A Randomized, Placebo-Controlled, Double-Blind Pilot Study of Pioglitazone Hydrochloride in Severe, Refractory Asthma
A Randomized, Placebo-Controlled, Double-Blind Pilot Study of Pioglitazone Hydrochloride in Severe, Refractory Asthma
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.
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.
-  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.