Endobronchial Dysplasia, Lung Cancer
Conditions
Keywords
chemoprevention, lung cancer, pioglitazone
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.
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.
Interventions
PROCEDUREfluorescence bronchoscopy
examination of the central airways with a bronchoscope. Both white light and fluorescent light will be used.
PROCEDUREquantitative high resolution CT scan
High resolution CT scan of the chest
DRUGPIOGLITAZONE 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.
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
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 details
243 subjects were consented to provide a pre-screening sputum cytology specimen, and of those, 92 enrolled onto full trial.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Pioglitazone 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. | 47 |
| Arm 2: Placebo 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 | 45 |
| Total | 92 |
Baseline characteristics
| Characteristic | Arm 1: Pioglitazone | Arm 2: Placebo | Total |
|---|---|---|---|
| Age, Continuous | 58.6 years STANDARD_DEVIATION 9.6 | 62.6 years STANDARD_DEVIATION 8.2 | 60.5 years STANDARD_DEVIATION 9.1 |
| Race/Ethnicity, Customized Ethnicity/Race Hispanic | 4 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Ethnicity/Race Non-Hispanic American Indian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnicity/Race Non-Hispanic Black | 2 Participants | 6 Participants | 8 Participants |
| Race/Ethnicity, Customized Ethnicity/Race Non-Hispanic White | 41 Participants | 36 Participants | 77 Participants |
| Sex: Female, Male Female | 8 Participants | 7 Participants | 15 Participants |
| Sex: Female, Male Male | 39 Participants | 38 Participants | 77 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 47 | 0 / 45 |
| other Total, other adverse events | 44 / 47 | 41 / 45 |
| serious Total, serious adverse events | 3 / 47 | 5 / 45 |
Outcome results
Primary
6-month Histology Score
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Pioglitazone | 6-month Histology Score | 3.07 Units on a scale | Standard Deviation 2.02 |
| Arm 2: Placebo | 6-month Histology Score | 3.71 Units on a scale | Standard Deviation 2.02 |
Comparison: The hypotheses tested were:~H0: α1 = 0 vs H1: α1 \~= 0p-value: 0.5395% CI: [-1.68, 0.89]Regression, Linear