A Randomized, Placebo-Controlled, Double-Blind Pilot Study of Pioglitazone Hydrochloride in Severe, Refractory Asthma
Condition: Severe, Refractory Asthma; Airway Inflammation; Airflow Obstruction
MeSH terms: Asthma; Inflammation
Intervention: Pioglitazone; Placebo
Intervention MeSH terms: Pioglitazone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Pioglitazone; Severe, Refractory Asthma; Peroxisome Proliferator-Activated Receptor Gamma; Airflow Obstruction; Airway Inflammation; Asthma

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.
    

Eligibility 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.