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.

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

A randomized study comparing the effect of loratadine added to montelukast with montelukast, loratadine, and beclomethasone monotherapies in patients with chronic asthma.

BACKGROUND: Loratadine added to montelukast has been suggested to improve endpoints of asthma. OBJECTIVE: This study investigated the additive effects of concomitant montelukast and loratadine when compared with montelukast, loratadine, and inhaled beclomethasone monotherapies in asthma. Methods. Patients (N = 406) were 15 to 65 years of age with a forced expiratory volume in 1 second (FEV(1))-predicted of 50% to 85%, FEV(1) reversibility > or = 15%, and a minimal level of daytime symptoms and beta -agonist use. This three-part 2X2 crossover-study consisted of two double-blind 6-week treatment periods where patients were administered once daily oral montelukast 10 mg, loratadine 10 mg, montelukast 10 mg + loratadine 10 mg, or twice daily inhaled beclomethasone 200 mu g. A subsequent 48-week extension study compared montelukast + loratadine with beclomethasone. The primary endpoint was the percentage change from baseline in FEV(1). RESULTS: Over 6 weeks of double-blind treatment, significant improvements (p < 0.05) in the primary endpoint of FEV(1) were seen for montelukast + loratadine versus loratadine (least-square mean percentage-point difference of 5.8%), beclomethasone versus montelukast + loratadine (2.35%), montelukast versus loratadine (5.94%), and beclomethasone versus montelukast (4.65%); a numerical improvement (p = 0.054) was seen for montelukast + loratadine versus montelukast (1.60%). Significant improvements for montelukast + loratadine versus montelukast were seen in some secondary endpoints (evening peak expiratory flow, nocturnal asthma symptom score, nocturnal awakenings, and asthma-specific quality of life) but not others. Significant improvements in most endpoints except daytime asthma symptoms score were seen for montelukast + loratadine versus loratadine. In the extension study, both montelukast + loratadine and beclomethasone improved several endpoints. All treatments were generally comparable in the percentage of patients with clinical and laboratory adverse experiences. CONCLUSION: In this study, the addition of loratadine to montelukast produced a small numerical, but not statistically significant, improvement in FEV(1) and, in general, no consistent improvement in other asthma endpoints. No improvement of montelukast + loratadine versus beclomethasone was seen in any endpoint.

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 mu 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.

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.

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.

Placebo-controlled study of montelukast and budesonide on short-term growth in prepubertal asthmatic children.

BACKGROUND: Inhaled corticosteroids and anti-leukotriene agents are widely used in the treatment of pediatric asthma. Although data on the effect of corticosteroids on growth are available, there are few such data on anti-leukotriene agents. The aim of this study was to assess the influence of montelukast on short-term lower leg growth rate (LLGR) in prepubertal children with asthma. METHODS: Forty-two boys (6- to 12-year old) and 29 girls (6- to 11-year old) with mild asthma were randomized to 1 of 2 crossover arms, with two treatment sequences per arm: montelukast 5 mg once daily/placebo or inhaled dry powder budesonide 200 microg twice daily/placebo. Budesonide was used as a positive control to ensure that the method was sensitive enough to detect a suppression of LLGR. The 3-week double-blind treatment period was followed by a 3-week washout. Primary outcome was LLGR over the 3-week treatment, measured by knemometry. RESULTS: Ninety-four percent of patients completed the study. Mean LLGR was similar between patients receiving montelukast and placebo treatments: mean difference, -0.02 mm/week [95% confidence interval -0.14, 0.11]. Mean LLGR in patients receiving budesonide was significantly less than for those receiving placebo (difference of -0.16 mm/week [-0.25, -0.06], P = 0.002). Mean LLGR was similar for patients taking placebo in the two arms (0.43 and 0.44 mm/week). CONCLUSION: Montelukast 5 mg did not significantly affect short-term LLGR in prepubertal children.

Evaluation of gamma-hydroxybutyric acid for genotoxicity in the mouse micronucleus assay.

Gamma-hydroxybutyric acid (GHB) is an endogenous compound found in the brain and other tissues of mammals. Neurotransmitter/neuromodulator functions have been ascribed to GHB, which has lately become a drug of abuse. In this study, we tested GHB for genotoxicity by measuring its ability to induce micronuclei in polychromatic erythrocytes (reticulocytes) in the peripheral blood of mice. Intraperitoneal injection with a dose of 25 mg/kg/day for 3 days or 50 mg/kg/day x 3 days resulted in a significant (by Dunnett's test) increase of 1.9- to 2.1-fold in micronuclei. However, because increases were small and because no consistent dose-dependent increase in induced micronuclear frequency could be demonstrated, our results do not conclusively show that GHB is an in vivo genotoxicant in mammals.

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

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 < or = 0.001]. Similar improvements were seen in Daytime Nasal Symptoms (-0.14 [-0.21, -0.07; p < or = 0.001]) and Nighttime Symptoms (-0.10 [-0.16, -0.04; p < or = 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 beta-agonist use (puffs/day) was reduced with montelukast (p < or = 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.

Randomized, placebo-controlled study of a selective PDE4 inhibitor in the treatment of asthma.

BACKGROUND: Phosphodiesterase-4 (PDE4) inhibitors have potential utility as a new therapeutic approach to improving symptoms and pulmonary function in asthma and COPD. This study evaluated the efficacy and safety of MK-0359, a selective and potent oral PDE4 inhibitor, in chronic asthma. METHODS: Adults (N=88) with > or =1 year asthma history and an FEV(1) 50-80% predicted were randomized to double-blind treatment with MK-0359 (15mg/day) or placebo for 14 days, then crossed-over to the other treatment for 14 days. The primary endpoint was the change from baseline in FEV(1) at the end of each 2-week treatment period. Secondary and other endpoints included the changes from baseline in Daytime asthma symptom score, Nighttime asthma symptom score, Total daily beta-agonist use (puffs/day), AM and PM peak expiratory flow (PEF) and overall asthma-specific quality-of-life. Safety and tolerability were assessed by clinical adverse experiences. RESULTS: MK-0359 significantly improved the primary endpoint (versus placebo): the least-squares mean difference in change from baseline in FEV(1) (L) was 0.09L (95% CI 0.01, 0.18). Endpoints of Daytime asthma symptom score, Nighttime asthma symptom score, Total daily beta-agonist use, AM PEF, PM PEF, and quality-of-life were also significantly improved. Nineteen patients (24.1%) on MK-0359 and 8 patients (10.4%) on placebo reported gastrointestinal clinical adverse experiences. Serious gastrointestinal clinical adverse experiences were reported in 3 patients while receiving MK-0359. CONCLUSION: Over a 14-day treatment period, the oral PDE4 inhibitor MK-0359 improved lower airway function, symptoms and rescue medication use in chronic asthma, although at the expense of gastrointestinal adverse experiences. (Clinical trial registry number: NCT00482898.).

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 (FEV(1)) > or = 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 FEV(1) (from pre-exercise FEV(1)) 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 < or = 0.001); numerically greater improvements were seen at 12 hours and 24 hours. A quicker time to recovery after challenge (p < or = 0.001) and a smaller area under the curve for percent-fall in FEV(1) during 60 minutes after challenge (p < or = 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.

Efficacy of montelukast for treating perennial allergic rhinitis.

Perennial allergic rhinitis (PAR) is a chronic inflammatory nasal condition in individuals exposed year-round to allergens. This was a double-blind study of 15- to 85-year-old patients randomly allocated to montelukast, 10 mg (n=630), placebo (n=613), or the positive control cetirizine, 10 mg (n=122) for 6 weeks. The primary efficacy end point was change from baseline in Daytime Nasal Symptoms Score (DNSS; mean of congestion, rhinorrhea, sneezing, and itching scores, rated daily by patients [scale: 0=none to 3=severe]) averaged during the initial 4 weeks (primary analysis) or entire 6 weeks of treatment. Also assessed were combined post hoc results of primary end point data from this study and another similarly designed study (Patel P, et al. Randomized, double-blind, placebo-controlled study of montelukast for treating perennial allergic rhinitis, Ann Allergy Asthma Immunol 95:551, 2005). Over 4 weeks, montelukast showed numerical improvement over placebo in DNSS (least-squares mean difference of -0.04 [95% confidence interval (CI}, -0.09, 0.01]); the difference between cetirizine and placebo was significant: -0.10 (95% CI, -0.19, -0.01). However, when averaged over 6 weeks, neither active treatment was significantly different from placebo. The Rhinoconjunctivitis Quality-of-Life score was significantly improved by montelukast (p < 0.05), but not by cetirizine, during 4 and 6 weeks. The treatment effect of montelukast, but not cetirizine, generally remained consistent through the 6 weeks of treatment. In pooled data, montelukast consistently improved DNSS versus placebo during all 6 weeks of treatment (-0.07 [95% CI, -0.10, -0.041). In conclusion, montelukast produced numerical improvement in daytime nasal symptoms and significant improvement in quality of life. In a pooled post hoc analysis, montelukast provided consistent improvement in daytime nasal symptoms over 6 weeks, supportive of an overall benefit in PAR.

Validation of the nighttime symptoms score as a clinically relevant measure of allergic rhinitis.

The aim of this study was to validate the nighttime symptoms score (NSS), which incorporates individual scores for difficulty going to sleep and nighttime awakening caused by nasal symptoms and nasal congestion on awakening, as a clinically relevant measure of allergic rhinitis (AR). Fifty-five general season AR (SAR) symptom items were generated by interviews with 14 patients with symptomatic SAR without concomitant asthma for use in an Importance Rating Questionnaire (IRQ). A second group of patients (n = 83) with symptomatic AR without asthma rated the importance of each item on the IRQ. Correlation coefficients were calculated to examine the relationships between the six sleep quality questions on the IRQ and the other AR symptoms and between the symptom questions of the NSS, the Daytime Nasal Symptoms Score (DNSS), and the individual domains of the Rhinoconjunctivitis Quality-of-Life Questionnaire (RQLQ). The majority (94%) of patients with active AR reported some degree of symptoms relating to sleep quality. The six sleep quality items on the IRQ were selected by 71-84% of patients. The sleep quality items were more highly correlated with each other (r = 0.48-0.85) than with the four items of the DNSS (r = 0.01-0.42). There was a moderate-to-strong correlation of the RQLQ sleep domain with the two sleep questions of the NSS (r = 0.44-0.57). The individual symptom questions of the NSS and the DNSS were only moderately correlated with each other. Sleep quality questions measure aspects of SAR that are not captured by daytime SAR symptoms. The results show that the NSS is a valid and relevant clinical measure of the impact of nighttime sleep disturbance on AR patients.

Onset and duration of protection against exercise-induced bronchoconstriction by a single oral dose of montelukast.

BACKGROUND: Leukotriene modifiers have been shown to protect against exercise-induced bronchoconstriction (EIB) with repeated, chronic dosing. OBJECTIVE: To study the onset and duration of protection against EIB after a single dose of montelukast, a leukotriene receptor antagonist. METHODS: In this randomized, crossover, double-blind study, 51 adult asthma patients with EIB (> or = 20% postexercise decrease in forced expiratory volume in 1 second [FEV1]) received a single oral dose of montelukast (10 mg), or placebo followed by exercise challenge 2, 12, and 24 hours after dosing. The primary end point was maximum percentage decrease in FEV1 from preexercise baseline during 60 minutes after the 2-hour challenge. RESULTS: At 2, 12, and 24 hours after dosing, the maximum decrease in FEV1 was 10.8% +/- 7.9%, 8.4% +/- 7.5%, and 8.3% +/- 7.3% for montelukast and 22.3% +/- 13.1%, 16.1% +/- 10.2%, and 16.9% +/- 11.7% for placebo, respectively (P < or = .001 at each time point). Postexercise recovery was quicker with montelukast than with placebo (P < or = .001); mean (95% confidence interval) differences were -26.8 minutes (-35.1 to -18.4 minutes), -16.0 minutes (-22.9 to -9.2 minutes), and -17.4 minutes (-24.9 to -9.9 minutes) at the 3 time points, respectively. At all time points, area under the curve for percentage decrease in FEV1 during 60 minutes after exercise was smaller after montelukast (P < or = .001); montelukast protected more patients against EIB (P < or = .001). Fewer patients required postexercise beta-agonist rescue at 2 hours after dosing with montelukast (P = .03). CONCLUSION: Montelukast provided significant protection against EIB as soon as 2 hours after a single oral dose, with persistent benefit up to 24 hours.

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.

Montelukast effectively treats the nighttime impact of seasonal allergic rhinitis.

BACKGROUND: Nighttime problems constitute a significant burden on the quality of life of patients with seasonal allergic rhinitis (SAR). The aim of this study was to evaluate the effectiveness of montelukast on nighttime AR symptoms. METHODS: In seven multicenter, double-blind, parallel-group trials, nighttime problems were assessed as the nighttime symptoms score (NSS), an average of three individual symptom scores: difficulty going to sleep, nighttime awakening, and nasal congestion on awakening (each rated 0 = none to 3 = severe). Patients (aged 15-82 years) were randomized to receive montelukast, 10 mg (n = 1751), placebo (n = 1557), or the positive control loratadine, 10 mg (n = 1616). RESULTS: In a combined analysis, changes from baseline (mean +/- SE) in NSS were -0.28 +/- 0.01, -0.16 +/- 0.01, and -0.24 +/- 0.01 for the montelukast, placebo, and loratadine groups, respectively. Difference versus placebo in least-squares mean change from baseline were -0.11 (95% confidence interval, -0.14, -0.08; p < or = 0.001) for montelukast and -0.09 (-0.12, -0.06; p < or = 0.001) for loratadine. Strong baseline correlations (R > 0.70; p < 0.001) of NSS and two of its individual symptoms with the sleep domain of the validated Rhinoconjunctivitis Quality of Life Questionnaire support the validity and importance of measuring nighttime morbidity in SAR. Furthermore, a clinically important benefit of montelukast on the nighttime impact of SAR was shown using an analysis anchored on the Patient's Global Evaluation. CONCLUSION: These data underscore the importance of nighttime problems in patients with SAR and the need to treat nighttime symptoms. In these studies, montelukast significantly improved the NSS, a clinically relevant and valid measure in patients with SAR.

Randomized, double-blind, placebo-controlled study of montelukast for treating perennial allergic rhinitis.

BACKGROUND: Perennial allergic rhinitis (PAR) is a persistent allergic inflammation of the upper respiratory tract due to year-round allergen exposure. OBJECTIVE: To evaluate the leukotriene receptor antagonist montelukast for the treatment of PAR. METHODS: Protocol 265 was a 2-arm study performed during the winter. After a placebo run-in period, adults with perennial allergen sensitivity and active symptoms of PAR were randomized to receive 10 mg of montelukast (n=1002) or placebo (n=990) once daily during a 6-week, double-blind, active-treatment period. The primary end point was the daytime nasal symptoms score, defined as the average of scores for nasal congestion, rhinorrhea, and sneezing rated daily by patients. RESULTS: Statistically significant improvements in PAR symptoms were seen in patients treated with montelukast. Their daytime nasal symptoms scores were reduced during treatment compared with those of the placebo group: the difference between treatments in least squares mean change from baseline was -0.08 (95% confidence interval [CI], -0.12 to -0.04; P < .001). Montelukast treatment also improved global evaluations of allergic rhinitis by patients and Rhinoconjunctivitis Quality of Life Questionnaire scores: differences vs the placebo group were -0.15 (95% CI, -0.27 to -0.04; P < .01) and -0.15 (95% CI, -0.24 to -0.06; P < .001), respectively. Other end points that showed statistically significant improvement with montelukast treatment were nighttime symptoms and each of the 4 nasal symptoms (congestion, rhinorrhea, sneezing, and itching). The treatment effects of montelukast were stable and persistent during the entire 6 weeks of treatment. CONCLUSION: Montelukast provided statistically significant relief of PAR symptoms during 6 weeks of treatment.

Onset of efficacy of montelukast in seasonal allergic rhinitis.

Montelukast has shown efficacy for seasonal allergic rhinitis (SAR); however, onset of action for SAR has not been presented. The aim of this study was to determine the onset of action of montelukast, 10 mg, measured in days after starting once-daily therapy, in spring and fall studies of SAR. Data were analyzed from four 2-week, double-blind, placebo-controlled phase III clinical trials. End points included the daytime nasal symptoms score, the nighttime symptoms score, the composite symptoms score (mean of the scores for daytime nasal symptoms and nighttime symptoms), and the daytime eye symptoms score. Using a 0-3 scale (no symptoms to severe symptoms), daytime symptoms were rated by patients once daily each evening; nighttime symptoms were rated once daily each morning. Analyses of data pooled across the four evening dosing studies showed that montelukast, compared with placebo, produced significant improvement (p < or = 0.001) from baseline by day 2 of treatment (after 2 doses) in the daytime nasal symptoms score, nighttime symptoms score, and composite symptoms score. Differences between montelukast and placebo for these end points in mean change from baseline at day 2 were -0.08 (95% CI, -0.12, -0.03), -0.08 (95% CI, -0.13, -0.04), and -0.08 (95% CI, -0.12, -0.04), respectively. These data represented a mean reduction for montelukast of 11-13% in symptom scores from baseline for each end point at day 2. When compared with the full 2-week response, these observed differences for each end point at day 2 (after 2 doses) represented a substantial proportion (over 70%) of the overall treatment benefits seen. Significant improvement (p < or = 0.001) in the daytime eye symptoms score was seen by day 1 (-0.08 [-0.12, -0.03]), after the first dose. In patients treated for SAR, montelukast has a beneficial effect on daytime and nighttime symptoms by the 2nd day of daily therapy.

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.

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

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 > or = 1 year, a baseline forced expiratory volume in one second (FEV1) value 50-90% predicted, and a beta agonist improvement of > or = 12% in FEV1. 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 FEV1 before a beta agonist was used and morning peak expiratory flow compared with montelukast and fluticasone (P < or = 0.001), whereas FEV1 after a beta 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.