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

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.

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