Official Title: “Asthma Clinical Research Network (ACRN) Trial - Macrolides in Asthma (MIA)”

Asthma can be caused by a variety of factors, including tobacco smoke, allergens, and respiratory airway infections. Many people use inhaled corticosteroid medications to treat their symptoms. These medications, however, are not effective for everyone. Clarithromycin is an antibiotic that may effectively treat asthma in these individuals. This study will evaluate the effectiveness of clarithromycin at controlling asthma symptoms.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: April 2009

Asthma prevalence has steadily increased in the United States since the early 1980s; currently, more than 20 million people are diagnosed with asthma.

Individuals with this disease may experience periodic attacks of wheezing, shortness of breath, chest tightness, and coughing. While there are many known causes of asthma, including tobacco smoke and other allergens, the exact cause of some asthma cases remains unknown.

Research has shown that in some individuals, respiratory airway infections may play a role in the onset and severity of the disease. Inhaled corticosteroids are commonly used to treat asthma; however, they do not effectively control symptoms for everyone. Clarithromycin, an antibiotic medication used to treat bacterial infections, may be an effective asthma treatment for individuals who do not respond well to inhaled corticosteroids. The purpose of this study is to evaluate the effectiveness of clarithromycin at reducing asthma symptoms.

This study will begin with a 4-week run-in period to standardize participants' asthma medication usage. During this time, all participants will stop their current asthma medications and instead will receive inhaled fluticasone twice a day. Albuterol will be available as a rescue medication if necessary. Study visits will take place every 2 weeks.

Blood and saliva samples will be obtained for laboratory tests and participants will complete standardized questionnaires to assess asthma symptoms and quality of life. Spirometry will be performed to measure lung function. Medication adherence will be monitored with a daily diary and an electronic pill counting device. At the end of Week 4, participants will be evaluated for study eligibility.

If eligible, participants will undergo a bronchoscopy and a lung biopsy to test for Mycoplasma pneumoniae and Chlamydia pneumoniae, two bacteria that have been identified as possible factors in the development of asthma.

The treatment phase of the study will last 16 weeks. Participants will be randomly assigned to receive either 500 mg of clarithromycin or placebo twice a day, plus inhaled fluticasone.

At monthly study visits, spirometry and blood collection will be performed. Standardized questionnaires to assess asthma symptoms will be completed every 2 weeks. Medical adherence will continue to be monitored. At the end of Week 16, participants will stop receiving clarithromycin or placebo, but will continue to receive fluticasone. Asthma symptoms, rescue medication usage, quality of life, and lung capacity will be assessed; tissue samples will be examined for the presence of Mycoplasma pneumoniae and Chlamydia pneumoniae. An 8-week washout period will follow to observe any lingering medication effects and to monitor for safety. Monthly study visits during this period will include spirometry and blood collection.

Intervention(s) in this Clinical Trial

• Drug: Clarithromycin
  • Clarithromycin 500 mg bid (Biaxin)
• Drug: Fluticasone propionate
  • Fluticasone propionate 88 mcg bid (Flovent® HFA 44 mcg two puffs bid)

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Clarithromycin 500 mg bid (Biaxin) + fluticasone propionate 88 mcg bid (Flovent® HFA 44 mcg two puffs bid)
• Active Comparator: 2
  • Fluticasone propionate 88 mcg bid (Flovent® HFA 44 mcg two puffs bid)

Primary Measures

• Asthma control questionnaire (ACQ) results
  • Time Frame: Measured during the 16-week treatment period
    Safety Issue?: No

Secondary Measures

• Asthma symptoms
  • Time Frame: Measured during the 16-week treatment period
    Safety Issue?: No
• Asthma rescue medication use
  • Time Frame: Measured during the 16-week treatment period
    Safety Issue?: No
• AM and PM peak expiratory flow (PEF)
  • Time Frame: Measured during the 16-week treatment period
    Safety Issue?: No
• Forced expiratory volume in one second (FEV1)
  • Time Frame: Measured during the 16-week treatment period
    Safety Issue?: No
• Asthma-specific quality of life
  • Time Frame: Measured during the 16-week treatment period
    Safety Issue?: No
• Methacholine provocative concentration (PC20)
  • Time Frame: Measured during the 16-week treatment period
    Safety Issue?: No
• Exhaled nitric oxide (eNO)
  • Time Frame: Measured during the 16-week treatment period
    Safety Issue?: No
• Blood cell counts
  • Time Frame: Measured during the 16-week treatment period
    Safety Issue?: Yes
• AM cortisol
  • Time Frame: Measured during the 16-week treatment period
    Safety Issue?: Yes
• Adverse events
  • Time Frame: Measured during the 16-week treatment period
    Safety Issue?: Yes

Inclusion Criteria:

• History of physician-diagnosed asthma
• Methacholine PC20 less than or equal to 16 mg/ml and/or FEV1 improvement greater than or equal to 12% in response to 180 mcg albuterol
• Stable asthma for at least 6 weeks prior to study entry
• FEV1 greater than or equal to 60% of predicted result following 180 mcg albuterol
• Juniper ACQ score greater than or equal to 1.5 (optimal ACQ score cut-off point for asthma that is "not well-controlled" by NIH/Global Initiative for Asthma [GINA] guidelines)
• Nonsmoker (less than 10 pack-per-year lifetime smoking history and no smoking in the year prior to study entry)
• Able to perform spirometry, as per American Thoracic Society criteria
• 75% adherence with diary cards, fluticasone (monitored with Doser), and placebo pill trial (monitored electronically with Electronic Drug Exposure Monitor [eDEM] pill dose counter) for the final 2 weeks of the four-week run-in period
• At Visit 1, in steroid-naïve participants, no significant adrenal suppression, defined as a plasma cortisol concentration less than 5 mcg/dL. If adrenal suppression occurs, a 250 mcg corticotropin (ACTH) stimulation test will be performed. Plasma cortisol levels will be collected at baseline, and 30 and 60 minutes after the ACTH stimulation test. Participants must have a cortisol concentration greater than 20 mcg/dL on at least one of the post-ACTH time points
• Absence of bronchoscopy-induced exacerbation; if bronchoscopy-induced exacerbation has occurred, prednisone therapy must have stopped at least 6 weeks prior to study entry
• Absence of respiratory tract infection; if infection has occurred, infection-related symptoms must have stopped at least 6 weeks prior to study entry
• Has experienced no more than two exacerbations or respiratory tract infections prior to study entry
• If female and able to conceive, willing to utilize two medically acceptable forms of contraception (one non-barrier method with single barrier method OR double barrier method)

Exclusion Criteria:

• Presence of lung disease other than asthma
• Presence of vocal cord dysfunction, due to potential confounding of ACQ score
• Significant medical illness other than asthma
• History of atrial or ventricular tachyarrhythmia
• Use of any medication that has a significant interaction with clarithromycin, including herbal or alternative therapies
• Asthma exacerbation within 6 weeks of the screening visit or during the run-in period prior to bronchoscopy
• Use of systemic steroids or change in dose of controller therapy within 6 weeks of the screening visit
• Inability, in the opinion of the study investigator, to coordinate use of dry powder or metered-dose inhaler or to comply with medication regimens
• Inability or unwillingness to perform required study procedures
• Prolonged heart rate corrected QT-interval (greater than 450 msec in women and greater than 430 msec in men) on echocardiogram (ECG) at study entry
• Low potassium or magnesium levels (based on local Asthma Clinical Research Network laboratory definitions)
• Abnormal elevation of liver function tests (AST, ALT, total bilirubin, or alkaline phosphatase)
• Abnormal prothrombin time (PT) or partial thromboplastin time (PTT) results
• Reduced creatinine clearance
• Contraindication to bronchoscopy, as determined by medical history or physical examination
• Regular consumption of grapefruit or grapefruit juice
• Pregnant or breastfeeding

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 60 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

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

Overall Clinical Trial Officials and Contacts

William J. Calhoun, MD Principal Investigator University of Texas, Galveston  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00318708

Study ID Number: 377

ClinicalTrials.gov Identifier: NCT00318708

Health Authority: United States: Food and Drug Administration

Click here for the Asthma Clinical Research Network (ACRN) web site