Research Question: Will a 12-week treatment with the antibiotic, azithromycin, result in a statistically significant and clinically meaningful improvement in overall asthma symptoms and other patient-oriented asthma outcomes one year after initiation of treatment of adult primary care patients with asthma?

Experimental Design: We propose a one-year randomized, placebo-controlled, blinded (investigator, patient, data collector, data analyst) trial of 12 weekly doses of azithromycin/placebo as adjunctive therapy (in addition to usual care) in 600 adult asthma patients recruited from practice-based research networks (e.g., Wisconsin Research and Education Network (WREN) and others). This “practical clinical trial” will (1) enroll a representative sample of asthma patients encountered in the practices of primary care physicians, (2) employ standard clinical trial methodology to ensure internally valid results and (3) measure outcomes important to patients, so that the results will be valid and applicable to the kinds of asthma patients encountered by family physicians and other primary care providers.

1.0 PROTOCOL SYNOPSIS

Approximately 600 eligible older children and adult patients with physician-diagnosed asthma will be randomized to 12-week treatment with azithromycin, a widely marketed azalide antibiotic with an excellent safety profile, or identical placebo as adjunctive therapy for usual care for asthma. The following patient-reported data will be collected via Zoomerang™ (a commercially-available data collection tool) periodically until one year after randomization: (1) study medication adherence and side effects weekly until 12 weeks, (2) asthma control and exacerbations every 6 weeks until 12 months, and (3) asthma quality of life and asthma controller medication changes every 3 months until 12 months. The primary hypothesis is that azithromycin will significantly improve asthma control (decrease symptoms and medication use) by 3 months (end treatment) and the improvement will continue to 12 months (end study). The primary outcome variable is overall asthma symptoms. Secondary outcomes are asthma medication use, quality of life and exacerbations. We will examine the predictive value of baseline patient characteristics including age, sex, smoking, co-morbid respiratory diagnoses and degree of airflow limitation. We will also examine for any imbalances between study groups in controller medication use, other antibiotic prescriptions and acute respiratory illnesses during the one-year study period.

We will enroll subjects from the practices of Wisconsin Research and Education Network (WREN) members, UW Department of Family Medicine physicians, Dean Medical Center primary care physicians, and from other practice-based research networks (PBRNs), medical group practices and individual primary care practices throughout North America.

Patients with physician-diagnosed asthma aged 18 and older will be identified at point-of-service (office, urgent care, emergency room or hospital), by administrative data base review, or by physician recall. Most subjects will be the patients of study physicians. Other physicians in the group practice may refer subjects. Subjects also may be self-referred after responding to posters placed in the clinics. Some sites may elect to identify cases by medical record or database review, in which case only the personal physician may initiate patient contacts.

Treatment is azithromycin tablets, 600 milligrams orally once daily for 3 days, then 600 milligrams once weekly for an additional 11 weeks (total dose 8400 milligrams) or identical placebo, in addition to usual care for asthma.

Accepts Healthy Volunteers

Inclusion Criteria:

• The intent of this protocol is to enroll a broadly generalizable sample of adult patients with physician-diagnosed asthma, either stable persistent or in exacerbation.

•Inclusion Criteria

• Age 18 and older (and at least 50 kg/110 pounds)

The lower weight limit was chosen to avoid exposure to greater than 12 mg/kg/day of azithromycin (a currently recommended dose for children). We specify no upper age limit because asthma occurs throughout the age range and because asthma in the elderly is particularly severe45 and warrants inclusion.

• Physician-diagnosed asthma

At the time of randomization, eligible subjects must either (a) be having a documented asthma exacerbation or (b) reporting at least mild persistent asthma symptoms, as defined by GINA (Global Initiative for Asthma). Subjects must also have asthma symptoms for at least six months prior to randomization. In addition, documentation of objective evidence of reversible airway obstruction, either spontaneously or after treatment, is required prior to randomization. This requirement can be met by documentary evidence, within 2 years of randomization, of either (1) a 12% or greater (and ≥200 mL) change in FEV146 or (2) a 25% or greater (and >60 L/min) change in PEFR47 either spontaneously or as a result of treatment.

Exclusion Criteria:

• Not English literate or without email and internet access

• Macrolide allergy

• Pregnancy or lactation Females of childbearing potential must agree to use an acceptable form of contraception during the treatment period.

• Chronic use of macrolides, tetracyclines or quinolones Chronic use is defined as 4 or more weeks of continuous use within 6 months of randomization.

• Asthma symptoms for less than 6 months prior to randomization Asthma symptoms must be present for at least 6 months to exclude patients without true chronic asthma.

• Unstable asthma requiring immediate emergency care All patients with asthma exacerbations will receive usual urgent or emergency care for asthma and must be improving or stable in the judgment of the treating physician prior to being enrolled.

• Specified co-morbidities likely to interfere with study assessments or follow up Excluded comorbidities include: cystic fibrosis, obstructive sleep apnea requiring CPAP, gastro-esophageal reflux disease (GERD) requiring daily medication, cardiomyopathy, congestive heart failure, terminal cancer, alcohol or other drug abuse, or any other serious medical condition that, in the opinion of the study physician, would seriously interfere with or preclude assessment of study outcomes or completion of study assessments.

• Specified medical conditions for which macrolide administration may possibly be hazardous Patients with acute or chronic hepatitis, cirrhosis or other liver disease, chronic kidney disease, or history of prolonged cardiac repolarization and QT interval or torsades de pointes, are excluded.

• Specified medications for which close monitoring has been recommended in the setting of macrolide administration Patients taking digoxin, theophylline, warfarin, ergotamine or dihydroergotamine, triazolam, carbamazepine, cyclosporine, hexobarbital or phenytoin are excluded. If any of these medications are started after randomization and before completion of the 12-week treatment phase, study medication will be discontinued and the patient may remain in the study.