Asthma Clinical Research Network (ACRN) Trial - Macrolides in Asthma (MIA)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Asthma

Intervention / Treatment
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* Drug: clarithromycin
* Drug: fluticasone propionate
* Drug: placebo clarithromycin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: clarithromycin + fluticasone<br>clarithromycin 500 mg twice daily (Biaxin) + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily) | Drug: clarithromycin<br>* clarithromycin 500 mg twice daily (Biaxin)<br>* Other names: Biaxin;Drug: fluticasone propionate<br>* fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)<br>* Other names: Flovent®;|
| Active Comparator: placebo + fluticasone<br>placebo clarithromycin twice daily + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily) | Drug: fluticasone propionate<br>* fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)<br>* Other names: Flovent®;Drug: placebo clarithromycin<br>* placebo clarithromycin twice daily<br>* Other names: placebo Biaxin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Juniper Asthma Control Questionnaire (ACQ) Results | The Juniper asthma control questionnaire (ACQ) consists of six questions answered by the asthma patient with respect to symptoms, rescue medication use, and night-time awakenings due to asthma. A seventh item in the ACQ is the percent predicted FEV1. Each of the seven items is scored from from 0 (best) to 6 (worst), and then the seven items are averaged to yield a number from 0 (best) to 6 (worst). Asthma patients needed to display an ACQ greater than or equal to 1.25 in order to be eligible for randomization. A reduction of 0.5 units or more in the ACQ over the 16 weeks of treatment is considered to be clinically significant. | Measured every four weeks during the 16-week treatment period, with the change (week 16 minus baseline) as the primary outcome | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Asthma Rescue Medication Use | number of rescue puffs per day | the week-16 average minus the baseline-week average | 
| AM Peak Expiratory Flow (PEF) | daily AM peak expiratory flow (PEF) measured in liters per minute | the week-16 average minus the baseline-week average | 
| Forced Expiratory Volume in One Second (FEV1) | Forced expiratory volume in one second (FEV1) from spirometry | the week-16 value minus the baseline-value | 
| Methacholine Provocative Concentration (PC20) | Logarithm-base 2 transformed Methacholine provocative concentration (PC20) based on FEV1 | the week-16 value minus the baseline-value | 
| Exhaled Nitric Oxide (eNO) | Exhaled nitric oxide (eNO) measured in parts per billion | the week-16 value minus the baseline-value | 
| Asthma Quality of Life Questionnaire (AQLQ) | The Asthma Quality of Life Questionnaire (AQLQ) consists of 32 questions, with each question ranging from 1 (worst) to 7 (best). The 32 questions are averaged to yield an overall score, which is reported here. Therefore, a positive change between the 16-week score and the baseline score represents improvement. | the week-16 value minus the baseline-value |