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Montelukast, a Leukotriene Receptor Antagonist, for the Treatment of Persistent Asthma in Children Aged 2 to 5 Years

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Montelukast, a Leukotriene Receptor Antagonist, for the Treatment of Persistent Asthma in Children Aged 2 to 5 Years Montelukast, a Leukotriene Receptor Antagonist, for the Treatment of Persistent Asthma in Children Aged 2 to 5 Years Barbara Knorr, MD*; Luis M. Franchi, MD‡; Hans Bisgaard, MD§; Jan Hendrik Vermeulen, MDʈ; Peter LeSouef, MD¶; Nancy Santanello, MD, MS*; Theresa M. Michele, MD*; Theodore F. Reiss, MD*; Ha H. Nguyen, PhD*; and Donna L. Bratton, MD# ABSTRACT. Background. The greatest prevalence of baseline period. Patients had a history of physician-di- asthma is in preschool children; however, the clinical agnosed asthma requiring use of ␤-agonist and a pre- utility of asthma therapy for this age group is limited by defined level of daytime asthma symptoms. Caregivers a narrow therapeutic index, long-term tolerability, and answered questions twice daily on a validated, asthma- frequency and/or difficulty of administration. Inhaled specific diary card and, at specified times during the corticosteroids and inhaled cromolyn are the most com- study, completed a validated asthma-specific quality-of- monly prescribed controller therapies for young children life questionnaire. Physicians and caregivers completed a with persistent asthma, although very young patients global evaluation of asthma control at the end of the may have difficulty using inhalers, and dose delivery can study. be variable. Moreover, reduced compliance with inhaled Efficacy end points included: daytime and overnight therapy relative to orally administered therapy has been asthma symptoms, daily use of ␤-agonist, days without reported. One potential advantage of montelukast is the asthma, frequency of asthma attacks, number of patients ease of administering a once-daily chewable tablet; ad- discontinued because of asthma, need for rescue medica- ditionally, no tachyphylaxis or change in the safety pro- tion, physician and caregiver global evaluations of file has been evidenced after up to 140 and 80 weeks of change, asthma-specific caregiver quality of life, and pe- montelukast therapy in adults and pediatric patients ripheral blood eosinophil counts. Although exploratory, aged 6 to 14 years, respectively. the efficacy end points were predefined and their analy- To our knowledge, this represents the first large, mul- ses were written in a data analysis plan before study ticenter study to address the effects of a leukotriene unblinding. At screening and at study completion, a com- receptor antagonist in children younger than 5 years of plete physical examination was performed. Routine lab- age with persistent asthma, as well as one of the few oratory tests were drawn at screening and weeks 6 and 12, asthma studies that incorporated end points validated for and submitted to a central laboratory for analysis. Ad- use in preschool children. verse effects were collected from caregivers at each clinic Objective. Our primary objective was to determine visit. the safety profile of montelukast, an oral leukotriene An intention-to-treat approach, including all patients receptor antagonist, in preschool children with persistent with a baseline measurement and at least 1 postrandom- asthma. Secondarily, the effect of montelukast on explor- ization measurement, was performed for all efficacy end atory measures of asthma control was also studied. points. An analysis-of-variance model with terms for Design and Statistical Analysis. We conducted a dou- treatment, study center and stratum (inhaled/nebulized ble-blind, multicenter, multinational study at 93 centers corticosteroid use, cromolyn use, or none) was used to worldwide: including 56 in the United States, and 21 in estimate treatment group means and between-group dif- countries in Africa, Australia, Europe, North America, ferences and to construct 95% confidence intervals. Treat- and South America. In this study, we randomly assigned ment-by-age, -sex, -race, -radioallergosorbent test, -stra- 689 patients (aged 2–5 years) to 12 weeks of treatment tum, and -study center interactions were evaluated by with placebo (228 patients) or 4 mg of montelukast as a including each term separately. Fisher’s exact test was chewable tablet (461 patients) after a 2-week placebo used for between-group comparisons of the frequency of asthma attacks, discontinuations from the study because of worsening asthma, need for rescue medication, and From the *Departments of Pulmonary-Immunology, Epidemiology, and the frequencies of adverse effects. Because of an imbal- Biostatistics, Merck Research Laboratories, Rahway, New Jersey and West ance in baseline values for eosinophil counts for the 2 Point, Pennsylvania; ‡Pediatric Pulmonary Service, Instituto de Salud del treatment groups, an analysis of covariance was per- Nin˜o, Lima, Peru; §Paediatric Department, Rigshospitalet, Copenhagen, formed on the eosinophil change from baseline with the Denmark; ʈ101 Panorama Medical Clinic, South Africa; ¶Department of Paediatrics, Children’s Hospital Medical Centre, Perth, Australia; and #Na- patient’s baseline as covariate. tional Jewish Center for Immunology and Respiratory Medicine, Denver, Study Participants. Of the 689 patients enrolled, ap- Colorado. proximately 60% were boys and 60% were white. Patients Drs Franchi, Bisgaard, Vermeulen, LeSouef, and Bratton were paid by were relatively evenly divided by age: 21%, 24%, 30%, Merck and Company, Inc, for their services as clinical investigators in this and 23% were aged 2, 3, 4, and 5 years, respectively. For study. In addition, Drs Bisgaard and Bratton have been members of the 77% of the patients, asthma symptoms first developed Merck speakers’ bureau and have served as consultants to the company. during the first 3 years of life. During the placebo base- Received for publication Sep 1, 2000; accepted Apr 23, 2001. line period, patients had asthma symptoms on 6.1 days/ Reprint requests to (B.K.) Pulmonary-Immunology, Merck Research ␤ Laboratories, Box 2000, RY-656, Rahway, NJ 07065. E-mail: barbara࿝ week and used -agonist on 6.0 days/week. [email protected] Results. In over 12 weeks of treatment of patients PEDIATRICS (ISSN 0031 4005). Copyright © 2001 by the American Acad- aged 2 to 5 years, montelukast administered as a 4-mg emy of Pediatrics. chewable tablet produced significant improvements http://www.pediatrics.org/cgi/content/full/108/3/Downloaded from www.aappublications.org/newse48PEDIATRICS by guest on September Vol. 10823, 2021 No. 3 September 2001 1of10 compared with placebo in multiple parameters of asthma form pulmonary function tests such as forced expi- control including: daytime asthma symptoms (cough, ratory volume in 1 second and peak flow maneuvers. wheeze, trouble breathing, and activity limitation); over- Therefore, in addition to the need for new asthma night asthma symptoms (cough); the percentage of days therapies for preschool children, there is a need for with asthma symptoms; the percentage of days without ␤ methods validated for use in assessing the treatment asthma; the need for -agonist or oral corticosteroids; effects of asthma therapies in multicenter studies in physician global evaluations; and peripheral blood eo- these children. sinophils. The clinical benefit of montelukast was evi- dent within 1 day of starting therapy. Improvements in Leukotriene blockers (receptor antagonists and asthma control were consistent across age, sex, race, and 5-lipoxygenase inhibitors) are the first new class of study center, and whether or not patients had a positive asthma therapy in nearly 2 decades. These agents, radioallergosorbent test. Montelukast demonstrated a which include montelukast, pranlukast, zafirlukast, consistent effect regardless of concomitant use of in- and zileuton, block the action or inhibit the synthesis haled/nebulized corticosteroid or cromolyn therapy. of the cysteinyl leukotrienes, bioactive mediators Caregiver global evaluations, the percentage of pa- with proinflammatory effects that play an important tients experiencing asthma attacks, and improvements in role in the pathophysiology of asthma. Cysteinyl quality-of-life scores favored montelukast, but were not leukotrienes cause bronchoconstriction, mucus secre- significantly different from placebo. tion, increased vascular permeability, and eosinophil There were no clinically meaningful differences be- migration to the airways, as well as promote smooth tween treatment groups in overall frequency of adverse muscle proliferation.6–10 Their synthesis and release effects or of individual adverse effects, with the excep- 11 tion of asthma, which occurred significantly more fre- appear not to be blocked by corticosteroid therapy. quently in the placebo group. There were no significant Montelukast is a potent, specific leukotriene recep- differences between treatment groups in the frequency tor antagonist. Administered once daily in tablet of laboratory adverse effects or in the frequency of ele- form, montelukast reduces the signs and symptoms vated serum transaminase levels. Approximately 90% of of chronic asthma in adults and children as young as the patients completed the study. 6 years of age, with a tolerability profile similar to Conclusions. Oral montelukast (4-mg chewable tab- that of placebo.12–13 Additionally, montelukast had let) administered once daily is effective therapy for been shown to attenuate exercise-induced broncho- asthma in children aged 2 to 5 years and is generally well constriction in these patients.14–15 tolerated without clinically important adverse effects. Although single center studies have been per- Similarly, in adults and children aged 6 to 14 years, formed,16 to our knowledge,
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