Azithromycin or montelukast as inhaled corticosteroid–sparing agents in moderate-to-severe childhood asthma study

doi:10.1016/j.jaci.2008.09.028

Journal of Allergy and Clinical Immunology

Volume 122, Issue 6, December 2008, Pages 1138-1144.e4

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https://doi.org/10.1016/j.jaci.2008.09.028 Get rights and content

Background

Clinical trials in children with moderate-to-severe persistent asthma are limited.

Objective

We sought to determine whether azithromycin or montelukast are inhaled corticosteroid sparing.

Methods

The budesonide dose (with salmeterol [50 μg] twice daily) necessary to achieve control was determined in children 6 to 17 years of age with moderate-to-severe persistent asthma. After a budesonide-stable period of 6 weeks, children were randomized in a double-masked, parallel, multicenter study to receive once-nightly azithromycin, montelukast, or matching placebos plus the established controlling dose of budesonide (minimum, 400 μg twice daily) and salmeterol twice daily. Primary outcome was time from randomization to inadequate asthma control after sequential budesonide dose reduction.

Results

Of 292 children screened, only 55 were randomized. Inadequate adherence to study medication (n = 80) and improved asthma control under close medical supervision (n = 49) were the major reasons for randomization failure. A futility analysis was requested by the Data Safety Monitoring Board. In data available for analyses, no differences were noted for either treatment compared with placebo in time to inadequate control status (median: azithromycin, 8.4 weeks [95% confidence limit, 4.3-17.3]; montelukast, 13.9 weeks [95% confidence limit, 4.7-20.6]; placebo, 19.1 weeks [95% confidence limit, 11.7-infinity]), with no difference between the groups (log-rank test, P = .49). The futility analysis indicated that even if the planned sample size was reached, the results of this negative study were unlikely to be different, and the trial was prematurely terminated.

Conclusion

Based on these results, neither azithromycin nor montelukast is likely to be an effective inhaled corticosteroid–sparing alternative in children with moderate-to-severe persistent asthma.

Section snippets

Study participants

Participants were recruited at 5 CARE Network centers from August 2006 to March 2007 (for more details, see Appendix E1 in this article's Online Repository at www.jacionline.org). Each center's institutional review board approved the study, and parents/guardians provided informed consent, with verbal assent given by children younger than 7 years and written assent given by older children.

Inclusion criteria were physician-diagnosed asthma, age of 6 to less than 18 years, and demonstration of

Study progress

Flow of participants into study enrollment was slower than expected, with a rate of 22 per month compared with the expected 56 per month. The 292 enrolled participants had historical characteristics consistent with moderate-to-severe persistent asthma, with 82% taking medium- to high-dose ICSs (800 μg of budesonide equivalent or higher): almost one half of these patients' symptoms were inadequately controlled before study entry by symptom report. Eighteen percent of enrolled participants had

Discussion

Moderate-to-severe persistent asthma in children accounts for a significant proportion of both morbidity and mortality from asthma, but interventions to improve these outcomes have not been thoroughly or systematically studied. The MARS trial was an attempt to study this group of children using therapeutic interventions considered to be relevant to their disease course given that significant side effects can occur from the high doses of ICSs required to control symptoms and prevent morbidity.

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: Disclosure of potential conflict of interest: L. B. Bacharier has received honoraria from AstraZeneca, Genentech, GlaxoSmithKline, Merck, and Aerocrine and has served on an advisory board for Schering-Plough. S. J. Szefler has served as a consultant for AstraZeneca, GlaxoSmithKline, Aventis, Genentech, and Merck and has received research support from the National Institutes of Health (NIH), the National Heart, Lung, and Blood Institute (NHLBI), and Ross Pharmaceuticals. R. S. Zeiger has served as a consultant for Aerocrine, AstraZeneca, GlaxoSmithKline, Genentech, Merck, Schering, and Novartis and has received research support from Sanofi Aventis and Genentech. V. M. Chinchilli has received research support from the NIH and NHLBI. F. D. Martinez has received lecture fees from and has served on an advisory board for Merck and has served as a consultant for GlaxoSmithKline. R. F. Lemanske has received speaker honoraria from Merck; has served as a consultant for MAP Pharmaceuticals; and has received research support from the NHLBI. D. T. Mauger has received research support from the NIH. W. J. Morgan has served as a consultant for the Cystic Fibrosis Foundation and Genentech and has received research support from the NIH. C. A. Sorkness has served as a consultant for GlaxoSmithKline and Novartis and has received research support from Novartis, the NHLBI, and the National Institute of Allergy and Infectious Diseases (NIAID). I. M. Paul has served as a consultant for McNeil Consumer Healthcare, the Consumer Healthcare Products Association, and Reckitt Brackiser Healthcare International and has received research support from GlaxoSmithKline, the National Honey Board, and Johnson & Johnson. T. Guilbert has received honoraria for serving as a consultant, speaker, or both for GlaxoSmithKline, AstraZeneca, Merck, and Antidote (formerly World Medical Conferences CME Programs) and has received research support from Altus Pharmaceuticals, Inspire Pharmaceuticals, and the NIH. M. Krawiec has served on the speakers' bureau for Merck and GlaxoSmithKline; has served as a consultant on a peer-reviewed publication for Adelphi; has served as a consultant for Parexel and Novartis; and has provided legal consultation or expert witness testimony on the topic of pediatric asthma. R. Covar has served as a consultant for Merck and has received research funding from Ross Abbott Laboratories and AstraZeneca. G. Larsen has served on an asthma advisory board for Genentech and has received research funding from the NIH. The rest of the authors have declared that they have no conflict of interest.

^∗: See Appendix E1 in this article's Online Repository at www.jacionline.org for a list of the Childhood Asthma Research and Education Network members.

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Asthma and lower airway diseaseAzithromycin or montelukast as inhaled corticosteroid–sparing agents in moderate-to-severe childhood asthma study

Background

Objective

Methods

Results

Conclusion

Section snippets

Study participants

Study progress

Discussion

J Allergy Clin Immunol

J Allergy Clin Immunol

Chest

J Pediatr

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Effect of low-dose troleandomycin on glucocorticoid kinetics and airway hyperresponsiveness in severely asthmatic children

Ann Allergy

National Asthma Education and Prevention Program Expert Panel Report. Guidelines for the diagnosis and management of asthma—update on selected topics 2002

National Asthma Education and Prevention Program expert panel report. Expert panel report 3: guidelines for the diagnosis and management of asthma

Side-effects of fluticasone in asthmatic children: no effects after dose reduction

Eur Respir J

Asthma and lower airway disease
Azithromycin or montelukast as inhaled corticosteroid–sparing agents in moderate-to-severe childhood asthma study