Events

Time Frame	4 years, 11 months
Arm/Group Title	Arm 1: Pioglitazone		Arm 2: Placebo
Arm/Group Description	Current or former smokers receive 6 months of treatment with pioglitazone fluorescence bronchoscopy: examination of the central airways with a bronchoscope. Both white light and fluorescent light will be used. quantitative high resolution CT scan: High resolution CT scan of the chest PIOGLITAZONE VS. PLACEBO 30 mg: Patients will be randomized to receive either pioglitazone or placebo. Pioglitazone hydrochloride, a thiazolidinedione antidiabetic agent and a potent peroxisome proliferator- activated receptor-gamma agonist. It is FDA approved for the treatment of Type II diabetes. It has been previously administered to non-diabetic subjects. The most common side effect of pioglitazone is fluid retention and modest weight gain. There is a potential risk that pioglitazone may cause an elevation in liver enzymes and more serious hepatotoxicity (rare). There is risk of edema and weight gain associated with pioglitazone therapy. 5% experienced peripheral edema in clinical trials.		Current or former smokers receive 6 months of treatment with placebo fluorescence bronchoscopy: examination of the central airways with a bronchoscope. Both white light and fluorescent light will be used. quantitative high resolution CT scan: High resolution CT scan of the chest
All Cause Mortality
	Arm 1: Pioglitazone		Arm 2: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/47 (2.1%)		0/45 (0%)
Serious Adverse Events
	Arm 1: Pioglitazone		Arm 2: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/47 (6.4%)		5/45 (11.1%)
Cardiac disorders
Atrial Fibrillation	1/47 (2.1%)	1	0/45 (0%)	0
Heart Failure	0/47 (0%)	0	1/45 (2.2%)	1
Hypertension	0/47 (0%)	0	1/45 (2.2%)	1
General disorders
Edema Limbs	0/47 (0%)	0	1/45 (2.2%)	1
Fever	0/47 (0%)	0	1/45 (2.2%)	1
Investigations
Weight Gain	0/47 (0%)	0	1/45 (2.2%)	1
Metabolism and nutrition disorders
Alcohol Intolerance	1/47 (2.1%)	1	0/45 (0%)	0
Nervous system disorders
Syncope	0/47 (0%)	0	1/45 (2.2%)	1
Psychiatric disorders
Depression	1/47 (2.1%)	1	0/45 (0%)	0
Suicidal Ideation	1/47 (2.1%)	1	0/45 (0%)	0
Respiratory, thoracic and mediastinal disorders
Bronchial Infection	1/47 (2.1%)	1	0/45 (0%)	0
Pleuritic Pain	0/47 (0%)	0	1/45 (2.2%)	1
Pneumonitis	0/47 (0%)	0	2/45 (4.4%)	2
Wheezing	0/47 (0%)	0	1/45 (2.2%)	1
Skin and subcutaneous tissue disorders
Skin Infection	0/47 (0%)	0	1/45 (2.2%)	1
Other (Not Including Serious) Adverse Events
	Arm 1: Pioglitazone		Arm 2: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	44/47 (93.6%)		41/45 (91.1%)
Blood and lymphatic system disorders
Anemia	11/47 (23.4%)		9/45 (20%)
Cardiac disorders
Hypertension	24/47 (51.1%)		21/45 (46.7%)
Sinus Tachycardia	5/47 (10.6%)		4/45 (8.9%)
Gastrointestinal disorders
Vomiting	3/47 (6.4%)		2/45 (4.4%)
General disorders
Edema Limbs	6/47 (12.8%)		11/45 (24.4%)
Non-Cardiac Chest Pain	4/47 (8.5%)		2/45 (4.4%)
Fever	2/47 (4.3%)		4/45 (8.9%)
Fatigue	2/47 (4.3%)		3/45 (6.7%)
Investigations
Weight Gain	20/47 (42.6%)		10/45 (22.2%)
Aspartate Aminotransferase Increased	11/47 (23.4%)		8/45 (17.8%)
GGT Increased	4/47 (8.5%)		7/45 (15.6%)
Alanine Aminotransferase Increased	6/47 (12.8%)		4/45 (8.9%)
White Blood Cell Decreased	6/47 (12.8%)		3/45 (6.7%)
Platelet Count Decreased	2/47 (4.3%)		4/45 (8.9%)
Alkaline Phosphatase Increased	2/47 (4.3%)		3/45 (6.7%)
Metabolism and nutrition disorders
Hypophosphatemia	22/47 (46.8%)		28/45 (62.2%)
Hypocalcemia	13/47 (27.7%)		9/45 (20%)
Hyperglycemia	4/47 (8.5%)		12/45 (26.7%)
Hypoglycemia	8/47 (17%)		3/45 (6.7%)
Hypokalemia	2/47 (4.3%)		5/45 (11.1%)
Hypoalbuminemia	1/47 (2.1%)		3/45 (6.7%)
Hyperkalemia	3/47 (6.4%)		0/45 (0%)
Musculoskeletal and connective tissue disorders
Myalgia	3/47 (6.4%)		1/45 (2.2%)
Nervous system disorders
Dizziness	4/47 (8.5%)		0/45 (0%)
Respiratory, thoracic and mediastinal disorders
Bronchial Infection	6/47 (12.8%)		4/45 (8.9%)
Cough	5/47 (10.6%)		5/45 (11.1%)
Productive Cough	5/47 (10.6%)		4/45 (8.9%)
Sore Throat	4/47 (8.5%)		2/45 (4.4%)
Dyspnea	2/47 (4.3%)		4/45 (8.9%)
Wheezing	3/47 (6.4%)		2/45 (4.4%)
Allergic Rhinitis	3/47 (6.4%)		1/45 (2.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.