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

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.