Effectiveness of montelukast administered as monotherapy or in combination with inhaled corticosteroid in pediatric patients with uncontrolled asthma: a prospective cohort study

Eligible patients were between 2 and 14 years of age and had been diagnosed with asthma for at least 6 months. In order to be included in the study, patients had to have a peak expiratory Flow (PEF) ≥ 80% of the predicted value (applicable only for patients older than 7 years old) and they had to be either currently untreated, using a short-acting β₂–agonist (SABA) on an as-needed basis or using an ICS at any dosage. In addition, one of the following conditions had to be satisfied: i) the physician and/or patient was dissatisfied with the current controller therapy; ii) the patient was reluctant to take ICS therapy, or; iii) the patient was insufficiently controlled with the current therapy through the preceding 6 weeks. Finally, eligible patients had to have uncontrolled asthma as per the 2003 Canadian Asthma Consensus Guidelines [6].

Patients were excluded if their asthma symptoms were controlled and if they were treated with montelukast or any of the following treatments at the time of entry into the study: long-acting β₂-agonist (LABA) alone or in a combination product, oral prednisone, regular use of theophylline and/or other asthma medications such as sodium cromoglycate or nedocromil. Patients using an antibiotic for respiratory tract infection at the time of entry into the study or treated with an antibiotic for respiratory tract infection (initiation of antibiotic treatment was permitted during the study) within 30 days were also excluded. A history of cystic fibrosis, immune deficiency requiring specific therapy or any other disease that could influence the evolution of asthma was also a reason for exclusion. Finally, patients with a history of hypersensitivity to any component of montelukast were excluded.

Considering that the primary outcome measure was the proportion of patients achieving asthma control based on the ACQ criteria (ACQ ≤ 0.75), a re-analysis of the data was conducted including only patients with ACQ > 0.75 at baseline the results of which are reported here.

All patients were treated with montelukast sodium (SINGULAIR®, Merck & Co. Inc., USA) taken once-daily at bedtime as monotherapy or in addition to their current ICS therapy. Patients aged between 6 and 14 years were treated with 5 mg montelukast sodium chewable tablets, while patients between 2 and less than 6 years of age were treated with 4 mg montelukast chewable tablets. The 4 mg granule formulation was also available for the latter age group on demand. The use of a short-acting β₂-agonist (SABA) as rescue medication was allowed during the study, but patients were asked to refrain from its utilization for 6 hours prior each study visit.

The primary effectiveness outcome measures was the proportion of patients achieving asthma control, defined as a score ≤ 0.75 [15] in the self-administered Asthma Control Questionnaire (ACQ) (completed by the patient or their caregiver) [16]. Secondary effectiveness outcome measures included: (i) the mean change in ACQ score between baseline and the 4- and 12-week assessments, considering a change of ≥ 0.5 in ACQ score as clinically important [16]; (ii) the change in quality of life of the caregivers between baseline and the 4- and 12-week assessments, as assessed using the Pediatric Asthma Caregivers Quality of Life Questionnaire (PACQLQ) [17], considering changes of ≥ 0.7 in PACQLQ as clinically important [17]; (iii) the patient (completed by the patient or their caregiver) and physician satisfaction with treatment as measured using the 5-point Likert scale ranging from 0 (very dissatisfied) to 4 (very satisfied), upon 4 and 12 weeks of treatment with montelukast; and (iv) the proportion of patients on montelukast combination therapy whose baseline ICS daily dosage was tapered to a lower ICS dose category after 4, 8 and 12 weeks of treatment. The ICS daily doses were categorized according to the 2006 report of the Global Initiative for Asthma (GINA) [18] as follows: (i) low dose, defined as ≤200 μg/day of fluticasone propionate or equivalent (≤200 μg/day of beclomethasone dipropionate and ≤200 μg/day of budesonide); (ii) moderate dose, defined as >200 to ≤500 μg/day of fluticasone propionate or equivalent (>200 to ≤400 μg/day of beclomethasone dipropionate and >200 to ≤400 μg/day of budesonide); and (iii) high dose, defined as >500 μg/day of fluticasone propionate or equivalent (>400 μg/day of beclomethasone dipropionate and >400 μg/day of budesonide).

Compliance with the study medication was assessed by tablet counts, as recorded in the study worksheets. Safety and tolerability were assessed with the incidence of treatment-emergent adverse events, which were coded and reported according to the MedDRA dictionary of terms, version 9.0 [19].

Descriptive statistics were produced for patient demographics and characteristics at baseline. Comparisons between baseline and follow-up visits were performed with the matched Chi-Square test for categorical scales and the paired Student’s t-test for continuous scales. Two-tailed tests were performed using a significance level (α) of 0.05. Subgroup analyses by treatment strategy and stratified analyses for preschool-aged children (less than 6 years old) and school-aged children (6 years of age or older) were performed. There were no imputations for missing data. All analyses were performed using the SPSS version 12.0 for Windows (SPSS Inc., Chicago, IL).

A total of 420 patients with uncontrolled asthma as per the 2003 Canadian Asthma Consensus Guidelines completed the baseline assessment of whom 92 (21.9%) had an ACQ score of ≤ 0.75 at baseline. Considering that the primary outcome measure was the proportion of patients achieving asthma control based on the ACQ criteria, only the 328 patients with ACQ > 0.75 were included in this analysis. Among these, 320 (97.6%) and 288 (87.8%) patients completed the 4- and 12-week assessment, respectively, while the optional 8-week assessment was performed on 197 (60.1%) patients. There were 40 (12.2%) patients who were discontinued from the study: 10 (3.0%) due to an adverse event, 8 (2.4%) withdrew consent, 9 (2.7%) were lost to follow-up, 4 (1.2%) due to protocol violation, 8 (2.4%) discontinued for other reasons, while the reason of discontinuation was missing for 1 (0.3%) patient.

The demographics and baseline characteristics of the study population are summarized in Table 1. The mean (SD) age was 6.92 (3.35) years, 192 (58.5%) patients were male and 209 (63.7%) were Caucasian. At baseline, 252 patients were on ICS therapy and were therefore included in the montelukast add-on group, the majority of whom were taking moderate doses of ICS (n = 143; 56.7%). The remaining 76 patients were not taking ICS at baseline and comprised the montelukast monotherapy treatment group. Overall, at baseline, 269 (82.0%) patients had night-time symptoms ≥ 1 night/week, 247 (75.3%) had daytime symptoms ≥ 4 days/week, and 122 (37.2%) reported absenteeism from school in the last week due to asthma. Notably, SABA utilization (≥4 doses in the last week) was reported twice as frequently by patients in the combination therapy compared to the monotherapy group (66.7% vs 34.2%).

Table 2 presents the proportions of patients who achieved asthma control after 4 and 12 weeks of treatment with montelukast, administered either as a monotherapy or in addition to ICS therapy, overall and stratified by treatment strategy and age group. The overall proportion of patients who achieved asthma control (ACQ score ≤ 0.75) was 54.9% (n = 175) at 4 weeks and 71.9% (n = 207) at 12 weeks. Among preschool patients, the proportion of patients with controlled asthma increased from 63.3% (n = 88) at 4 weeks to 77.3% (n = 99) at 12 weeks, while among school aged patients, these proportions were 48.3% (n = 87) and 67.5% (n = 108), respectively. This significant rate of asthma control was consistent across both treating strategies; montelukast alone and in combination with ICS.

The mean (SD) ACQ score of the total study sample decreased from 1.94 (0.82) at baseline to 0.85 (0.83) at 4 weeks and 0.61 (0.79) at 12 weeks of treatment, representing statistically and clinically significant absolute mean (SD) changes of −1.08 (1.00) and −1.34 (1.03) from baseline to 4 and 12 weeks, respectively (p < 0.001) (Table 3). Among the patients treated with montelukast monotherapy, the mean (SD) ACQ score significantly decreased from 1.67 (0.69) at baseline to 0.71 (0.70) at 4 weeks and to 0.50 (0.52) 12 weeks (Figure 1A). Among the patients treated with the montelukast add-on treatment strategy, the mean (SD) ACQ score significantly decreased from 2.02 (0.83) at baseline to 0.90 (0.86) at 4 weeks and to 0.64 (0.86) at 12 weeks (Figure 1B).

The mean ACQ scores throughout the treatment period for the monotherapy and combination therapy patients, stratified by age group are also shown in Figure 1A and B. Among preschool and school-aged patients treated with montelukast monotherapy, the mean (SD) ACQ score significantly decreased from 1.68 (0.75) and 1.66 (0.65) at baseline to 0.79 (0.76) and 0.64 (0.65) at 4 weeks, to 0.54 (0.59) and 0.47 (0.45) at 12 weeks (Figure 1A), representing statistically and clinically significant absolute mean (SD) changes of −1.13 (0.94) and −1.18 (0.64) from baseline to 12 weeks, respectively (Table 3). Similarly, statistically and clinically significant decreases in the ACQ score were also observed among preschool and school aged patients treated with montelukast add-on therapy (Figure 1B and Table 3). Among children 7 years of age or older the PEF assessment showed a statistically significant improvement increasing from 253.9 L/min at baseline to 275.0 L/min at 12 weeks of treatment (P < 0.001).

The mean (SD) PACQLQ score of the total study sample increased from 4.63 (1.36) at baseline to 5.89 (1.24) at 4 weeks (mean (SD) change = 1.55 (1.40); P < 0.001) and 6.28 (1.00) at 12 weeks (mean (SD) change = 1.82 (1.30); P < 0.001). Among the patients who adopted the montelukast monotherapy treatment strategy, the mean (SD) PACQLQ score increased from 5.34 (1.14) at baseline to 6.32 (0.89) at 4 weeks and 6.51 (0.85) at 12 weeks. The absolute mean (SD) change in PACQLQ of 0.98 (1.12) at 4 weeks and 1.13 (1.04) at 12 weeks was both clinically (change in PACQLQ > 0.7) and statistically significant (p < 0.001) (Table 3). Among the patients who adopted the montelukast add-on treatment strategy, the mean (SD) PACQLQ score increased from 4.42 (1.35) at baseline to 5.76 (1.30) at 4 weeks and 6.21 (1.03) at 12 weeks corresponding to a mean (SD) absolute change of 1.34 (1.34) at 4 weeks and 1.78 (1.36) at 12 weeks (p < 0.001) (Table 3). In both treatment strategies, significant changes were observed in both the emotional and activity limitation domains of the PACQLQ questionnaire. Comparable clinically and statistically significant changes in PACQLQ scores were observed among preschool and school aged patients (Figure 2A and B and Table 3).Figures 3 and 4 summarize the results of the patients and physicians global satisfaction with montelukast, respectively. At baseline, 54.9% of the patients were dissatisfied or very dissatisfied with their current asthma therapy and 12.8% were satisfied or very satisfied. After 4 and 12 weeks of treatment with montelukast, 8.8% and 2.4% of the patients were dissatisfied/very dissatisfied and 73.9% and 85.3% were satisfied/very satisfied, respectively. With regards to the physician’s global satisfaction, 74.6% of the treating physicians were dissatisfied or very dissatisfied with their patient’s current asthma therapy and 4.6% were satisfied or very satisfied at baseline. After 4 and 12 weeks of treatment with montelukast, 8.3% and 4.1% of the physicians were dissatisfied/very dissatisfied while 66.6% and 87.8% were satisfied/very satisfied, respectively. Overall, the changes in patient and physician satisfaction upon treatment with montelukast for 4 and 12 weeks were statistically significant (p < 0.001) without any significant differences between preschool and school aged patients (data not shown).

The proportions of patients who tapered their baseline ICS daily dosage use to a lower ICS dose category after adding montelukast to their treatment regimen are reported in Table 4. There were 45 (18.4%), 40 (25.2) and 44 (20.0) patients who reduced their ICS dosage after the addition of montelukast to their current ICS treatment regimen at 4, 8 and 12 weeks, respectively. Similar results were observed for preschool and school aged patients.

Compliance with the treating regimen was high during the follow-up period with patients taking by average 91.6%, 93.6% and 92.2% of their prescribed doses upon 4, 8 and 12 weeks of treatment, respectively. During the course of the study, there were 182 non-serious adverse events (NSAEs) reported by 112 (34.1%) patients. Of these, 157 (86.3%) were probably or definitely not related to study medication and 15 led to study drug discontinuation in 12 (3.7%) patients. There were 25 (13.7%) NSAEs possibly, probably or definitely related to montelukast. Of these, the most frequent NSAEs related to montelukast were nightmares and sleep terror (n = 6), abdominal pain (n = 5), insomnia (n = 2) and headache (n = 2). A total of 3 serious adverse events (SAEs) were experienced by 3 patients: 1 asthma episode, 1 bronchitis and 1 pneumonia, none of which were judged to be related to the study medication by the treating physicians.