Airflow Obstruction, Airway Inflammation, Severe, Refractory Asthma
Conditions
Keywords
Pioglitazone, Severe, Refractory Asthma, Peroxisome Proliferator-Activated Receptor Gamma, Airflow Obstruction, Airway Inflammation, Asthma
Brief summary
Background: \- Individuals who have severe asthma that is not easily controlled by current treatments are in need of new treatments to prevent potentially life-threatening asthma attacks. Experiments in mice have found that a medication called pioglitazone hydrochloride (Actos ), which is used to treat patients with diabetes, may be effective for treating severe asthma. Researchers are interested in determining whether Actos is effective in improving the quality of life in subjects with severe asthma who continue to have symptoms despite maximum standard medical therapy. Objectives: \- To assess the effectiveness of pioglitazone hydrochloride as a treatment for patients with severe asthma that is not controlled by standard treatments. Eligibility: \- Individuals between 18 and 75 years of age who have been diagnosed with and treated for severe asthma for at least 1 year. Design: * Potential participants will have a screening visit to determine eligibility for the study. The visit will involve breathing tests, chest x rays, heart and lung monitoring, and blood tests. * Eligible participants will have a full medical history and will answer a series of questionnaires about their quality of life with asthma. * Phase 1: Patients will record lung function and asthma symptoms morning and evening for 4 weeks. At the end of this period, patients will be evaluated with breathing, allergy, and blood tests, as well as questionnaires. Patients will also provide a sputum sample. * Phase 2: Patients will receive regular doses of either pioglitazone hydrochloride or a placebo for 16 weeks. Patients will return to the National Institutes of Health every 4 weeks for tests. * Phase 3: Wash-out period without study drugs for 4 weeks, similar to Phase 1. * Phase 4: Patients will receive regular doses of either pioglitazone hydrochloride or a placebo for 16 weeks. Patients who received placebo will be given the study drug, and vice versa. Patients will return to the National Institutes of Health every 4 weeks for tests. * Phase 5: Medications will be stopped, and patients will return to the National Institutes of Health 4 weeks later for final tests.
Detailed description
New therapies are needed for patients with asthma who are sub-optimally controlled by standard measures. Pioglitazone hydrochloride (Actos ) is a highly selective and potent agonist for the peroxisome proliferator-activated receptor-Gamma (PPAR Gamma). Studies in murine models of allergic asthma have shown that PPAR Gamma agonists down-regulate allergen-mediated airway inflammation and airway hyperresponsiveness. This protocol is a randomized, placebo-controlled, doubleblind, crossover (phase II) pilot study of the efficacy of pioglitazone for the treatment of patients with severe, refractory asthma. The primary end-point for this study will be quality of life as determined by the Asthma Quality of Life Questionnaire (AQLQ) score. Secondary end-points will include indices of airway inflammation, airflow obstruction, airway hyperreactivity, and asthma symptoms.
Interventions
DRUGPioglitazone
DRUGPlacebo
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: * Subjects will be between 18 and 75 years of age, male or female, with a diagnosis of severe, refractory asthma, as defined by the American Thoracic Society, for at least one year. * Subjects must have a history of reversible airflow obstruction as defined by a positive methacholine bronchoprovocation challenge or a positive response to inhaled bronchodilators at some point in the course of their disease or a greater than 20% variability in the Forced Expiratory Volume in 1 second (FEV1) or the peak expiratory flow (PEF) documented during serial measurements of lung function over time. * Left ventricular ejection fraction greater than or equal to 50% by echocardiogram * For women of childbearing potential, negative pregnancy test prior to study and willingness to adhere to reliable birth control methods during the study. * Subjects must have the ability to provide informed consent
Exclusion criteria
* A known history of hypersensitivity to pioglitazone. * Asthma exacerbation requiring treatment with additional oral corticosteroids in the previous 6 weeks, or a life-threatening asthma attack requiring cardiopulmonary support in the previous 6 months. * Cigarette smoking within the previous 12 months or a prior history of \> 20 cumulative pack-years. * Investigational therapy for any indication within I month prior to the screening visit. * History of lung disease other than asthma (ie., COPD, sarcoidosis). * History of diabetes mellitus requiring treatment with any medication, insulin secreting tumor, or symptomatic hypoglycemia. * HIV/AIDS * History of congestive heart failure with current symptoms consistent with NYHA classification II, Ill or IV. * Preexisting edema (2+ or greater). * Hemoglobin \< 11 gm/dl for males and \< 10 gm/dl for females. * Active liver disease or abnormal liver function tests \> 2 times upper limit of normal. * History of bladder or colon cancer. * History of other cancer not in remission. * Active breast feeding. * Use of the following medications, which can interact with pioglitazone: * Gemfibrizol (Lopid) * Atazanivir (Reyataz) * Ritonavir (Norvir) * Rifampin (Rifadpin) * Carbamzepine (Tegretol) * Phenobarbital (Luminal) * Phenytoin (Dilantin) * Rifapentine (Priftin) * Secobarbital (Seconal) * Amiodarone (Cordarone, Pacerone) * Palitaxel (Taxol) * Replaglinide (Prandine) * Ketoconazole (Nizoral) * Atorvastatin (Lipitor ) * Fosphenytoin (Cerebyx) * Itraconazole (Sporanox) * Trimethoprim (in Bactrim) * Thioridazine * Certain over-the-counter herbs and supplements. These will be reviewed by the investigators for possible interactions with the study medication A determination of whether the supplement is safe to use with pioglitazone will be made on a case-by-case basis. * Any condition that, in the investigator s opinion, places the patient at undue risk for complications from pioglitazone therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 16 Weeks - Juniper Asthma Quality of Life Questionnaire (AQLQ) Score | 16 weeks | Juniper Asthma Quality of Life Questionnaire (AQLQ) score at the end of the pioglitazone treatment period as compared to the placebo treatment period. The AQLQ is scored on a 7-point scale with 7 = not impaired at all, 1 = severly impaired |
| Baseline - Juniper Asthma Quality of Life Questionnaire (AQLQ) Score | Baseline | Juniper Asthma Quality of Life Questionnaire (AQLQ) score at the end of the pioglitazone treatment period as compared to the placebo treatment period. The AQLQ is scored on a 7-point scale with 7 = not impaired at all, 1 = severly impaired |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants All subjects who started the study. | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 11 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 8 / 15 | 11 / 15 |
| serious Total, serious adverse events | 2 / 15 | 4 / 15 |
Outcome results
Primary
16 Weeks - Juniper Asthma Quality of Life Questionnaire (AQLQ) Score
Juniper Asthma Quality of Life Questionnaire (AQLQ) score at the end of the pioglitazone treatment period as compared to the placebo treatment period. The AQLQ is scored on a 7-point scale with 7 = not impaired at all, 1 = severly impaired
Time frame: 16 weeks
Population: All subjects who completed both treatment phases of the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | 16 Weeks - Juniper Asthma Quality of Life Questionnaire (AQLQ) Score | 4.7 units on a scale | Standard Deviation 1.3 |
| Placebo | 16 Weeks - Juniper Asthma Quality of Life Questionnaire (AQLQ) Score | 4.6 units on a scale | Standard Deviation 1.3 |
Primary
Baseline - Juniper Asthma Quality of Life Questionnaire (AQLQ) Score
Juniper Asthma Quality of Life Questionnaire (AQLQ) score at the end of the pioglitazone treatment period as compared to the placebo treatment period. The AQLQ is scored on a 7-point scale with 7 = not impaired at all, 1 = severly impaired
Time frame: Baseline
Population: All subjects who completed both treatment phases of the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | Baseline - Juniper Asthma Quality of Life Questionnaire (AQLQ) Score | 4.478 units on a scale | Standard Deviation 0.9866 |
| Placebo | Baseline - Juniper Asthma Quality of Life Questionnaire (AQLQ) Score | 4.306 units on a scale | Standard Deviation 1.342 |