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Montelukast in Asthmatic Patients 6 Years-14 Years Old With an FEV^Sub 1^ > 75%*

Posted on: Saturday, 18 December 2004, 03:00 CST

Key words: Asthma, pediatric * Efficacy * FEV^sub 1^ * Leukotriene receptor antagonist * Quality of life

SUMMARY

Objectives: Montelukast is a potent leukotriene receptor antagonist effective for treating asthma symptoms in adult and pdiatrie patients. The purpose of this analysis was to assess the clinical efficacy of montelukast, a potent leukotrienereceptor antagonist, in a subgroup analysis of patients aged 6years-14years with milder asthma, defined as a percentage predicted forced expiratory volume in 1 s (FEV^sub 1^) > 75% using data from a clinical trial of pediatric patients with a broad range of asthma severities.

Research design and methods: The original previously published clinical trial was an 8-week multi-center, randomized, double- blind, parallelgroup study conducted in 47 centers in the United States and Canada. The study compared the efficacy of once daily montelukast 5 mg to placebo in patients 6years-14years old with persistent asthma and an FEV^sub 1^ ranging from 50% to 85% of predicted. A total of 87 patients in the montelukast group and 51 patients in the placebo group were selected from the original cohort of 336 patients based on percentage predicted FEV^sub 1^ of > 75%. The primary endpoint was percentage change in FEV^sub 1^ from baseline compared with placebo over 8 weeks of active treatment.

Results: Montelukast significantly improved the primary endpoint of percentage change in FEV^sub 1^ compared with placebo (p= 0.005). Other efficacy endpoints were significantly improved on montelukast similar to efficacy in the original study.

Conclusion: Montelukast significantly improved FEV^sub 1^, clinic measured peak expiratory flow (PEF), reduced nocturnal awakenings, and improved quality of life in children with milder persistent asthma defined as an FEV^sub 1^ > 75% of predicted.

Introduction

Asthma is a common chronic disease of childhood occurring in almost 4 million children in the United States under the age of 14'. The burden of asthma on children and their families is substantial, adversely affecting activity, sleep, and social functioning2. Control of asthma will be optimal with therapies that allow children to fully participate in school and social activities and enable them to have a better quality of life.

Table 1. Characteristics of cohort groups in selected patient populations

Consensus guidelines recommend the use of controller therapy for persistent asthma3 ''. The use of a controller agent is based on observations that airway inflammation is present even in mild asthma% necessitating treatment to first control airway inflammation8,9. Inhaled corticosteroids (ICS) are often used as a first line controller, however, other efficacious agents may be considered as alternative first line therapy. Montelukast, a potent leukotriene receptor antagonist, targets the key leukotriene- mediated pathway of airway inflammation10,11. The important role of lcukotrienes in the pathology associated with asthma has been demonstrated in large clinical trials where montelukast given once daily orally, significantly improved symptoms of asthma in 2-year- 14-year old children12,13 and adults", and inhibited exercise- induced bronchoconstriction in both children15,16 and adults'". A prospective observational analysis comparing effectiveness of montelukast to fluticasone found that pediatric patients with mild asthma had similar oral prednisolone, β-agonist, and asthma- related health care use over 12 months on either agent18.

Previous clinical trials demonstrating the efficacy of montelukast have enrolled pediatric12,13 and adult" asthmatics with a broad range of asthma severity. A metaanalysis of studies of adults with mild asthma demonstrated significant improvements in symptoms, lung function, and quality of life with montelukast'''. Treatment with montelukast was shown to be comparable to ICS in multiple parameters of asthma control in a small group of mild asthmatics 8years-14years old20. To date, there has been no analysis specifically evaluating the effect of montelukast on a large group of pediatric patients with milder asthma, who are excellent candidates for treatment with a steroid-free tablet as an alternative to inhaled steroid therapies. The purpose of this investigation was to determine how montelukast affected airway function, physical activity, and quality of life of patients aged 6years-14years with milder asthma defined as having a percentage- predicted FEV^sub 1^ > 75%.

Methods

Study Design

Data for this analysis were taken from a large multicenter, double-blind, randomized, placebo-controlled, 8-week parallel-group study comparing the clinical efficacy of a 5-mg cherry chewablc tablet of montelukast (201 patients) with placebo (135 patients) given once daily at bedtime in 6-year-l 4-year old children with persistent asthma12. Patients in the original study had an FEV, between 50% and 85%, at least a 15% reversibility after β- agonist use, a pre-specified minimum of daytime asthma symptoms score, and had to have used, on average, at least one puff of albuterol/day during the 2-week placebo run-in period. Of these patients, 122 (36.3%) were also taking inhaled corticosteroids (ICS) at baseline. Patients recorded AM PEF using a peak flow meter (Mini- Wright model, Clement Clark, Columbus, Ohio) and recorded daily symptoms on an asthma diary card.

Inclusion Criteria

For this analysis, a patient population with milder asthma was defined by the level of FEV^sub 1^ as a percentage of predicted value. From the original database, 138 patients were identified as having milder asthma with an FEV^sub 1^ > 75% of predicted (cohort 1). To further define milder cohorts the analysis was expanded to include mild asthmatics (FEV^sub 1^ > 80% predicted) and use of β-agonists (albuterol). Available information on β- agonist use included daily use and puffs/day. For milder patients to be included, β-agonist use was limited to less than daily and less than 2 puffs/day. Using these criteria, in addition to the primary cohort of 138 patients, five other subsets of cohort 1, (cohorts 2-6 respectively) were analyzed (Table 1). Baseline characteristics of cohort 1 were compared to the patient population with an FEV^sub 1^ < 75% from the original study'^ (Table 2). Patients with an FEV^sub 1^ > 75% but not using ICS were evaluated separately.

Table 2. Demographics and characteristics of pediatric asthmatic patients with FEV^sub 1^ > 75% (cohort 1)

Evaluations

FEV^sub 1^ was the pre-specified primary endpoint in the original study. Other endpoints with baseline measurements were daytime asthma symptoms, AM PEF, clinicmeasured PEF, nocturnal awakenings, quality-of-life questionnaire, and change in peripheral blood eosinophils from baseline. In the original study, several efficacy endpoints without baseline measurements were included in the analysis, however, the original study was not powered to detect differences in endpoints other than FEV^sub 1^ so the current subgroup analyses had even lower power. For several efficacy measures, baseline values in these patients were near-normal, making an analysis of change from baseline inappropriate.

Spirometry (FEV^sub 1^ and PEF) was performed between 6a.m. and 9a.m. at each clinic visit. PEF was measured by patients in the morning upon arising (AM PEF). A diary card that contained daytime asthma symptom scores and a nocturnal asthma score was used in the study21. Nocturnal asthma score was rated O (no awakenings) to 3 (awake all night). The 3 daytime asthma symptoms scores (frequency and bother of asthma and activity) were rated on a 6-point scale (0- 5) with O as best. Daytime symptoms were recorded in the evening at bedtime and nocturnal asthma scores were recorded in the morning on arising. Nocturnal awakenings (any non-zero response on the nocturnal asthma score was an awakening) were calculated from the nocturnal asthma score. Patients also recorded as-needed short- acting β-agonist use (albuterol). Patients over the age of 9 years completed a validated, self-administered, pediatric asthma- specific, quality-of-life questionnaire at randomization and at the last visit of the active treatment period2. The questionnaire contained items relating to asthma that children have identified as troublesome in their lives and included 23 items in 3 domains of activity, symptoms, and emotions rated on a 7-point scale from 1 (worst) to 7 (best).

Statistical Analysis

For all endpoints, the average percentage change or change during the treatment period was compared between the 2 treatment groups. FEV^sub 1^ and total daily short-acting β-agonist use were analyzed as percentage change from baseline and all other endpoints were analyzed as change from baseline. For nocturnal awakenings, all patients with any nighttime awakening during the baseline period were included. The nocturnal asthma score was calculated at baseline and on treatment for these patients.

All patients with a baseline and at least one ontreatment value were included in the analysis (intent-totreat analysis). For each endpoint, treatment comparisons between the placebo and montelukast treatment groups were based on an analysis of covariance (ANCOVA) model with the corresponding baseline value included as a covariate and treatment group included as a facto\r.

Results

Patients

A total of 138 patients (41.1%) met the criterion of an FEV^sub 1^ > 75% of predicted (cohort 1) from the original 336 participants. Of these, 66 patients had an FEV^sub 1^ that was > 80% of predicted (19.6% of the original study group) (Table 1). Eighty-nine (64.4%) did not use rescue β-agonists (albuterol) every day and 54 (39.1%) in cohort 1 used β-agonists on the average of ≤ 2 puffs/day. Additional subgroups defined by β-agonist use are shown in Table 1. The distribution of demographics and baseline characteristics (Table 2) and baseline efficacy variables (Table 3) in patients with an FEV^sub 1^ > 75%, (cohort 1) were similar for the two treatment groups. Ninety-four per cent of patients had a history of allergic rhinitis, and 95% of patients had a history of exerciseinduced asthma. Seven patients in the placebo group and 24 patients in the montelukast group reported nocturnal awakenings during the run-in period. For montelukast and placebo groups combined, the mean FEV^sub 1^ was 2.1 0.56 L, the mean percentage- predicted FEV^sub 1^ was 80.7 3.6%, and the post-bronchodilator FEV^sub 1^ reversibility was 19.5 6.4%. A comparison of baseline characteristics of the patient population in cohort 1 (FEV^sub 1^ > 75%) versus patients with an FEV^sub 1^ ≤ 75% showed similarities of age and duration of asthma. Daily rescue -agonist use and postbronchodilator FEV^sub 1^ reversibility were less in cohort 1 than in the population with an FEV^sub 1^ < 75% (Table 4).

Table 3. Baseline characteristics of pediatric asthmatic patients with FEV^sub 1^ > 75% (cohort 1)

Table 4. Summary of patient characteristics at baseline comparing patients with FEV^sub 1^ > 75% (cohort 1) to patients from the original study by Knorr et al.', with FEV^sub 1^ < 75%

Efficacy

In patients with FEV^sub 1^ > 75% (cohort 1) montelukast 5 mg significantly improved lung function, as defined by the primary endpoint of FEV^sub 1^, by 7.28% (from baseline 2.08 L to 2.24 L), compared with 2.36% (from baseline 2.12L to 2.18L) in the placebo group after 8 weeks of treatment (p = 0.005) (Table 5).

Secondary outcomes for cohort 1 are summarized in Table 5. Montelukast significantly improved lung function (FEV^sub 1^ and clinic-measured PEF), nocturnal awakenings, nocturnal asthma score, and reduced asthmatic inflammation (measured by peripheral blood eosinophils). Montelukast significantly improved FEV^sub 1^ (p = 0.005) and clinic-measured PEF (p = 0.045) compared with placebo. Restful sleep, as measured by the reduction in the reporting of nocturnal awakenings and any nocturnal asthma symptoms, improved significantly on montelukast compared with placebo (p = 0.030, p = 0.020 respectfully). Montelukast also significantly reduced peripheral blood eosinophils compared with placebo (p = 0.010).

Efficacy seen in all other cohorts was consistent with the results from cohort 1 (Figures 1 and 2). Cohorts 2 and 3 showed significant improvement in FEV^sub 1^ compared with placebo (p = 0.009, < 0.001, respectively) (Figure 1). Cohorts 2, 3, and 5 showed significant improvements in clinic-measured PEF (p = 0.006, 0.031, and 0.037, respectively) compared with placebo (Figure 1). The reporting of any nocturnal asthma was also significantly reduced in cohort 4 (p = 0.035) (Figure 1). β-agonist use (puffs/day) was significantly reduced in cohort 4 (p = 0.044) and cohort 5 (p = 0.046) (Figure 1).

Table 5. Efficacy endpoints for pediatric asthmatic patients with FEV^sub 1^ > 75% (cohort 1) expressed as mean change or percentage change from baseline values

Figure 1. Difference (95% confidence interval) in mean change or percentage change from baseline in FEV^sub 1^, AM PEF and clinic measured PEF^sub 1^ daytime asthma symptoms score, nocturnal asthma, peripheral blood eosinophil count, and daily rescue β-agonist use (puffs/day) for cohorts 1-6

Quality-of-life parameters (activity, symptoms, emotions, and combined) improved in cohort 1 for montelukast compared with placebo (p = 0.018), and in cohorts 2(p = 0.024), 4 (p = 0.027), and 6 (p = 0.029) (Figure 2). Improvements in activity were significant for all cohorts (p < 0.05 for all) (Table 6; Figure 2).

Ninety-four patients (68%) of cohort 1 were not using ICS throughout the study. Table 7 summarizes a comparison of treatment differences comparing montelukast to placebo for these patients versus the entire cohort 1. Observed treatment differences were not due to a treatment effect in the proportion of patients on ICS and the differences for non-ICS users were consistent with the improvements seen in cohort 1 for all efficacy parameters.

Figure 2. Difference (95% confidence interval) in mean change or percentage change from baseline in quality of life average of three domains and individual domains for cohorts 1-6

Table 6. Quality of life efficacy endpoints for pediatric asthmatic patients with FEV^sub 1^ > 75% (cohort 1) expressed as mean change or percentage change from baseline values

Discussion

This post hoc analysis demonstrated that montelukast provided significant improvement in multiple parameters of asthma control and quality of life in children with milder asthma (FEV^sub 1^ > 75% of predicted) aged 6 years-14 years old; similar to the original study12. This positive treatment effect for montelukast was also evident in patients not taking ICS throughout the study.

Leukotrienes are key mediators of asthmatic inflammation. Montelukast is a potent leukotriene-receptor antagonist approved to treat symptoms of asthma in patients 12 months to adult22. This analysis, focusing on pediatric patients with milder asthma, was taken from a study that demonstrated the clinical efficacy of montelukast in 6-year-14-year old asthmatics with percentage predicted FEV^sub 1^ between 50% and 85%12. While montelukast significantly improved FEV and other parameters of asthma control across all patients in the original study, it was of interest to determine the efficacy in patients with milder asthma (FEV^sub 1^ > 75% of predicted).

Severity of asthma can be categorized using assessments associated with lung function (FEV^sub 1^ and/or PEF variability), need for asthma reliever medication (i.e., short-acting β- agonist) use, and clinical symptoms3. We analyzed patients with asthma severity (cohort 1) based on FEV^sub 1^ > 75% of predicted. Other smaller cohorts were identified by various cut points of FEV^sub 1^ and rescue β-agonist use. Eevels of clinical symptoms that could be used to categorize asthma control, such as daytime symptoms occurring less than daily or nighttime symptoms occurring less than weekly, identified only small numbers of patients and were not used to define additional patient cohorts.

The original study, evaluated the efficacy of montelukast compared to placebo in mild to severe 6-year-14-year old asthmatics12. Since the publication of this clinical trial 6 years ago, asthma guidelines recommend ICS as first-line therapy for treatment of mild asthma with leukotriene receptor antagonists as an alternate option3,4. There are, however, no large efficacy trials to date examining the effect of montelukast in the mild pdiatrie patient. We conducted this post hoc analysis using a patient population from the Knorr study12 to determine the efficacy of montelukast in milder asthmatics. The analyses presented are exploratory in nature and need to be viewed within the context of post hoc subgroup analyses. Because the original study was not powered for these subgroup analyses, the evidence of a clear treatment effect within milder patients is supported by defining milder in different ways and by exploring the treatment effect in multiple endpoints. Within this context and because of the multiple testing issue, the p-value and statistical significance become less important than the demonstration of a consistency of effect across multiple endpoints and within different subgroups. Because subgroup analyses always include fewer patients than does the overall analysis, there is a greater risk of making a type II error, i.e. falsely concluding that there is no difference when in fact one does exist23. In these analyses we demonstrate a significant difference in the comparison of the efficacy of montelukast to placebo. The evidence of a clear treatment effect within milder patients is supported by defining mild in different ways and by looking at the commonly accepted measures of efficacy. Although the sample size is not always adequate to demonstrate statistical significance, the order of magnitude of the treatment differences is clear. The net result of our analyses is that even within these subgroups there is a clear treatment effect of the same order as that seen in the whole patient population.

Table 7. A comparison of treatment differences and 95% confidence intervals for montelukast compared to placebo in patients with FEV^sub 1^ > 75%; all patients in cohort I versus patients in cohort 1 who were not using inhaled corticosteroid (ICS)

Montelukast significantly improved FEV^sub 1^ and clinic- measured PEF in all FEV^sub 1^ > 75% cohorts (p < 0.05). FEV^sub 1^ and clinic-measured PEF also improved in patients with an FEV^sub 1^ > 80% although this was not significant for all cohorts. Patient- measured AM PEF improved although the change was not statistically significant. Measures of pulmonary function may be normal to near- normal at baseline in many of these patients so it is notable that montelukast improved airway function, given the relatively high baseline values. Of note, clinical trials of effective therapies in mild asthmatic patients do not always demonstrate improvements in pulmonary function tests24,25. Other studies have shown improvements in FEV^sub 1^ in patients with mild asthma treated with the leukotriene receptor antagonist zafirlukast26. Montelukast significantly improved FEV^sub 1^ compared withplacebo in a meta- analysis of mild adult asthmatic cohorts defined by pulmonary function as well as clinical endpoints19.

In the original study, montelukast had a rapid onset of action, evident from the first day, which was sustained over the course of the trial12. Other controller agents, such as inhaled corticosteroids27,28 and cromolyn sodium29 may require a longer course of treatment before a clinical effect is evident. Rapid improvements in symptoms may enhance patients' compliance with medication. Additionally, there has been no evidence of tolerance to montelukast in previous adult studies14 suggesting that montelukast has a sustained effect as long-term therapy for chronic asthma.

Measurements other than pulmonary function are valuable in evaluating a treatment effect in pediatric patients with persistent asthma. In this study, montelukast reduced rescue β-agonist use in all of the cohorts studied; this was significant for two mild cohorts (FEV^sub 1^ > 80%) (p < 0.05). Short-acting β-agonist usage in this milder group of asthmatics was less than daily or less than 2 puffs/day at baseline, so a reduction in this already low level of rescue therapy use is noteworthy.

Patients with mild asthma do not experience nocturnal awakenings nightly4. However, any nocturnal awakenings are troublesome and do impact on the well being of both the patient and the family. Montelukast significantly improved restful sleep, as measured by the reduction in nocturnal awakenings in the cohorts with an FEV^sub 1^ > 75% and > 80% and in the smaller cohorts. An increase in nocturnal awakenings in pediatric patients is associated with clinical instability30 suggesting that reduction in nocturnal awakenings with montelukast is an important component of improved asthma control5,6. Additionally, restful sleep is an important factor in a child's ability to perform academically. Snoring has been significantly associated with poor school performance in primary school children31, demonstrating that sleep disturbances directly affect a child's life.

Montelukast provided significantly better control of asthmatic inflammation, compared with placebo, as measured by significantly reduced peripheral blood eosinophil counts in these milder patients (FEV^sub 1^ > 75%) (p = 0.010]. Eosinophils are one of the key effector cells contributing to the pathology associated with asthma and increased peripheral blood eosinophils have been shown to positively correlate with asthma severity32. Confirming results of other studies, the results from this analysis demonstrate that montelukast can reduce eosinophilia in pediatric patients with milder asthma. This finding further underscores that inflammation is an important target for treatment, even in patients with nearly normal lung function, consistent with the recommendations of asthma guidelines3.

Clinical measures may not provide a complete picture of the impact of asthma on a child's life. One of the primary goals of managing childhood asthma is to help pediatric patients participate in exercise and school activities on a level with their peers5,6,33. Over 90% of the children in our study reported having exercise- induced asthma symptoms. Treatment with montelukast improved exercise tolerance, as reported in the quality-of-life questionnaire. Activity scores improved in all cohorts on montelukast compared with placebo (p < 0.05), suggesting that asthma was less disruptive in the child's day-to-day activities. Improvements in quality of life in these patients paralleled decreases in nocturnal awakenings, and decreased need for rescue β-agonists seen with montelukast. Important objectives of asthma management include control of the disease by improving lung function to normal or near-normal levels, reducing or abolishing symptoms and nocturnal awakenings, minimizing rescue β-agonist use, and maintaining normal physical activity3-6. In this analysis of children aged 6 years-14 years with an FEV^sub 1^ > 75%, montelukast compared to placebo improved lung function, sleep, and patients' quality of life. The results of this analysis demonstrate that montelukast had a significant benefit for asthma control in children aged 6 years-14 years with an FEV^sub 1^ > 75%.

Conclusion

The results of this analysis demonstrate that montelukast had a significantly improved FEV^sub 1^, clinic measured PEF, reduced nocturnal awakenings and peripheral blood eosinophils, and improved quality of life in children aged 6 years-14 years with an FEV^sub 1^ > 75%.

Acknowledgment

This study was funded by a grant from Merck Research Laboratories. Drs Swern, Tozzi, Knorr and Reiss are employed by Merck Research Laboratories; Dr Becker is a consultant for Merck Research Laboratories.

* Presented as a poster at the American Thoracic Society Meeting, Seattle Washington, May 16-21, 2003

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

Paper CMRO-2703J3, Accepted for publication: 17 August 2004

Published Online: 14 September 2004

doi: 10.1185/030079904X4644

Allan Becker1, Arlene Swern2, Carol A. Tozzi2, Qinfen Yu2, Theodore Reiss2 and Barbara Knorr2

1Section of Allergy and Clinical Immunology, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada

2Merck Research Laboratories, Ftahway, New Jersey, USA

Address for correspondence: Dr Allan B. Becker, Children's Hospital of Winnipeg, Pdiatrie Allergy & Clinical Immunology, 820 Sherbrook St., Room AE 101, Winnipeg, Manitoba R3A IR9, Canada. Tel.: +1-204-787-2455; Fax: +1-204-787-5040; email: becker@Ms.UManitoba.CA

Copyright Librapharm Oct 2004

Source: Current Medical Research and Opinion

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