Childhood Asthma Research and Education (CARE) Network Trial - Montelukast or Azithromycin for Reduction of Inhaled Corticosteroids in Childhood Asthma (MARS)

The MARS trial is a randomized, double-blind, parallel group study that compares the capacity of azithromycin or montelukast to placebo as effective adjunctive therapy that allows reduction of inhaled corticosteroids in children ages 6 to 17 years with moderate-to-severe persistent asthma. The primary null hypothesis is that in children with moderate-to-severe persistent asthma, a macrolide antibiotic (Mac - azithromycin) or a leukotriene receptor antagonist (LTRA - montelukast) will provide a steroid-sparing effect when compared to placebo as the dose of inhaled corticosteroids (ICS - budesonide) is reduced. This will be tested following achievement of control of symptoms with moderate to high-dose ICS in combination with a long-acting bronchodilator agonist (LABA - salmeterol). Use of these doses for the inhaled corticosteroid will be based on NHLBI step-up guidelines to achieve asthma control. Inadequate asthma control is defined as either:

1. chronic poor control: a) symptoms, or albuterol use for symptoms or low peak flow, or peak flow less than 80% baseline on greater than 3 days per week on average, or b) nocturnal awakenings for asthma symptoms requiring albuterol 2 or more nights over 2 weeks of observation, or c) FEV1 less than 80% of the best pre-randomization value on 2 consecutive visits 1-4 days apart, or
2. an asthma exacerbation as determined by need for systemic corticosteroids

Treatment in the run-in period will be determined by the child's status at the first visit. At enrollment (V0) all patients will be given budesonide as the ICS and salmeterol as the LABA. Children will be treated with salmeterol BID and a dose of ICS based on chronic medication use with stepping-down based on time and symptoms until criteria for inadequate control as indication for stepping-up the dose of ICS. When inadequate control is documented (V1), a four-day course of prednisone will be administered and the dose of ICS (still administered with salmeterol BID) will be doubled to establish control. The children will be followed with monthly clinic visits and interim phone calls, emphasizing use of daily diary to document symptoms and doses of albuterol required. Reestablishment of control during a 2-week interval will prompt randomization. If control is not yet established by the first increase in ICS dose during the stabilization period, the dose can be doubled along with a second prednisone course until a maximum of budesonide of 1600 mcg/day is attained. The daily dose of budesonide at randomization will be a minimum of 800 mcg to allow for a maximum of 4-fold reduction of dose, and a maximum of 1600 mcg to allow for patient safety considering side effects of high dose ICS.

When clinical control is achieved by the increased dose of ICS, a child will then be randomized (V2) to one of the three treatment arms, (1) placebo (one placebo tablet and one or two placebo capsules), (2) azithromycin (one placebo tablet and one or two capsules containing azithromycin with the dose based on weight), or (3) montelukast (one tablet containing montelukast with the dose based on age as indicated in the package insert and one or two placebo capsule). Children will be followed for an additional six weeks on the dose of ICS that achieved control ("1X") + salmeterol BID with the study medication (V3). They will then undergo three 6-week periods of ICS reduction (V4, V5, V6), first to ¾ of the control dose ("0.75X"), then ½ of the control dose ("0.5X") and then ¼ of the control dose ("0.25X"), each using salmeterol BID as concomitant medication. The ICS dosing and salmeterol will be open-label. Criteria for treatment failure and discharge from the study will be an established set of criteria that indicate reappearance of inadequate control of asthma or an exacerbation of asthma.

At the end of the double-blind administration of oral study medication (V6), patients not discharged from the study because of having met one of the criteria for inadequate control of asthma will have their study medication discontinued, with subjects continuing to take placebo capsules in addition to ¼ ICS plus salmeterol. They will then be followed for an additional 6-week single-blind wash-out period with an interim contact by phone at 3 weeks to determine the course of asthma control to determine the persistence of effect off of the study medication (V7).

The procedures to be performed at V0 are informed consent, pregnancy test, complete physical exam, spirometry, and bronchodilator response. The procedures to be performed at V1 are spirometry, complete blood count, blood IgE and eosinophils, brief physical exam, EKG, and genotyping. The following procedures will be performed at each of V2 through V7: brief physical exam, spirometry, forced oscillometry, exhaled nitric oxide, asthma control questionnaire, asthma-specific quality-of-life questionnaire, and sinusitis questionnaire. In addition, allergy skin testing will be performed at V2, pregnancy tests at V2 through V6, methacholine challenge at V2 and V3, and polymerase chain reaction for atypical organisms and macrolide antibiotic resistance (nasal wash) at V2, V5, and V7.

Finally, children will maintain daily diary records of morning and evening symptoms, peak expiratory flow rates, and rescue medication use.