Objectives

The CARE-MARS study aimed to determine if azithromycin or montelukast use would allow reduction of inhaled corticosteroids in children with moderate to severe persistent asthma.

Background

Children with moderate to severe persistent asthma comprise a small percentage of all children with asthma, but account for most of its morbidity. Therapy with medium to high doses of inhaled corticosteroids (ICS) supplemented with additional controller medication(s) is generally effective in achieving control of symptoms. Concern over systemic side effects from long-term use of medium to high dose ICS medications has prompted physicians to seek non-steroid medications that would allow ICS doses to be decreased. The Childhood Asthma Research and Education (CARE) Network initiated the Montelukast or Azithromycin for Reduction of Inhaled Corticosteroids in Childhood Asthma (MARS) protocol to explore non-corticosteroid medications, specifically a macrolide and a leukotriene receptor antagonist, which might allow reduction of daily doses of ICS so as to lower the incidence of corticosteroid side effects.

Participants

Eligible participants had physician-diagnosed asthma, were aged 6 to less than 18 years, and demonstrated moderate to severe persistent asthma by history of symptoms and current controller medication use over the previous month. All children demonstrated ability to perform reproducible spirometry, and had airway lability demonstrated either by an improvement in FEV1 of ≥ 12% after 4 puffs of albuterol or airway hyperresponsiveness reflected by a 20% fall in FEV1 after a methacholine dose of ≤ 12.5 mg/ml. Exclusion criteria included asthma too severe as indicated by more than 3 hospitalizations in the preceding 12 months, history of intubation or mechanical ventilation within the last year, or any history of hypoxic seizure due to asthma; history of severe sinusitis requiring sinus surgery within the past 12 months; use of maintenance oral or systemic antibiotics for treatment of an ongoing condition; contraindication for use of azithromycin or montelukast; presence of lung disease other than asthma; and use of certain medications.

Of 292 children screened, 55 were randomized to a treatment group. 17 were randomized to the azithromycin group, 19 to the montelukast group, and 19 to the placebo group.

Design

CARE-MARS was a randomized, double-masked, parallel, multi-center study. Participants were recruited at five CARE Network centers. Enrolled participants completed a run-in period. During the run-in, participants demonstrated evidence of inadequate control on ICS plus salmeterol, with subsequent documentation that step-up to a higher dose of ICS (to a maximum of 1600 mcg daily, again with salmeterol) established control.

When asthma control criteria were met by the increased dose of ICS, a patient was randomized to one of the three treatment arms: placebo, azithromycin 250 mg (for those 25–40 kg) or 500 mg (for those >40 kg) once daily, or montelukast 5 mg or 10 mg once daily (based on age). The three treatment arms were stratified according to clinical center and ICS dose (budesonide 800 mcg/day vs. 1600 mcg/day) that achieved asthma control during run-in.

Following randomization, participants received the study treatment as well as open label ICS at the dose that achieved control plus salmeterol for an additional six weeks. They then proceeded through three 6-week periods of ICS reduction, first to 75% of the control dose, then 50% of the control dose and then 25% of the control dose, each using salmeterol as concomitant medication. After the lowest dose was achieved and control maintained for an additional 6 weeks, the active study medication was changed to placebo (blinded to participant) and follow-up was continued for an additional 6 weeks.

The participants were monitored via clinic visits every 2–4 weeks. Electronic peak expiratory flow (PEF) measurements, asthma symptom scores, and albuterol use were recorded in diaries twice daily. Nasal washes were obtained at randomization, at week 18, and end of trial (either after the last planned visit or at time of treatment failure).

The primary outcome was time from randomization to inadequate asthma control following sequential budesonide dose reduction.

Conclusions

Due to enrollment and efficiency of randomization being lower than expected, a futility analysis was requested. The results of this analysis indicated that even if the planned sample size was reached, results of this study were unlikely to be different and the trial was prematurely terminated. In conclusion, neither azithromycin nor montelukast is likely to be an effective ICS-sparing alternative in children with moderate to severe persistent asthma.

Strunk RC, Bacharier LB, Phillips BR, et al. Azithromycin or montelukast as inhaled corticosteroid-sparing agents in moderate-to-severe childhood asthma study. J Allergy Clin Immunol. 2008;122(6):1138-1144.e4. doi:10.1016/j.jaci.2008.09.028

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