Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years

Background. The greatest prevalence of asthma is in preschool children; how ever, the clinical utility of asthma therapy for this age group is limited by a narrow therapeutic index, long-term tolerability, and frequency and/or difficulty of administration. Inhaled corticosteroids and inhaled cromolyn are the most commonly prescribed controller therapies for young children w ith persistent asthma, although very young patients may have difficulty usi ng inhalers, and dose delivery can be variable. Moreover, reduced complianc e with inhaled therapy relative to orally administered therapy has been rep orted. One potential advantage of montelukast is the ease of administering a once-daily chewable tablet; additionally, no tachyphylaxis or change in t he safety profile has been evidenced after up to 140 and 80 weeks of montel ukast therapy in adults and pediatric patients aged 6 to 14 years, respecti vely. To our knowledge, this represents the first large, multicenter study to add ress the effects of a leukotriene receptor antagonist in children younger t han 5 years of age with persistent asthma, as well as one of the few asthma studies that incorporated end points validated for use in preschool childr en. Objective. Our primary objective was to determine the safety profile of mon telukast, an oral leukotriene receptor antagonist, in preschool children wi th persistent asthma. Secondarily, the effect of montelukast on exploratory measures of asthma control was also studied. Design and Statistical Analysis. We conducted a double-blind, multicenter, multinational study at 93 centers worldwide: including 56 in the United Sta tes, and 21 in countries in Africa, Australia, Europe, North America, and S outh America. In this study, we randomly assigned 689 patients (aged 2-5 ye ars) to 12 weeks of treatment with placebo (228 patients) or 4 mg of montel ukast as a chewable tablet (461 patients) after a 2-week placebo baseline p eriod. Patients had a history of physician-diagnosed asthma requiring use o f beta -agonist and a predefined level of daytime asthma symptoms. Caregive rs answered questions twice daily on a validated, asthma-specific diary car d and, at specified times during the study, completed a validated asthma-sp ecific quality-of-life questionnaire. Physicians and caregivers completed a global evaluation of asthma control at the end of the study. Efficacy end points included: daytime and overnight asthma symptoms, daily use of beta -agonist, days without asthma, frequency of asthma attacks, num ber of patients discontinued because of asthma, need for rescue medication, physician and caregiver global evaluations of change, asthma-specific care giver quality of life, and peripheral blood eosinophil counts. Although exp loratory, the efficacy end points were predefined and their analyses were w ritten in a data analysis plan before study unblinding. At screening and at study completion, a complete physical examination was performed. Routine l aboratory tests were drawn at screening and weeks 6 and 12, and submitted t o a central laboratory for analysis. Adverse effects were collected from ca regivers at each clinic visit. An intention-to-treat approach, including all patients with a baseline meas urement and at least 1 postrandomization measurement, was performed for all efficacy end points. An analysis-of-variance model with terms for treatmen t, study center and stratum (inhaled/nebulized corticosteroid use, cromolyn use, or none) was used to estimate treatment group means and between-group differences and to construct 95% confidence intervals. Treatment-by-age, - sex, -race, -radioallergosorbent test, stratum, and -study center interacti ons were evaluated by including each term separately. Fisher's exact test w as used for between-group comparisons of the frequency of asthma attacks, d iscontinuations from the study because of worsening asthma, need for rescue medication, and the frequencies of adverse effects. Because of an imbalanc e in baseline values for eosinophil counts for the 2 treatment groups, an a nalysis of covariance was performed on the eosinophil change from baseline with the patient's baseline as covariate. Study Participants. Of the 689 patients enrolled, approximately 60% were bo ys and 60% were white. Patients were relatively evenly divided by age: 21%, 24%, 30%, and 23% were aged 2, 3, 4, and 5 years, respectively. For 77% of the patients, asthma symptoms first developed during the first 3 years of life. During the placebo baseline period, patients had asthma symptoms on 6 .1 days/ week and used beta -agonist on 6.0 days/week. Results. In over 12 weeks of treatment of patients aged 2 to 5 years, monte lukast administered as a 4-mg chewable tablet produced significant improvem ents compared with placebo in multiple parameters of asthma control includi ng: daytime asthma symptoms (cough, wheeze, trouble breathing, and activity limitation); overnight asthma symptoms (cough); the percentage of days wit h asthma symptoms; the percentage of days without asthma; the need for beta -agonist or oral corticosteroids; physician global evaluations; and periph eral blood eosinophils. The clinical benefit of montelukast was evident wit hin 1 day of starting therapy. Improvements in asthma control were consiste nt across age, sex, race, and study center, and whether or not patients had a positive radioallergosorbent test. Montelukast demonstrated a consistent effect regardless of concomitant use of inhaled/nebulized corticosteroid o r cromolyn therapy. Caregiver global evaluations, the percentage of patients experiencing asthm a attacks, and improvements in quality-of-life scores favored montelukast, but were not significantly different from placebo. There were no clinically meaningful differences between treatment groups in overall frequency of adverse effects or of individual adverse effects, wit h the exception of asthma, which occurred significantly more frequently in the placebo group. There were no significant differences between treatment groups in the frequency of laboratory adverse effects or in the frequency o f elevated serum transaminase levels. Approximately 90% of the patients com pleted the study. Conclusions. Oral montelukast (4-mg chewable tablet) administered once dail y is effective therapy for asthma in children aged 2 to 5 years and is gene rally well tolerated without clinically important adverse effects. Similarl y, in adults and children aged 6 to 14 years, montelukast improves multiple parameters of asthma control. Thus, this study confirms and extends the be nefit of montelukast to younger children with persistent asthma.