Safety, Tolerability, and Exploratory Efficacy of Montelukast in 6- to 24-Month-Old Patients With Asthma

Key words: Allergic rhinitis – Atopy – Controlled clinical trial – Montelukast – Pediatric asthma

ABSTRACT

Objective: The purpose of this study was to determine the safety and tolerability profile of montelukast 4-mg oral granules compared with placebo in children aged 6-24 months with asthma.

Methods: This was a randomized, double-blind, placebo- controlled, parallel-group study. Children 6-24 months of age at first visit with a history of at least three episodes of physician- diagnosed asthma or ‘asthma-like’ symptoms and in need of controller therapy were randomized to either montelukast 4-mg oral granules or placebo once daily in the evening for 6 weeks. The primary variables were the frequency of clinical and laboratory adverse experiences. The exploratory efficacy endpoints included days without β- agonist use, β-agonist use per day, unscheduled physician or hospital visits for asthma, oral corticosteroid rescues for asthma, asthma attacks, discontinuation due to worsening of asthma, and total blood peripheral eosinophil counts.

Results: The most common clinical adverse experiences were upper respiratory tract infection, asthma, fever, diarrhea, and vomiting occurring with similar frequencies between treatment groups. There were no clinically meaningful differences between the two treatment groups in clinical or laboratory adverse experiences and no significant differences in frequency of patients with elevated serum transaminases. Differences between the montelukast and placebo treatment groups in the exploratory efficacy endpoints of days without β-agonist use, oral corticosteroid rescues, emergency care, asthma attacks, and discontinuations due to worsening asthma were not significant.

Conclusions: Montelukast, 4-mg oral granules, was well tolerated over 6 weeks of treatment in children aged 6-24 months with asthma.

Introduction

Asthma is the most common chronic disease of childhood, and its prevalence is increasing worldwide1-3. Asthma often appears within the first 3 years of life3,4 and may be associated with deterioration of lung function into adulthood5-8. Recent studies suggest that asthma originates as a chronic inflammatory disease of the airways and is characterized by symptoms of wheezing, airway narrowing, and airways obstruction. Typically, episodes of wheezing begin during childhood and account for up to 60% of pediatric hospital admissions by the age of 5(6),9. Despite its prevalence in early childhood, early wheezing is generally benign, and most children do not continue to wheeze6,10,11. However, a significant number of children have persistent wheezing at 6 years of age. The observation that many children with persistent wheezing at 6 years old have a family history of asthma, eczema or allergic rhinitis, elevated serum IgE levels, and reduced values for maximal expiratory flow (V^sub max^) functional residual capacity suggests that young patients at risk of loss of pulmonary function can be identified at an early age6,11. These data suggest the importance of identification of children at risk for developing asthma and the need for safe and effective therapy at an early stage of the disease.

While therapeutic interventions can decrease severity of symptoms, asthma is frequently undertreated12,13. Treatment options available for young children are limited by a narrow therapeutic index, concerns about growth suppression, and difficulty with or frequency of administration.

Leukotriene-receptor antagonists [montelukast, pranlukast, and zafirlukast] and 5-lipoxygenase inhibitors (zileuton) block the action or inhibit synthesis of cysteinyl leukotrienes, pro- inflammatory mediators produced by eosinophils, mast cells, and alveolar macrophages. Cysteinyl leukotrienes play a role in the pathogenesis of asthma, causing bronchoconstriction, mucus secretion, increased vascular permeability, smooth muscle cell proliferation and eosinophil migration14-18. Leukotriene levels are elevated in adult asthmatics19,20, and the available evidence suggests that this is also the case in infants and young children. Alveolar macrophages isolated from wheezy infants release greater amounts of leukotrienes compared with those from healthy infants21. Persistent wheezing in children less than 3 years old is associated with increases in inflammatory cells and elevated levels of inflammatory mediators, including the leukotrienes LTE^sub 4^ and LTB^sub 4^, in the lower airways9. Thus, the role of cysteinyl leukotrienes in the pathophysiology of asthma appears to be similar from early childhood to adulthood. Montelukast, a potent, specific, leukotriene-receptor antagonist given once a day, has proven to provide significant reduction in the symptoms of asthma in adults and children22-29 and improvement in exploratory efficacy endpoints in children as young as 2 years of age30. Montelukast has a favorable safety profile and is generally well tolerated22-31. These data suggest that montelukast could provide benefit in patients younger than 2 years of age. The primary purpose of this 6-week study was to evaluate the safety and tolerability of a new formulation of montelukast (4-mg oral granules) administered in apple sauce once daily in the evening in children aged 6-24 months with asthma. The effect of montelukast compared with placebo on exploratory efficacy measures also was evaluated.

Methods

Patient selection

Patients were between the ages 6 and 24 months and within the 5th- 95th percentile for height and weight for age at the pre-study visit (first study visit). Each patient had a history of physician- diagnosed asthma or ‘asthma-like’ symptoms, including, but not limited to, cough, wheezing, and shortness of breath. The patient must also have had at least three episodes of these asthma or ‘asthma-like’ symptoms occurring after 8 weeks of age, with at least one episode within 6 months of the pre-study visit. Additionally, patients had to be in need of a controller therapy according to criteria established in the Global Initiative for Asthma (GINA) guidelines32. Specifically, patients were in need of β-agonist treatment two or more times per week on average during the month prior to the first study visit. Patients who had required oral or parenteral corticosteroids within 2 weeks of the first visit were excluded from the study.

Patients were not eligible for the study if they had been born prematurely, had an unresolved respiratory tract infection, or any serious condition requiring hospitalization or emergency room treatment within 4 weeks, or an asthma exacerbation within 2 weeks of the pre-study visit. All patients used short-acting ‘as needed’ β-agonist therapy throughout the study. Patients who were on a stable dose of inhaled/nebulized corticosteroids, inhaled/nebulized cromolyn, or nedocromil for at least 2 weeks prior to the pre-study visit were allowed to continue on these medications at the same dose.

Patients were withdrawn if they experienced a clear worsening of the signs and/or symptoms of asthma requiring more than one rescue with oral corticosteroids, had a serious adverse experience, or experienced a protocol violation.

The protocol was approved by the institutional review boards (in the United States) or ethical review committees (in other countries) of all participating sites. Written informed consent was obtained from parents or legal guardians of all patients.

Montelukast dose selection

Administration of montelukast to pediatric patients requires special age-appropriate formulations. Accordingly, an oral granules formulation of montelukast was developed for young pediatric patients. Since asthma is a similar disease in children and adults and treated with the same medications, pediatric doses may be selected by determining the dose in children that provides similar systemic drug exposure to that observed with the optimal adult dose selected in dose-ranging studies. The 4-mg oral granules dose of montelukast selected for use in this study provided similar systemic drug exposure to that observed with the adult 10-mg film-coated tablet, the optimal adult dose selected in dose-ranging studies in asthma33.

Study design

This was a randomized, double-blind, placebo-controlled, parallel- group, multicenter study evaluating the safety and tolerability of montelukast (4-mg oral granules formulation) with matching-image placebo. Treatments were given once daily mixed with 1 tablespoon of apple sauce at bedtime to children aged 6-24 months with asthma. Patients were seen at the clinic every 2 weeks during the active treatment period. A complete physical examination was performed at the pre-study visit and at visit 5 (or upon discontinuation if before visit 5). Vital signs, including heart and respiratory rates and body temperature, were measured at every visit. An action plan for worsening asthma was reviewed at the pre-study visit and at every subsequent visit during the study. Adverse experiences were collected throughout the trial.

The study was conducted at 65 centers (in Africa, Asia, Europe, North America, and South America) between August 2000 and February 2001 under in-house blinding procedures. After a pre-study period, patients who met the inclusion criteria were randomly allocated according to a computer-generated schedule to r\eceive either montelukast or placebo for 6 weeks in a ratio of 2:1 (montelukast:placebo). The study design is diagrammed in Figure 1.

Figure 1. Study outcomes

Exploratory efficacy evaluations

Caregivers completed an asthma-specific calendar modified for use in children aged 6-24 months from a diary previously used in montelukast studies in children aged 2-5 years30. Caregivers recorded daily whether or not the patient required an unscheduled visit to the doctor, emergency room, or hospital for asthma; oral corticosteroid therapy; and ‘as-needed’ β-agonist use throughout the study.

Exploratory efficacy endpoints

The objective of the study was to evaluate the safety and tolerability of montelukast in children aged 624 months with asthma. Although not powered for efficacy, the study evaluated the effect of montelukast and placebo on several efficacy endpoints. Because these efficacy endpoints have not been previously evaluated in clinical placebo-controlled studies in this age group, they were considered exploratory. Evaluations included days without β-agonist use; β-agonist use per day; total peripheral blood eosinophil counts; the number of unscheduled physician, emergency room, or hospital visits due to worsening asthma symptoms; oral corticosteroid rescues for worsening asthma symptoms; asthma attacks (composite of unscheduled visits and oral steroid rescues); and discontinuations due to worsening asthma symptoms.

Statistical analysis

The study was designed to have at least 150 patients completing the study, with approximately 100 patients in the montelukast treatment group and 50 patients in the placebo treatment group completing the active-treatment period. The study was not powered for the exploratory endpoints, and the 2:1 montelukastiplacebo randomization scheme allowed for a larger number of patients to be exposed to montelukast to address the safety evaluation. (For example the study had a power of 80% to detect a treatment difference if the incidence of an adverse effect was 19.4% in the montelukast group and 1% in the placebo group using a two-sided test with α-level of 0.05). All statistical tests were two-tailed with α =0.050.

Adverse experiences and frequency of abnormal laboratory values were compared between treatment groups using Fisher’s exact test. Laboratory safety parameters and vital signs were summarized by treatment groups.

The efficacy analyses were based on a modified intention-to- treat principle; therefore, all patients who had at least one post- treatment measurement were included in the analysis. The continuous exploratory efficacy endpoints were analyzed using an analysis of variance (ANOVA) model for endpoints with no baseline measurements or an analysis of covariance (ANCOVA) model for endpoints with baseline measurements. The model had factors for treatment, study country, age group (< 12 months, ≥ 12 months), stratum defined by concomitant asthma controller medication (inhaled/nebulized corticosteroid use, inhaled/nebulized cromolyn use, or none) and baseline as a covariate if collected. The underlying assumptions for the ANCOVA model were checked via Shapiro-Wilk statistics for normality and Levene's test for homogeneity of variance between the treatment groups.

The subgroup analyses for patients with risk factors associated with development of persistent asthma (e.g. a history of allergic rhinitis or atopic dermatitis or a history of atopic dermatitis and having an asthmatic parent) were performed using the same model.

Results

Patient accounting

Of the 359 patients screened for inclusion in the study, 175 were randomly assigned to the montelukast group and 81 to the placebo group (Figure 1). Approximately 68% of patients were boys and 57% were white. The mean age was 14.6 months; 33% were between 6 months and < 12 months old at study entry (Table 1). The majority of patients were receiving controller therapy for asthma at randomization; 50% received inhaled/nebulized corticosteroids and 9.8% received cromolyn (Table 1). Overall, the two treatment groups were generally comparable in baseline characteristics of asthma (Table 1). However, patients randomized to montelukast had slightly more severe asthma as evidenced by the total courses of oral corticosteroids taken in the past year (1.57 for montelukast vs. 1.45 for placebo), the number of days on oral corticosteroids in the past year (7.52 for montelukast vs. 7.37 for placebo), and the number of patients requiring oral corticosteroid rescues in the month (4% for montelukast vs. 0% for placebo) and the year (11.4% for montelukast vs. 7.4% for placebo) before the study start. The differences were particularly notable in the patients < 12 months of age. In this age subgroup, patients randomized to montelukast had received more oral corticosteroids and were more likely to be on inhaled corticosteroids. Specific comparisons were made between groups for oral corticosteroids taken in the past year (1.41 for montelukast vs. 0.67 for placebo), the number of days on oral corticosteroids in the past year (7.51 for montelukast vs. 3.42 for placebo), and the number of patients requiring oral corticosteroid rescues in the month (9.8% for montelukast vs. 0% for placebo) and the year (17.6% for montelukast vs. 0% for placebo) before the study start.

Thirteen patients did not complete the study: six (3.4%) in the montelukast group and seven (8.6%) in the placebo group (Figure 1). Three patients in the montelukast group (1.7%) and three in the placebo group (3.7%) discontinued the study due to a clinical adverse experience. Other discontinuations were due to protocol violations, withdrawn consent, or a patient moving from the area.

Safety evaluation

There were no significant differences between the montelukast and placebo treatment groups in percentages of patients who reported clinical adverse experiences. The incidence of drug-related adverse experiences was similar in both groups. No serious clinical adverse experiences were considered to be drug-related in either treatment group. Upper respiratory tract infection, asthma, fever, diarrhea, and vomiting were the most common specific clinical adverse experiences, occurring in more than 10% of patients in both treatment groups (Table 3). Although not statistically significant, upper respiratory infection occurred more commonly in the montelukast group (32%) than in the placebo group (21%). To evaluate the incidence of adverse experiences involving the upper respiratory tract, all adverse experiences were examined as a group, including influenza-like disease, upper respiratory infection, viral infection, nasal congestion, nasal secretion, nasopharyngitis, otitis, otitis media, pharyngitis, rhinitis, serous otitis media, sinusitis, tonsillitis, bronchiolitis, cough, respiratory infection, tracheitis, and tracheobronchitis. The incidence of adverse experiences involving the upper respiratory tract was 54.9% in the montelukast group and 51.9% in the placebo group. The illnesses were generally transient and either resolved during the study period or did not require discontinuation of therapy. The montelukast group experienced fewer adverse experiences of worsening asthma (1.15%) than did the placebo group (2.47%), but this was not statistically significant.

Table 1. Baseline characteristics of patients in evaluation of montelukast in 6- to 24-month-old patients with asthma

Table 2. Baseline use of concomitant asthma controller medication in 6- to 24-month-old patients with asthma

There were no clinically meaningful differences in the changes from baseline in vital signs, height and weight measurements, or physical examination measurements between treatment groups.

Laboratory adverse experiences occurred in less than 5% of patients and the incidence was similar in the montelukast and placebo groups. There were four patients (2.4%) in the montelukast group who had laboratory adverse experiences. Three of the four patients who had adverse experiences also had concurrent infections, including infections of the upper respiratory tract or urinary tract or Epstein-Barr virus. None of the laboratory adverse experiences resulted in discontinuation of therapy. There were no significant differences between treatment groups in the frequencies of patients exceeding the predefined limits of change. There were no significant differences between montelukast and placebo treatment groups in the frequency of patients with elevated serum transaminases (alanine aminotransferase and aspartate aminotransferase).

Exploratory efficacy evaluation

A summary of exploratory efficacy endpoints is presented in Table 4. There was no statistically significant difference in days without β-agonist use (p = 0.081) or in β-agonist treatments per day (p = 0.218) between the treatment groups. The frequency of oral corticosteroid rescues was similar between the groups (p = 0.106). There was no significant difference between groups in exploratory endpoints including the percentage of patients with unscheduled visits to a physician, emergency room, or hospital (p = 0.289); asthma attacks (p = 0.724); discontinuation of treatment due to worsening of asthma (p = 0.594); and in peripheral blood eosinophil counts (p = 0.974). For the ANOVA/ANCOVA model, the equal variance assumption was not violated for all the endpoints. Normality assumptions seemed to be violated, however, the non-parametric analysis corroborated the results for the ANOVA/ANCOVA analysis results. Treatment effects were consistent across study country, gender, race, age group, and concomitant medication use.

Table 3. Frequency of most common clinical adverse experiences in 6- to 24-month-old patients with asthma

Efficacy in subgroups at risk of developing persistent asthma

A number of epidemiologic studies have shown a strong association between asthma that persists beyond age 5 and certain clin\ical risk factors in infants and young children. These include eczema and/or allergic rhinitis in the child and/or a parent with asthma6,11. Because these risk factors identified a particularly vulnerable population likely to need long-term controller therapy for asthma, a post hoc analysis examined the efficacy of montelukast for this subgroup of patients. Therefore, days without β-agonist use were analyzed, and it was determined that there was a significant improvement with montelukast compared with that for placebo in patients with a history of allergic rhinitis (p = 0.013) or atopic dermatitis (p = 0.011) and in patients with a history of atopic dermatitis and one or more parents with asthma (p = 0.024) (Table 5).

Discussion

This study demonstrated that once-daily treatment with montelukast 4-mg oral granules was well tolerated with an adverse experience profile similar to placebo in patients aged 6-24 months with asthma.

There were no clinically meaningful differences between montelukast and placebo in the frequency of clinical or laboratory adverse experiences. There were few discontinuations due to adverse experiences in both treatment groups and fewer in the montelukast group than in the placebo group. Worsening of asthma occurred less frequently in the montelukast group, but the difference was not significant. The safety and tolerability profile was similar to that observed in children aged 2-5 years with asthma who were treated for a 12-week30 or 1-year period29 and to studies in older children25,27,28 and adults22-24.

Although the long-term safety profile of montelukast will have to be assessed in this age group, no change in safety or tolerability has been observed in pediatric patients aged 2-5 years treated for 12 weeks30 or 1 year29, patients 6-14 years (treated up to 1.8 years), or in adults (treated up to 4.1 years) with montelukast therapy31. The safety and tolerability profile of montelukast in patients < 2 years old in this study is similar to the experience in older children and adults.

Table 4. Analysis of exploratory efficacy endpoints for children 6- to 24-months of age with asthma

Table 5. ANOVA analysis of percentage of days without β- agonist use comparing montelukast with placebo in subgroups of patients at risk of developing persistent asthma at age 6

Patients in the montelukast group experienced more oral corticosteroid rescues compared with the placebo group, although the number of oral corticosteroid rescues was not significantly different from placebo. Patients in the montelukast group had more frequent use of corticosteroid therapy prior to entering this study compared with patients in the placebo group. Thus, the more frequent use of oral corticosteroids may reflect either greater severity of asthma in these patients or a lower threshold for oral corticosteroid use in the investigators caring for these patients.

A limitation of the study is the difficulty in diagnosing asthma in children of this age group. A challenge for physicians caring for children with asthma symptoms is objectively measuring respiratory function to evaluate the degree of pulmonary dysfunction. Spirometry is the standard technique used in school-aged children and adults and is a key measurement in categorizing asthma severity in treatment guidelines32. In children 2 years and older, respiratory function has been successfully measured in a clinic or hospital setting34-35. However, these measurements require the use of a mouthpiece and are generally not suitable for children less than 2 years of age. Evaluation of asthma in very young children must rely on subjective symptoms assessment (frequency and severity) by caregivers with no suitable objective criteria. Children in this study had to have a minimum of symptoms, including (but not limited to) cough, wheezing, or shortness of breath on three occasions consistent with at least step 2 of the GINA guidelines32. So children with a range of asthma severities from mild to moderate could have been included in this study. Of note, 59.8% of patients were receiving at least one asthma controller medication and were still symptomatic when they entered the study supporting a range of asthma severities.

Asthma generally begins during the first years of life3,7; however, many children with symptoms do not progress to chronic disease6. There are distinct subpopulations of children who have episodes of wheezing during early childhood and who are at risk of developing persistent asthma by age 6(36,37), including those wheezing during the first 3 years of life and either one major factor of parental history of asthma or eczema or two of three minor factors (i.e. eosinophilia, wheezing without colds, and allergic rhinitis)36. Because of the difficulty in diagnosing asthma in the very young children included in this study, a subgroup of children who had risk factors for development of chronic asthma was identified36. In a post hoc analysis, montelukast significantly increased the days without β-agonist use in patients with a history of atopic dermatitis, allergic rhinitis, or atopic dermatitis and a parental history of asthma. These findings warrant further examination in future clinical trials.

Conclusion

This study has demonstrated that a 4-mg oral granules formulation of montelukast was well tolerated with a safety profile similar to placebo in children aged 6-24 months. In the entire study population, montelukast had a numerically favorable but not statistically significant improvement in exploratory efficacy endpoints. This study suggests that montelukast would be a well tolerated therapy for asthma in children as young as 6 months of age.

Acknowledgments

Declaration of interests: This study was supported by a grant from Merck Research Laboratories, Rahway, NJ. Drs van Adelsberg, Wei, Tozzi, Knorr, and Reiss are employees of Merck. Dr Moy was an investigator in the study and an advisor on the study design.

The authors would like to acknowledge the technical assistance of Michelle Zakson-Aiken.

Investigators: Oscar Aldrey, MD, Caracas, Venezuela; Jerzy Alkiewicz, MD, Poznan, Poland; Thor Baekken, MD, Norway; Eugenio Baraldi, MD, Padova, Italy; Jose Bardelas, MD, High Point, NC; Alan Barrientos Tobar, MD, Guatemala City, Guatemala; William E. Berger, MD, Mission Viejo, CA; Denis Beruhe, MD, Montreal, Canada; Michael Blaiss, MD, Cordova, TN; Kathryn Blake, PharmD, Jacksonville, FL; Eddy Bodart, MD, Belgium; Attilio Boner, MD, Verona, Italy; Maria Boza Costagliola, MD, Santiago, Chile; Donna L. Bratton, MD, Denver, CO; Edwin A Bronsky, MD, Salt Lake City, UT; Paul Chervinsky, MD, North Dartmouth, MA; Danuta Chmielewska-Szewczyk, MD, Warsaw, Poland; Frans De Baets MD, Gent, Belgium; Elida Duenas Meza, MD, Bogota, Columbia; Eugenia Elizondo Vargas, MD, San Jose, Costa Rica; Mark Everard, MD, Sheffield, United Kingdom; Stanley P. Galant, MD, Orange, CA; Maria Luz Garcia-Garcia, MD, Madrid, Spain; A. Joanne Gates, MD, New Orleans, LA; Joan Chernoff Gluck, MD, Miami, FL; Daniel Goh Yam Thiam, MD, Singapore; Anne Goh, MD, Singapore; Robin Green, MD, Johannesburg, South Africa; Frances Guerra Lillo, MD, Lima, Peru; Martin E. Hurwitz, MD, Ypsilanti, MI; Estaban Keklikian, MD, Buenos Aires, Argentina; Edward M. Kerwin, MD, Medford, OR; Piotr Kuna, MD, Lodz, Poland; Yu Lung Lau, MD, Hong Kong; Carolina Luna Rojas, MD, Mexico City, Mexico; Brian Lyttle, MD, Ontario, Canada; Jorge Maspero, MD, Buenos Aires, Argentina; Somnath Mukhopadhyay, MD, Dundee, United Kingdom; Anjuli S.Nayak, MD, Normal, IL; Michael J. Noonan, MD, Portland, OR; Paul Pianosi, MD, Nova Scotia, Canada; Bruce M. Prenner, MD, San Diego, CA; Keith S. Reisinger, MD, Pittsburgh, PA; Clement L. Ren, MD, Stony Brook, NY; Estelle Simons, MD, Winnepeg, CA; Renato Stein, MD, Porto Alegre, Brazil; Paul Stephenson, MD, Suffolk, United Kingdom; Alejandro Teper, MD, Buenos Aires, Argentina; Gabor Uhereczky, MD, PhD, Budapest, Hungary; Jan Vermeulen, MD, Panorama, South Africa; Jose Ramon Villa-Asensi, MD, Madrid, Spain; Steven F. Weinstein, MD, Huntington Beach, CA; Johannes Heinrich Wildhaber, MD, Zurich, Switzerland; Franklin Yamamoto, MD, Honolulu, HI.

References

1. Mannino DM, Homa DM, Akinbami LJ, et al. Surveillance for asthma – United States, 1980-1999. MMWR Surveill Summ 2002;51(1):1- 13

2. Woolcock AJ, Peat JK. Evidence for the increase in asthma worldwide. Ciba Found Symp 1997;206:122-34

3. Yunginger JW, Reed CE, O’Connell EJ, et al. A community-based study of the epidemiology of asthma. Incidence rates, 1964-1983. Am Rev Respir Dis 1992;146:888-94

4. Croner S, Kjellman N-IM. Natural history of bronchial asthma in childhood: a prospective study from birth up to 12-14 years of age. Allergy 1992;47:150-7

5. Burrows B, Knudson RJ, Cline MG, Lebowitz MD. A reexamination of risk factors for ventilatory impairment. Am Rev Respir Dis 1988; 138:829-36

6. Martinez FD, Wright AL, Taussig LM, et al. Asthma and wheezing in the first six years of life. New Engl J Med 1995;332:133-8

7. Martinez FD. Recognizing early asthma. Allergy 1999;54(Suppl. 49):24-8

8. Carlsen KH. What distinguishes the asthmatic amongst the infant wheezers? Pediatr Allergy Immunol 1997;8(Suppl 10):40-5

9. Krawiec ME, Wescott JY, Chu HW, et al. Persistent wheezing in very young children is associated with lower respiratory inflammation. Am J Respir Crit Care Med 2001;163:1338-43

10. Sheriff A, Peters TJ, Henderson J, Strachan D, ALSPAC Study Team. Avon Longitudinal Study of Parents and Children. Risk factor associations with wheezing patterns in children followed longitudinally from birth to 3(1/2) years. Int J Epidemiol 2001;30(6):1473-84

11. Rusconi F, Galassi C, Corbo GM, et al. Risk factors for early, persistent, and late-onset wheezing in young children. Am J Respir Crit Care Med 1999;160:1617-22

12. Kaur B, Anderson HR, Austin J, et al. Prevalence of asthma symptoms, diagnosis, and treatment in 1\2-14 year old children across Great Britain (international study of asthma and allergies in childhood, ISAAC UK). Br Med J 1998;316:118-24

13. Grant EN, Daugherty SR, Moy JN, et al. Prevalence and burden of illness for asthma and related symptoms among kindergartners in Chicago public schools. Ann Allergy Asthma Immunol 1999;83:113-20

14. Busse WW. The role of leukotrienes in asthma and allergic rhinitis. Clin Exp Allergy 1996;26:868-79

15. Laitinen LA, Laitinen A, Haahtela T, et al. Leukotriene E^sub 4^ and granulocytic infiltration into asthmatic airways. Lancet 1993;341:989-90

16. Dahlen SE, Hedquist P, Hammerstrom B, Samuelsson B. Leukotrienes are potent constrictors of human bronchii. Nature 1980;288:484-6

17. Drazen JM, Israel E, O’Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway. New Engl J Med 1999;340:197- 206.

18. Cohen P, Noveral JP, Bhaia A, et al. Leukotriene D^sub 4^ facilitates airway smooth muscle cell proliferation via modulation of the IGF axis. Am J Physiol 1995;269:L151-L157

19. Smith CM, Hawksworth RJ, Thein FC, et al. Urinary leukotriene- E4 in bronchial asthma. Eur Respir J 1992;5:693-9

20. Cowburn AS, Sladek K, Soja J, et al. Over expression of leukotriene C^sub 4^ synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J Clin Invest 1998;101:834-46

21. Azevedo I, de Blic J, Scheinmann P, et al. Enhanced arachidonic acid metabolism in alveolar macrophages from wheezy infants. Am J Respir Crit Care Med 1995;152:1208-14

22. Reiss TF, Chervinsky P, Dockhorn RJ, et al. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma. Arch Intern Med 1998;158(11):1213-20

23. Israel E, Chervinsky PS, Friedman B, et al., for the Montelukast Beclomethasone Comparison Study Group. Effects of montelukast and beclomethasone on airway function and asthma control. J Allergy Clin Immunol 2002;110:847-54

24. Price DB, Hernandez D, Magyar P, et al., for the Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy (COMPACT) International Study Group. Randomized controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients with asthma. Thorax 2003;58:211- 6

25. Knorr B, Matz J, Bernstein JA, et al. Montelukast for chronic asthma in 6- to 14-year-old children: a randomized, double-blind trial. J Am Med Assoc 1998;279:1181-96

26. Bisgaard H, for the Study Group on Montelukast and Respiratory Syncytial Virus. A randomized trial of montelukast in respiratory syncytial virus postbronchiolitis. Am J Respir Crit Care Med 2003;167:379-83

27. Becker A, Swern A, Tozzi CA, et al. Montelukast in asthmatic patients 6 years-14 years old with an FEV1 > 75%. Curr Med Res Opin 2004;20:1651-9

28. Garcia MLG, Wahn U, Gilles L, et al. Montelukast compared to fluticasone in control of asthma in 6 to 14 year old patients with mild asthma: The MOSAIC study. Pediatrics (in press)

29. Bisgaard H, Garcia MLG, Zielen S, et al. Montelukast reduces viral induced asthma exacerbations in 2 to 5 year old children with intermittent asthma. Am J Respir Crit Care Med 2005;171:315-22

30. Knorr B, Franchi LM, Bisgaard H, et al. Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics 2001;108(3):E48

31. Storms W, Michele TM., Knorr B, et al. Clinical safety and tolerability of montelukast, a leukotriene receptor antagonist, in controlled clinical trials in patients aged > 6 years. Clin Exp Allergy 2001;31:77-87

32. Global initiative for asthma. Pocket guide for asthma management and prevention. NIH Publication No. 96-3659B. Bethesda (MD): National Institutes of Health; 1998

33. Migoya E, Kearns GL, Hartford A, et al. Pharmacokinetics of montelukast in asthmatic patients 6 to < 24 months old. J Clin Pharm 2004;44:487-94

34. Klug B, Bisgaard H. Specific airway resistance, interrupter resistance, and respiratory impedance in healthy children aged 2-7 years. Pediatr Pulmonol 1998;25:322-31

35. Ducharme FM, Davis GM. Measurement of respiratory resistance in the emergency department. Chest 1997;111:1519-25

36. Castro-Rodriguez JA, Holberg CJ, Morgan WJ, et al. Relation of two different subtypes of croup before age three to wheezing, atopy, and pulmonary function during childhood: a prospective study. Pediatrics 2001;170:512-8

37. Martinez FD, Helms PJ. Types of asthma and wheezing. Eur Respir J 1998;12(Suppl. 27):3S-8S

CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2895_3, Accepted for publication: 20 April 2005

Published Online: 18 May 2005

doi: 10.1185/030079905X48456

Janet van Adelsberg(a), James Moy(b), Lynn X Wei(a), Carol A Tozzi(a), Barbara Knorr(a) and Theodore F Reiss(a)

a Merck Research Laboratories, Rahway NJ, USA

b University Consultants in Allergy & Immunology, Rush- Presbyterian-St. Luke’s Medical Center, Chicago IL, USA

Address for correspondence: Janet van Adelsberg, MD, Merck Research Laboratories, 126 East Lincoln Avenue, RY34-B280, Rahway NJ, 07065, USA. Tel.: +1 732 594 9349; Fax: +1 732 94 3250; e-mail: janet_vanadelsberg@merck.com

Copyright Librapharm Jun 2005