Montelukast, a Leukotriene-Receptor Antagonist, for the Treatment of Mild Asthma and Exercise-Induced Bronchoconstriction
Jonathan A. Leff, M.D., William W. Busse, M.D., David Pearlman, M.D., Edwin A. Bronsky, M.D., James Kemp, M.D., Leslie Hendeles, Pharm.D., Robert Dockhorn, M.D., Sudeep Kundu, Ph.D., Ji Zhang, Ph.D., Beth C. Seidenberg, M.D., and Theodore F. Reiss, M.D.
Background Patients with mild asthma frequently have only exercise-inducedbronchoconstriction, a symptom of inadequate control of asthma.We evaluated the ability of montelukast, a leukotriene-receptorantagonist, to protect such patients against exercise-inducedbronchoconstriction.
Methods We randomly assigned 110 patients (age, 15 to 45 years)with mild asthma and a decrease in the forced expiratory volumein one second (FEV1) of at least 20 percent after exercise ontwo occasions during a placebo run-in period to receive 10 mgof montelukast (54 patients) or placebo (56 patients) once dailyat bedtime for 12 weeks in a double-blind study. Treatment wasfollowed by a two-week, single-blind washout period during whichall patients received placebo. Exercise challenges were performedat base line; 20 to 24 hours after dosing at weeks 4, 8, and12; and at the end of the washout period. The primary end pointwas the area under the curve for FEV1 (expressed as the percentchange from base-line values) in the first 60 minutes afterexercise. This measure summarized the extent and duration ofbronchoconstriction after exercise.
Results At 12 weeks, montelukast therapy offered significantlygreater protection against exercise-induced bronchoconstrictionthan placebo therapy (expressed as the percentage of inhibitionof the end points), as evidenced by the improvement in the areaunder the FEV1 curve (degree of inhibition, 47.4 percent; P=0.002).Montelukast therapy was also associated with a significant improvementin the maximal decrease in FEV1 after exercise (P=0.003) andthe time from the maximal decrease in FEV1 to the return oflung function to within 5 percent of pre-exercise values (P=0.04).The differences between groups in the various measures of lungfunction were similar at 4, 8, and 12 weeks; there was no evidenceof rebound worsening of lung function in the montelukast groupafter the washout period. After 12 weeks of treatment, patientsin the montelukast group were more likely to rate their asthmacontrol as better and less likely to require rescue therapywith a -agonist during or after exercise challenge. The ratesof adverse events were similar in the two groups.
Conclusions As compared with placebo, once-daily treatment withmontelukast provided significant protection against exercise-inducedasthma over a 12-week period. Tolerance to the medication andrebound worsening of lung function after discontinuation oftreatment were not seen.
Exercise-induced bronchoconstriction is common among adultswith mild-to-severe asthma, limiting activity and worseningthe quality of life.1 The presence of airway hyperresponsivenessto exercise suggests a lack of control of asthma. Accordingly,the degree of protection afforded by a drug against exercise-inducedbronchoconstriction may be used to assess therapeutic benefitin patients with mild asthma who have near-normal airway functionand minimal symptoms.
The cause of exercise-induced bronchoconstriction is incompletelyunderstood, although airway cooling and drying are hypothesizedto stimulate the release of inflammatory mediators such as thecysteinyl leukotrienes (leukotriene C4, D4, and E4),1 whichare excreted in urine as leukotriene E4 (a stable metaboliteof leukotriene C4 and D4) after exercise challenge.2,3 Inhibitorsof the synthesis of leukotriene4,5 and leukotriene-receptorantagonists3,6,7,8,9 have been shown to protect against exercise-inducedbronchoconstriction.
Montelukast is a potent, specific antagonist of leukotrienereceptors10,11 that was recently approved in the United Statesand other countries for the treatment of chronic asthma. Theprotective effects of two doses of montelukast on exercise-inducedbronchoconstriction have been shown at 20 to 24 hours afterdosing.3,7 In a 12-week, placebo-controlled study, we evaluatedthe effect of once-daily montelukast on airway hyperresponsivenessto exercise and methacholine challenges and on the overall clinicalcondition of patients with mild asthma.
Methods
Patients
After screening about 250 patients, we recruited 110 nonsmokingpatients (age, 15 to 45 years) who had had asthma for more thanone year, were using only inhaled -agonists, had a decreasein the forced expiratory volume in one second (FEV1) of 20 percentor more in response to a challenge with methacholine (4 mg permilliliter), and had a decrease in FEV1 of 20 percent or moreafter a standardized exercise challenge on two occasions. Allpatients were in good health on the basis of medical history,physical examination, and routine laboratory tests. All patientshad quit smoking at least one year before the study and hada history of no more than 7 pack-years of smoking.
Patients were not eligible for the study if they had been treatedfor asthma in an emergency room within one month before thestudy, had been hospitalized for asthma within three monthsbefore the study, had had an unresolved upper respiratory tractinfection within six weeks before the study, or had had an unresolvedsinus infection within one week before the study. The use ofcorticosteroids, long-acting antihistamines, theophylline, oralor long-acting -adrenergic agonists, inhaled anticholinergicagents within one month before the study, and the use of cromolynor nedocromil within two weeks before the study were also reasonsfor exclusion. Immunotherapy at a constant dose was allowed.Treatment with short-acting antihistamines and inhaled -agonistswas permitted as needed, except in the 48 hours and 6 hours,respectively, before scheduled clinic visits. Caffeinated beverageswere not permitted in the eight hours before visits.
Patients were withdrawn from the study if treatment was interruptedfor more than six consecutive days, if treatment with an excludedmedication was initiated, in the event of pregnancy, or in theevent of worsening asthma that required treatment with corticosteroids.
The protocol was approved by the institutional review boardsof all participating centers, and written informed consent wasobtained from all participants. The study was conducted betweenMay 11 and December 6, 1995.
Study Design
This randomized, double-blind, placebo-controlled, parallel-grouptrial was conducted at six centers. After a 1-week, single-blind,base-line period during which patients received placebo oncedaily, patients were randomly assigned to receive 10 mg of montelukast(Singulair, Merck, West Point, Pa.) or matching placebo, withor without food, once daily at bedtime for 12 weeks. All exercisechallenges were performed 20 to 24 hours after the bedtime dose(the trough of the dosing interval) during the base-line periodand 4, 8, and 12 weeks after treatment began. Methacholine challengewas performed during the base-line period and at 4 and 12 weekson days on which exercise challenge was not performed. Aftera two-week washout period during which time all patients receivedplacebo in a single-blind fashion, exercise and methacholinechallenges were again performed.
Exercise Challenge
After a two-minute warmup, patients exercised for six minuteson a treadmill while inhaling compressed dry air at room temperaturethrough a face mask, at a workload that increased the heartrate to 80 to 90 percent of the age-predicted maximum (calculatedas 220 – age). Every effort was taken to perform exercisechallenges at the same time of day. Small adjustments in workload(treadmill speed or grade) were made, if necessary, to achievetargeted heart rates. The FEV1 before exercise was calculatedas the mean of measurements performed 20 and 5 minutes beforeexercise and was required to be at least 65 percent of the predictedvalue for the exercise challenge to proceed. Spirometry wasperformed 0, 5, 10, 15, 30, 45, and 60 minutes after exercise.If by 60 minutes the FEV1 had not returned to within 5 percentof the pre-exercise value, additional measurements were obtained75 minutes and, if necessary, 90 minutes after exercise. Atthe discretion of the investigator, patients could receive aninhaled -agonist for distressing symptoms at any time duringor after exercise challenge. Patients maintained their usualpattern of activities, except they refrained from strenuousexercise for at least 18 hours before exercise challenge.
Methacholine Challenge
To assess nonspecific bronchial hyperresponsiveness, methacholinechallenge was performed between 6 and 10 a.m. with a nebulizer(model 646, DeVilbiss, Somerset, Pa.) and a dosimeter (Scientificand Medical Instrument Co., Doylestown, Pa.)12 whose standardoutput was within 15 percent of the median output. Patientsused the same nebulizer throughout the study. The concentrationof methacholine required to decrease the FEV1 by 20 percent(PC20) was measured. Patients received 0.156 mg of methacholineper milliliter initially, and concentrations were then doubled(up to a maximum of 25 mg per milliliter) at intervals of fiveminutes until a decrease in FEV1 of 20 percent or more occurred.The PC20 was computed from the methacholine dose–responsecurve (the change in FEV1 in relation to the methacholine concentration)by linear interpolation on a log scale. Methacholine solutionswere prepared by one central pharmacy.
Spirometry
A standard spirometer (model PB-100/110, Puritan Bennett, Lenexa,Kans.) was used at each study site. Patients were encouragedto perform at least three maneuvers during each measurementto meet American Thoracic Society criteria for acceptabilityand reproducibility.13 The largest FEV1 value from each setof measurements was used for analysis. Spirometry training andquality control were centralized.
Global Assessment of Asthma Control
Patients evaluated the overall control of asthma after the 12-weektreatment period by using a seven-point scale to answer thefollowing question: "Since the beginning of the study, my asthmais now very much better (score, 0), much better (1), better(2), the same (3), worse (4), much worse (5), or very much worse(6)."
Statistical Analysis
The primary end point was the area under the curve (AUC) forFEV1 (expressed as the percent change from base-line values)in the first 60 minutes after exercise challenge, summarizingthe extent and duration of bronchoconstriction after exercise(Figure 1). The maximal decrease in FEV1 after exercise andthe length of time from the maximal decrease in FEV1 to thereturn to within 5 percent of the FEV1 value measured beforeexercise were secondary end points.
Figure 1. End Points Used to Assess the Degree of Exercise-Induced Bronchoconstriction.
The following end points were assessed: the area under the curve for the percent decrease in FEV1 in the first 60 minutes after exercise, the maximal decrease in FEV1 after exercise, and the time from the maximal decrease in FEV1 to the return to within 5 percent of the FEV1 value before exercise.
If a -agonist was administered as rescue therapy after an exercisechallenge, subsequent FEV1 values were excluded; the last FEV1measurement before rescue therapy was carried forward. In sucha case, the maximal decrease in FEV1 was calculated from thelowest value recorded before -agonist rescue. If rescue therapywas administered after exercise or if the FEV1 did not recoverto within 5 percent of base line within 90 minutes after exercise,the time to recovery was defined as 100 minutes. If the FEV1did not drop below 95 percent of the base-line value, the timeto recovery was defined as zero.
The change in values from the second of the two exercise challengesconducted before treatment to week 12 of treatment was analyzedfor all end points. When a measurement at week 12 was not recorded,the measurement from week 8 or week 4 (if the value for week8 was also missing) was used in an analysis-of-variance model,14with factors for center and treatment. We assessed the consistencyof the protective effects by including pre-exercise FEV1 valuesand the interaction between treatment and pre-exercise FEV1values in the analysis-of-variance model. Significance testingwas also performed at weeks 4 and 8. The degree of protectionagainst bronchoconstriction afforded by montelukast therapy,as compared with placebo treatment, was expressed, for eachend point, as the percentage of inhibition induced by montelukasttherapy, and was calculated with the following equation: 100x (1 – mean response to montelukast therapy ÷ meanresponse to placebo treatment). We assessed tolerance by comparingthe slopes of the changes in values between treatment groupsfor the three end points over the 12-week treatment period usinga mixed-effects model,15 which takes into account variabilitywithin and between patients.
For the methacholine challenge, we used the same analysis-of-variancemodel to analyze the change in PC20 values over time. The patients'global assessment of asthma control was analyzed with a Cochran–Mantel–Haenszeltest for ordered categorical data. The seven-point scale wasreduced to three categories for the purposes of analysis: "better"(a score of 0, 1, or 2), "no change" (a score of 3), or "worse"(a score of 4, 5, or 6). Fisher's exact test was used to comparedifferences between groups in the proportion of patients requiring-agonist rescue therapy at each visit.
We used an intention-to-treat approach, including all patientswith a base-line measurement and at least one subsequent measurement,for all exercise and PC20 end points. All significance testingwas two-tailed; a P value of 0.05 or less was considered toindicate statistical significance.
A total of 80 patients (40 patients in each group) was requiredin order to detect at a power of 90 percent a difference of50 percent in the AUC between the two treatment groups. Thepower calculation was based on the variability observed in previousmontelukast exercise-challenge studies.3,7
Results
Randomization and Withdrawal
Of the 110 patients enrolled in the study, 56 were randomlyassigned to the placebo group and 54 to the montelukast group.There were no clinically important demographic differences betweenthe two groups (Table 1). Thirteen patients did not completethe study: seven in the placebo group and six in the montelukastgroup. In the placebo group, four patients stopped treatmentbecause of worsening asthma, two were withdrawn because of protocoldeviations, and one withdrew consent. In the montelukast group,one patient stopped treatment because of sinusitis, one patientstopped treatment because of respiratory distress, one stoppedtreatment because of pregnancy, one was withdrawn because ofa protocol deviation, one was lost to follow-up, and one withdrewconsent.
Table 1. Base-Line Characteristics of the Patients.
Two patients in each group had only base-line exercise dataand were excluded from the exercise analysis. Two patients inthe placebo group and one patient in the montelukast group hadonly base-line data on methacholine challenge and were excludedfrom methacholine analysis.
Effect of Montelukast on Exercise-Induced Bronchoconstriction
The mean (±SD) FEV1 before exercise was similar in theplacebo and montelukast groups at the second base-line measurement(3.33±0.69 and 3.35±0.66 liters, respectively)and at week 12 (3.33±0.71 and 3.45±0.65 liters,respectively).
The degree of protection against bronchoconstriction affordedby montelukast therapy at week 12 was significantly greaterthan that offered by placebo treatment (Figure 2 and Table 2).Montelukast therapy was associated with a significant improvementin the AUC (degree of inhibition as compared with placebo, 47.4percent; P=0.002). There was no significant interaction betweentreatment and pre-exercise FEV1 values, indicating that theprotective effect of montelukast was consistent among the patients.Twelve weeks of therapy with montelukast was also associatedwith significant improvements in the maximal decrease in FEV1after exercise (P=0.003) and the time from the maximal decreasein FEV1 to the return to within 5 percent of pre-exercise FEV1(P=0.04) (Table 2). Three patients in the placebo group (6 percent)and 12 patients in the montelukast group (23 percent) had amaximal decrease in FEV1 of less than 10 percent at 12 weeks,and 31 patients (57 percent) and 13 patients (25 percent), respectively,had a maximal decrease in FEV1 of more than 30 percent.
Table 2. Analysis of End Points at the End of 12 Weeks of Treatment.
During the 12-week treatment period, the differences betweengroups in the various measures remained stable (Figure 3). Twoweeks after the cessation of therapy, the mean values in themontelukast group approached those in the placebo group (Figure 3).
Figure 3. Effects of Treatment with Montelukast and Placebo on the Three End Points over Time.
During the two-week washout period, all patients received placebo in a single-blind fashion. Values are means ±SE. Asterisks indicate significant differences (P<0.05) between groups.
Global Assessment of Asthma Control and Use of -Agonist Rescue Therapy after Exercise Challenge
Twelve weeks of montelukast therapy significantly improved thecontrol of asthma, as determined by the patients' global assessmentscores (P=0.009). In the montelukast group, 73.1 percent ofpatients characterized the control of asthma as better, 21.2percent as unchanged, and 5.8 percent as worse, as comparedwith respective values of 44.4 percent, 46.3 percent, and 9.3percent in the placebo group. Significantly fewer patients inthe montelukast group than in the placebo group required rescuetherapy with a -agonist after exercise challenge at each visitduring the treatment period. The respective values for the montelukastand placebo groups were 7.8 percent and 27.8 percent at week4, 8.0 percent and 24.5 percent at week 8, and 14.3 percentand 36.0 percent at week 12 (P<0.05 for all comparisons).
Methacholine Challenge
The mean PC20 values in the montelukast group and the placebogroup were similar at base line (0.46±0.41 vs. 0.45±0.35mg per milliliter). During the methacholine challenge, patientsin the montelukast group required proportionately more doublingdoses than patients in the placebo group (0.45 vs. 0.14), butthe difference between the two groups was not significant (P=0.16).
Adverse Effects
There were no significant differences between groups in thefrequency of clinical or laboratory adverse effects. The threemost commonly reported adverse effects were headache (32 percentof patients in the placebo group, as compared with 20 percentof patients in the montelukast group), upper respiratory tractinfections (23 percent vs. 28 percent), and worsening asthma(10 percent vs. 4 percent). One patient in each group had elevationsin serum aminotransferase levels to more than three times theupper limit of normal. In each case, the elevations were transientand self-limiting. Withdrawal of montelukast during the washoutperiod did not cause an increased incidence of worsening asthmaas compared with placebo.
Discussion
We found that once-daily treatment with 10 mg of montelukast,as compared with placebo, provided significant protection againstexercise-induced bronchoconstriction over a 12-week period.Although previous studies involving exercise challenge showedthat once-daily treatment with montelukast exerted a dose-relatedprotective effect at the end of the dosing interval after thesecond dose,3,7 we found that long-term therapy at the 10-mgdose provided consistent protection. The absence of a diminutionin the degree of protection against exercise-induced bronchoconstrictionafter long-term therapy due to the development of tolerancedifferentiates montelukast therapy from other therapies. Forexample, tolerance develops after one week of treatment witha short-acting inhaled -agonist, albuterol,16 and the degreeof tolerance that develops is similar to that occurring afterfour weeks of treatment with the long-acting -agonist salmeterol.17,18In a placebo-controlled study of exercise-induced bronchoconstrictionin children who were seven to nine years of age, 12 weeks ofinhaled beclomethasone (400 µg daily) resulted in significantimprovement of asthma control at 1 and 2 months; however, toleranceto the drug had developed by 3 months.19 In addition, in a crossoverstudy of a different leukotriene-receptor antagonist (cinalukast),tolerance to the lowest dose, but not higher doses, developedafter one week of therapy.20 The leukotriene antagonism inducedby this compound may have caused up-regulation of leukotrienereceptors, an effect overcome by higher doses.20
The magnitude of protection against exercise-induced bronchoconstrictionafforded by montelukast in our study is consistent with thatreported in other studies.3,7 A previous experimental leukotriene-receptorantagonist demonstrated more complete protection,6 but exercise-inducedbronchoconstriction at base line was less severe in that trialthan in ours (mean decrease in FEV1, 25 percent vs. 37 percent),which may account for the differences in results.
Although there was no residual protective effect of montelukasttwo weeks after treatment was stopped, neither was there reboundworsening of exercise-induced bronchoconstriction. This absenceof rebound worsening is consistent with the effect of the drugon other clinical measures of asthma control reported in previoustrials after the cessation of treatment.21,22,23
In addition, montelukast therapy had very few adverse effects,as has been found in clinical trials after up to three monthsof treatment21,22,23 and in limited numbers of patients afterup to one year of therapy.24
Although patients in the montelukast group had a significantimprovement in PC20 as compared with base-line values, the differencebetween groups was not significant. The 12-week treatment periodmay have been too short to induce a change in nonspecific hyperresponsiveness;in studies of inhaled glucocorticoids a treatment period of6 months is frequently required for such changes to become apparent.25It is also possible that a small but undetectable effect occurredor that because the patients had relatively mild asthma, theinitial hyperresponsiveness may not have been severe enoughto show significant improvement with montelukast therapy.
Supported by a grant from the Merck Research Laboratories.
Drs. Pearlman, Bronsky, Kemp, and Hendeles have been membersof a speakers' bureau sponsored by Merck. Drs. Busse and Kemphave been members of a Merck scientific advisory panel.
We are indebted to Barbara Knorr, M.D., and Kerstin Malmstrom,Ph.D., for critical review; to Charles Irvin, Ph.D., for adviceon methacholine challenge; to Donna E. Weinland and Debra Guerreirofor study monitoring; and to Rhonda Cooper for preparing themethacholine.
Source Information
From the Departments of Pulmonary-Immunology and Biostatistics, Merck Research Laboratories, Rahway, N.J. (J.A.L., S.K., J.Z., B.C.S., T.F.R.); the University of Wisconsin, Madison (W.W.B.); the Colorado Allergy and Asthma Clinic, Aurora (D.P.); the AAAA Medical Research Group, Salt Lake City (E.A.B.); the Allergy and Asthma Medical Group and Research Center, San Diego, Calif. (J.K.); the University of Florida School of Pharmacy, Gainesville (L.H.); and International Medical Technical Consultants, Kansas City, Mo. (R.D.).
Address reprint requests to Dr. Reiss at Merck and Company, P.O. Box 2000, Rahway, NJ 07065-0914.
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Exercise-Induced Asthma
Aziz I., Lipworth B. J., Dickey B. F., Adachi R., Honig P. K., Jenkins J. K., Stempel D. A., McFadden E.R., Strauss L., Nelson J. A., Reiss T. F., Hansen-Flaschen J.
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N Engl J Med 1998;
339:1783-1786, Dec 10, 1998.
Correspondence
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-agonist during or after exercise challenge. The rates of adverse events were similar in the two groups. 
4 mg per milliliter), and had a decrease in FEV1 of 20 percent or more after a standardized exercise challenge on two occasions. All patients were in good health on the basis of medical history, physical examination, and routine laboratory tests. All patients had quit smoking at least one year before the study and had a history of no more than 7 pack-years of smoking. 
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