S. Balachandra Dass

Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial

Abstract Objectives To assess the effect of montelukast versus salmeterol added to inhaled fluticasone propionate on asthma exacerbation in patients whose symptoms are inadequately controlled with fluticasone alone. Design and setting A 52 week, two period, double blind, multicentre trial during which patients whose symptoms remained uncontrolled by inhaled corticosteroids were randomised to add montelukast or salmeterol. Participants Patients (15-72 years; n = 1490) had a clinical history of chronic asthma for ≥ 1 year, a baseline forced expiratory volume in one second (FEV 1) value 50-90% predicted, and a β agonist improvement of ≥ 12% in FEV 1. Main outcome measures The primary end point was the percentage of patients with at least one asthma exacerbation. Results 20.1% of the patients in the group receiving montelukast and fluticasone had an asthma exacerbation compared with 19.1% in the group receiving salmeterol and fluticasone; the difference was 1% (95% confidence interval -3.1% to 5.0%). With a risk ratio (montelukast-fluticasone/salmeterol-fluticasone) of 1.05 (0.86 to 1.29), treatment with montelukast and fluticasone was shown to be non-inferior to treatment with salmeterol and fluticasone. Salmeterol and fluticasone significantly increased FEV 1 before a β agonist was used and morning peak expiratory flow compared with montelukast and fluticasone (P ≤ 0.001), whereas FEV 1 after a β agonist was used and improvements in asthma specific quality of life and nocturnal awakenings were similar between the groups. Montelukast and fluticasone significantly (P = 0.011) reduced peripheral blood eosinophil counts compared with salmeterol and fluticasone. Both treatments were generally well tolerated. Conclusion The addition of montelukast in patients whose symptoms remain uncontrolled by inhaled fluticasone could provide equivalent clinical control to salmeterol.

The effect of montelukast on rhinitis symptoms in patients with asthma and seasonal allergic rhinitis

SUMMARY Objective: The objective of this study was to evaluate montelukast 10 mg daily as treatment for allergic rhinitis in patients with symptomatic allergic rhinitis and active asthma during the allergy season. Methods: This was a multicenter study of 831 patients (ages 15 years–85 years) with seasonal allergen sensitivity, active symptoms of seasonal allergic rhinitis, and active asthma. Following a single-blind, placebo run-in period of 3 days–5 days, patients were randomized to oral montelukast 10 mg (n = 415) or placebo (n = 416) daily during the 2-week, double-blind, active-treatment period. Main outcome measures: The primary endpoint was Daily Rhinitis Symptoms score, average of Daytime Nasal Symptoms and Nighttime Symptoms, as self-rated by patients on a 0–3 scale on daily diaries. Results: Montelukast reduced the Daily Rhinitis Symptoms score: difference between montelukast and placebo in mean change from baseline was –0.12 [95% CI –0.18, –0.06; p ≤ 0.001]. Similar improvements were seen in Daytime Nasal Symptoms (–0.14 [–0.21, –0.07; p ≤ 0.001]) and Nighttime Symptoms (–0.10 [–0.16,–0.04; p ≤ 0.001]). Improvements (p < 0.05) were seen in Daytime Eye Symptoms and in the secondary endpoints of Global Evaluations of AR by Patient and by Physician, and Rhinoconjunctivitis Quality of Life. In exploratory analyses, improvement in rhinitis symptoms was numerically (though not statistically) larger in patients with greater levels of asthma at study start. Montelukast provided benefit in the Global Evaluations of Asthma by Patient and by Physician: mean differences were –0.24 [–0.41, –0.06; p = 0.008] and –0.17 [–0.33,–0.01; p = 0.037]. Similarly, as-needed β-agonist use (puffs/day) was reduced with montelukast ( p ≤ 0.005). Conclusion: Montelukast provides significant relief from symptoms of seasonal allergic rhinitis, while also conferring a benefit for asthma, in patients with both allergic rhinitis and asthma.

Study of montelukast for the treatment of respiratory symptoms of post-respiratory syncytial virus bronchiolitis in children.

RATIONALE A pilot study (Bisgaard H; 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;167:379-383) reported the efficacy of montelukast in post-respiratory syncytial virus (RSV) bronchiolitic respiratory symptoms. OBJECTIVES To evaluate the efficacy and safety of montelukast, 4 and 8 mg, in treating recurrent respiratory symptoms of post-RSV bronchiolitis in children in a large, multicenter study. METHODS This was a double-blind study of 3- to 24-month-old children who had been hospitalized for a first or second episode of physician-diagnosed RSV bronchiolitis and who tested positive for RSV. Patients (n = 979) were randomized to placebo or to montelukast at 4 or 8 mg/day for 4 weeks (period I) and 20 weeks (period II). The primary end point was percentage symptom-free days (%SFD; day with no daytime cough, wheeze, and shortness of breath, and no nighttime cough). MEASUREMENTS AND MAIN RESULTS No significant differences were seen between montelukast and placebo in %SFD over period I: mean +/- SD for placebo and for montelukast at 4 and 8 mg were 37.0 +/- 30.7, 38.6 +/- 30.4, and 38.5 +/- 29.9, respectively. Least-squares mean differences (95% confidence interval) between montelukast (4 mg) and placebo and between montelukast (8 mg) and placebo were 1.9% (-2.9, 6.7) and 1.6% (-3.2, 6.5), respectively. Secondary end points were similar across treatments. Both doses were generally well tolerated. During the first two treatment weeks, average %SFD was approximately 29%. In post hoc analyses of patients (n = 523) with persistent symptoms (%SFD < or = 30% over Weeks 1-2), differences in %SFD were seen between montelukast and placebo over Weeks 3-24: difference were 5.7 (0.0, 11.3) for montelukast (4 mg) minus placebo and 5.9 (0.1, 11.7) for montelukast (8 mg) minus placebo. CONCLUSIONS In this study, montelukast did not improve respiratory symptoms of post-RSV bronchiolitis in children.

A randomized placebo-controlled study of intravenous montelukast for the treatment of acute asthma

BACKGROUND Current treatments for acute asthma provide inadequate benefit for some patients. Intravenous montelukast may complement existent therapies. OBJECTIVE To evaluate efficacy of intravenous montelukast as adjunctive therapy for acute asthma. METHODS A total of 583 adults with acute asthma were treated with standard care during a < or = 60-minute screening period. Patients with FEV(1) < or =50% predicted were randomly allocated to intravenous montelukast 7 mg (n = 291) or placebo (n = 292) in addition to standard care. This double-blind treatment period lasted until a decision for discharge, hospital admission, or discontinuation from the study. The primary efficacy endpoint was the time-weighted average change in FEV(1) during 60 minutes after drug administration. Secondary endpoints included the time-weighted average change in FEV(1) at various intervals (10-120 minutes) and percentage of patients with treatment failure (defined as hospitalization or lack of decision to discharge by 3 hours postadministration). RESULTS Montelukast significantly increased FEV(1) at 60 minutes postdose; the difference between change from baseline for placebo (least-squares mean of 0.22 L; 95% CI, 0.17, 0.27) and montelukast (0.32 L; 95% CI, 0.27, 0.37) was 0.10 L (95% CI, 0.04, 0.16). Similar improvements in FEV(1)-related variables were seen at all time points (all P <.05). Although treatment failure did not differ between groups (OR 0.92; 95% CI, 0.63, 1.34), a prespecified subgroup analysis suggests likely benefit for intravenous montelukast at US sites. CONCLUSION Intravenous montelukast added to standard care in adults with acute asthma produced significant relief of airway obstruction throughout the 2 hours after administration, with an onset of action as early as 10 minutes.

Linear growth in prepubertal asthmatic children treated with montelukast, beclomethasone, or placebo: a 56-week randomized double-blind study

BACKGROUND Antileukotrienes and inhaled corticosteroids are asthma controller agents widely used in the treatment of pediatric asthma. OBJECTIVE To evaluate the effects of montelukast and beclomethasone on linear growth in prepubertal asthmatic children for 1 year. METHODS This was a 30-center study of boys (6.4-9.4 years old) and girls (6.4-8.4 years old) at Tanner stage I with mild, persistent asthma. After a placebo run-in period, 360 patients were randomized in equal ratios to double-blind, double-dummy treatment with 5 mg of montelukast, 200 microg of beclomethasone twice daily (positive control), or placebo for 56 weeks; 90% of the patients completed the study. The primary end point was linear growth velocity, measured using a stadiometer. RESULTS Linear growth rates were similar between the montelukast and placebo groups; the mean difference for the year was 0.03 cm. The mean growth rate with beclomethasone was significantly less than with placebo (-0.78 cm) or montelukast (0.81 cm) (P < .001 for both). Median percentage of days with beta-agonist use was greater with placebo (14.58%) vs montelukast (10.55%) or beclomethasone (6.65%) (P < .05 for all). More patients used oral corticosteroid rescue with placebo (34.7%) than with montelukast (25.0%) or beclomethasone (23.5%). An imbalance in bone marker levels was seen with beclomethasone but not with montelukast. CONCLUSION In prepubertal asthmatic children, montelukast did not affect linear growth, whereas the growth rate with beclomethasone was significantly decreased during 1 year of treatment.

Clinical studies of the DP1 antagonist laropiprant in asthma and allergic rhinitis

BACKGROUND Prostaglandin D(2) is a proinflammatory mediator believed to be important in asthma and allergic rhinitis (AR). Allelic variants in the prostaglandin D(2) receptor type 1 (DP1) gene (PTGDR) have been suggested to be associated with asthma susceptibility. OBJECTIVES We sought to investigate the efficacy of the DP1 antagonist laropiprant (alone or with montelukast) in asthma and seasonal AR and explore whether sequence variations in PTGDR are associated with asthma severity. METHODS For asthma, in a double-blind crossover study, 100 patients with persistent asthma were randomized to placebo or laropiprant, 300 mg/d for 3 weeks, followed by addition of montelukast, 10 mg/d for 2 weeks. PTGDR promoter haplotypes were categorized as high, medium, or low transcriptional efficiency. The primary efficacy end point was FEV(1). For AR, in a double-blind parallel-group study, 767 patients sensitized to a regionally prevalent fall allergen with symptomatic fall rhinitis were allocated to laropiprant, 25 mg/d or 100 mg/d; cetirizine, 10mg/d; or placebo for 2 weeks. The primary end point was the Daytime Nasal Symptoms Score. RESULTS For asthma, no significant differences in FEV(1) or asthma symptoms were noted for laropiprant versus placebo or laropiprant plus montelukast vs montelukast (differences between montelukast and placebo: P <or= .001). No clear association was seen between haplotype pair (ie, diplotype) and asthma severity. For AR, although cetirizine (vs placebo) demonstrated an improvement in the Daytime Nasal Symptoms Score (P < .001), laropiprant did not. CONCLUSION Laropiprant did not demonstrate efficacy in asthmatic patients or patients with AR. Variations in PTGDR did not appear related to baseline asthma severity or treatment response (NCT00533208; NCT00783601).

Protection against exercise-induced bronchoconstriction two hours after a single oral dose of montelukast

The objective of this double-blind cross-over study was to evaluate montelukast for the prevention of exercise-induced bronchoconstriction (EIB). Sixty-two patients with EIB (post-exercise decrease in forced expiratory volume in 1 second (FEV1) ≥ 20% at pre-randomization) were randomized to montelukast 10 mg or placebo, followed by exercise-challenge 2, 12, and 24 hours postdose. The primary endpoint was the maximum percent-fall in FEV1 (from pre-exercise FEV1) during 60 minutes after exercise-challenge at 2 hours postdose. This endpoint was improved after montelukast (mean ± SD = 11.7% ± 10.8) versus placebo (17.5% ± 13.8) (p ≤ 0.001); numerically greater improvements were seen at 12 hours and 24 hours. A quicker time to recovery after challenge (p ≤ 0.001) and a smaller area under the curve for percent-fall in FEV1 during 60 minutes after challenge (p ≤ 0.01) were seen with montelukast at 2 hours. At this timepoint, more patients taking montelukast (45/54) than taking placebo (37/54) were protected against EIB (p = 0.039). We concluded that montelukast provided significant protection against EIB at 2 hours after a single dose.

Protective effect of montelukast on lower and upper respiratory tract responses to short-term cat allergen exposure

BACKGROUND Challenge with short-term exposure to airborne cat allergen in sensitized patients produces pulmonary function changes and rhinitis symptoms. OBJECTIVE To determine the benefit of montelukast, 10 mg, for patients with concomitant asthma and allergic rhinitis as demonstrated by protection against both lower and upper airway responses to cat allergen challenge. METHODS This randomized, crossover study treated patients with montelukast vs placebo during two 2-week, double-blind treatment periods, separated by a 1-week washout period. After each treatment period, patients underwent a 60-minute or less exposure to high levels of airborne cat allergen. Lower and upper airway responses were measured by spirometry and symptom scores. RESULTS Of 52 patients with data from both treatment arms, 79% of patients taking montelukast and 67% taking placebo were exposed to the full 60-minute allergen challenge. Montelukast provided significant (P < or = .001) protection against allergen challenge in the lower airway coprimary end point of area under the curve during challenge (AUC0-60min) for percentage decrease in forced expiratory volume in 1 second: mean of 10.5% per hour and 14.7% per hour for montelukast and placebo, respectively. Although the effect on the overall nasal symptoms score (NSS) coprimary end point of AUC0-60min was not statistically significance (P = .12), nasal congestion during the challenge and NSS during recovery showed statistically significant (P = .048) protection by montelukast. Additional analyses of simultaneous lower and upper airway responses showed that more patients taking montelukast (22, 43%) vs placebo (13, 26%) were protected from both asthma and rhinitis (P = .02), with an odds ratio of 2.24 (95% CI, 1.16-4.32) in favor of montelukast. CONCLUSIONS Montelukast has a protective effect against both lower and upper airway responses during exposure to high levels of cat allergen.

Review of Recent Results of Montelukast Use as a Monotherapy in Children with Mild Asthma

BACKGROUND Asthma is a chronic disease with a heterogeneous phenotype that is often associated with allergic sensitization in childhood. The earliest definable form of asthma is mild (intermittent or persistent), a severity level that may be characteristic of a majority of children with asthma. Several asthma controllers are indicated for use in children. International guidelines recommend the use of inhaled corticosteroids as the preferred controller therapy in mild persistent asthma. OBJECTIVE This article reviewed recent results from randomized, double-blind studies of children with mild asthma treated with montelukast, a leukotriene receptor antagonist that is approved for the treatment of asthma and allergic rhinitis in children and adults. METHODS A literature search of MEDLINE was conducted to gather relevant, English-language articles using search terms such as randomized controlled studies, double-blind studies, montelukast, leukotriene receptor antagonist, pediatric asthma, mild asthma, exercise-induced asthma, and bronchoconstriction. Recent articles (since 1998) that described the use of montelukast as a monotherapy were chosen for this review. RESULTS Relevant studies included a 48-week, placebo-controlled study of 2- to 5-year-old mild intermittent asthmatics (N = 549); a 12-week, placebo-controlled study of 2- to 5-year-old mild persistent asthmatics (N = 689); an analysis of a mild persistent asthmatic cohort (N = 138) from an 8-week, placebo-controlled study of 6- to 14-year-old asthmatics; a 12-month study comparing montelukast with fluticasone in 6- to 14-year-old mild persistent asthmatics (N = 949); and 3 placebo-controlled studies in children with exercise-induced asthma (N = 123). The results from these studies, encompassing end points measuring lung function and symptoms, found that montelukast provided effective and beneficial asthma control to children aged 2 to 14 years with mild asthma. CONCLUSION The evidence suggests that montelukast is an effective monotherapy controller in children with mild asthma.

Clinical Studies of Combination Montelukast and Loratadine in Patients with Seasonal Allergic Rhinitis

Background. Concomitant use of montelukast and loratadine may improve symptoms of seasonal allergic rhinitis (SAR) more than treatment with either drug alone. Objective. We compared the efficacy of this combination versus placebo, nasal beclomethasone, montelukast, and loratadine in study 1 and versus placebo, montelukast, and loratadine in study 2. Methods. Patients were randomly allocated to double-blind treatment with intranasal beclomethasone 200 μ g/twice daily (study 1 only), placebo, montelukast 10 mg+loratadine 10 mg, montelukast 10 mg, or loratadine 10 mg once daily. The primary endpoint was the Composite Symptom Score (CSS): average of daily diary scores for Daytime Nasal Symptoms and Nighttime Symptoms. Results. In study 1, improvements in the change from baseline in CSS were seen for montelukast+loratadine (least-squares means [95% CI] = −0.43 [−0.51, −0.35]), beclomethasone (−0.57 [−0.64, −0.49]), montelukast, and loratadine. All treatments were significantly better than placebo; montelukast+loratadine had a significantly greater effect on CSS than montelukast alone but no difference compared to loratadine was detected. Beclomethasone provided significantly greater improvement versus montelukast+loratadine on the primary and secondary endpoints except for the rhinoconjunctivitis quality-of-life score. In study 2, the combination treatment was similar to montelukast, loratadine, and placebo for the primary and secondary endpoints. Conclusion. In study 1, montelukast+loratadine had a significantly greater effect on CSS than placebo and montelukast alone; however, in all comparisons, nasal beclomethasone had a greater effect on daily symptoms. In contrast, the combination of montelukast+loratadine in study 2 did not provide greater improvement compared with placebo, montelukast, or loratadine monotherapy, perhaps due to a large placebo effect.