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

Airway Inflammation Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00994175
• Other study ID #: 090244
• Secondary ID: 09-H-0244
• Status: Completed
• Phase: Phase 2
• First received: October 10, 2009
• Last updated: February 25, 2017
• Start date: September 23, 2009
• Est. completion date: June 24, 2016

Study information

• Verified date: February 23, 2017
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 59
• Est. completion date: June 24, 2016
• Est. primary completion date: June 24, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

• 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.

Related Conditions & MeSH terms

• Airflow Obstruction
• Airway Inflammation
• Asthma
• Inflammation
• Severe, Refractory Asthma

Intervention

Drug:
• Pioglitazone

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland
United States	INOVA Fairfax Hospital	Falls Church	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (3)

Berry MA, Hargadon B, Shelley M, Parker D, Shaw DE, Green RH, Bradding P, Brightling CE, Wardlaw AJ, Pavord ID. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med. 2006 Feb 16;354(7):697-708. — View Citation

Erin EM, Leaker BR, Nicholson GC, Tan AJ, Green LM, Neighbour H, Zacharasiewicz AS, Turner J, Barnathan ES, Kon OM, Barnes PJ, Hansel TT. The effects of a monoclonal antibody directed against tumor necrosis factor-alpha in asthma. Am J Respir Crit Care Med. 2006 Oct 1;174(7):753-62. Retraction in: Am J Respir Crit Care Med. 2011 Feb 1;183(3):418. — View Citation

Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med. 2005 Oct 20;353(16):1711-23. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Quality of life as determined by the validated Asthma Quality of Life Questionnaire (AQLQ)		3 years
Secondary	Airway inflammation, airflow obstruction, asthma symptoms, asthma exacerbations, blood eosinophil counts, serum IgE and exhaled nitric oxide levels		3 years

External Links

•   NIH Clinical Center Detailed Web Page