01polos-vol5no3 1/26/70 6:27 pm page 402 inhaled ... · patient-reported symptoms,and use of rescue...

Vol. 5, No. 3, 2005 • The Journal of Applied Research402

Oral Montelukast Sodium versusInhaled Fluticasone Propionate inAdults with Mild PersistentAsthmaJean Bousquet, MD*Joris Menten, MSc†

Carol A. Tozzi, PhD†

Peter G. Polos, MD, PhD†

*Service des Maladies Respiratoires, Hospital Arnaud de Villeneuve, Montpellier France†Merck & Co., Inc., Whitehouse Station, New Jersey

would be considered at least as effectiveas fluticasone if the treatment differ-ence (average percentage of asthma-free days on fluticasone minus averagepercentage of asthma-free days on mon-telukast) was below 10% (3 days/month). Secondary endpoints were “as-needed” b-agonist use, days with symp-toms, rescue-free days, asthma-specificquality of life, forced expiratory volumein 1 second (FEV1), morning peak expi-ratory flow, asthma attacks, nocturnalawakenings, patient global assessmentof asthma, blood eosinophil count, andsafety and tolerability.

Results: Patients taking fluticasone had6.44% (95% confidence interval [CI]2.24, 10.64) more asthma-free days thandid patients taking montelukast (<2days/month/patient). The CI includedthe non-inferiority boundary of 10%.Both montelukast and fluticasoneshowed an improvement in asthma-related efficacy endpoints, except FEV1,which was improved only for patientstaking fluticasone. Both montelukastand fluticasone were well tolerated.

Conclusions: Both agents demonstratedefficacy for most of the primary and

KEY WO R D S : m o n t e l u k a s t , f l u t i c a s-o n e, a s t h m a , F E V1, b- a g o n i s t

ABSTRACTObjective: Asthma consensus guidelinesrecommend the use of a controller agentto control asthma symptoms and reduceinflammation in patients with mild asth-ma. The objective of this study was tocompare montelukast to inhaled flutica-sone on the percentage of asthma-freedays in patients with mild persistentasthma during 48 weeks of active treatment.

Methods: This was a randomized, multi-center study with a 3-week single-blindrun-in period, followed by a 12-weekdouble-blind active treatment period,and a 36-week open-label active treat-ment period. Patients (aged 15 to 80years) with mild persistent asthma asestablished by the Global Initiative forAsthma (GINA) guidelines were ran-domized to receive oral montelukast 10 mg (n=325) or fluticasone 100 µg (n=320) twice daily by metered-doseinhaler. An analysis of covariance modelwas used to analyze the primary end-point of asthma-free days. Montelukast

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secondary endpoints. Results for mostendpoints were essentially equivalent;however, patients taking fluticasone hadmore asthma-free days and improvedFEV1 than did patients taking mon-telukast.

INTRODUCTIONCurrent therapeutic guidelines recom-mend inhaled steroids as first-line treat-ment for mild persistent asthma sinceairway inflammation is a significant partof the pathology.1–5 Patients with mildasthma suffer from recurrent (thoughinfrequent) symptoms and limitations intheir activities. The cysteinyl leukotrienesLTC4, LTD4, and LTE4 play an integralrole in the pathophysiology of asthma.6,7

Montelukast, a selective potentleukotriene-receptor antagonist givenonce daily, has been shown to effectivelyreduce symptoms of asthma in adultsand in children (including those youngerthan 2 years of age). It has also beenshown to reduce symptoms of allergicrhinitis.8–14

Traditionally, the efficacy of anti-asthma therapy is assessed by improve-ments in forced expiratory volume in 1second (FEV1), as well as home-moni-tored peak expiratory flow (PEF),patient-reported symptoms, and use ofrescue medication; however, the correla-tion between these measures is oftenpoor, suggesting that they measure dif-ferent aspects of the disease.15,16

Recently, emphasis has shifted to anevaluation of outcomes that impactpatients’ lives. Measures such as asthma-free days, asthma rescue medication-freedays, and quality-of-life assessmentsshow sensitivity and responsiveness instudies of mild asthmatic patients andhelp to define therapeutic effectiveness.Mild and moderate asthmatic patientstaking montelukast have been reportedto have experienced clinically importantimprovements in airway function, asth-ma exacerbations, asthma attacks, and

symptoms.8–10,17

Although inhaled corticosteroids areeffective in reducing symptoms of asth-ma, concerns about safety and non-com-pliance suggest that other agents thateffectively reduce airway inflammationand are convenient to use may be aviable alternative.18–21 In a previouslypublished study, once-daily oral mon-telukast was similar to twice-a-dayinhaled fluticasone in improving asthmarescue-free days and other symptoms ofasthma in adults with mild asthma over12 weeks of treatment.17 The purpose ofthe present study was to compare theeffects of oral montelukast versusinhaled fluticasone in increasing asthma-free days over a 12-week double-blindperiod and to evaluate the maintenanceof treatment effect in a 36-week open-label period in patients with mild per-sistent asthma.

METHODSStudy DesignProtocol 905 was a 51-week, 3-period,randomized, double-blind, multicenterstudy at 77 sites in 22 countries inEurope, Asia, and South America. Thestudy consisted of a 3-week run-in peri-od (Period 1), a 12-week double-blindtreatment period (Period 2), and a 36-week open-label treatment period(Period 3). During Period 1, patientsreceived single-blind oral and inhaledplacebo during the last 2 weeks of the 3-week period. During Period 2, patientswere randomized using a computer-gen-erated allocation schedule to receiveeither oral montelukast 10 mg (n=325)once daily at bedtime or fluticasone 100 µg (n=320) twice daily by metered-dose inhaler (MDI). This schedule incor-porated the random switch of therapyfor the 12-week double-blind period tothe 36-week open-label phase for 10%of the patients while 90% remained onthe initial therapy. Written informedconsent approved by the respective



institutional review boards was obtainedfrom all participants.

Inclusion CriteriaPatients with mild persistent asthma asdefined by Global Initiative for Asthma(GINA) guidelines were included.2

Patients were nonsmoking males andfemales, 15 to 80 years of age, with a his-tory of asthma for at least 4 months, abaseline FEV1 value �80% of predicted,and with either b-agonist reversibility ofat least 12% (FEV1 or PEF) or a posi-tive exercise challenge test within theprevious month. Patients also had tohave demonstrated daytime symptomsand short-acting b-agonist use on atleast 2 days—but not every day—of thefirst week of the run-in period. Patientswere to be in need of, but not on, con-troller medication, and at the time ofenrollment could only be taking b-agonists.

Exclusion CriteriaPatients treated in an emergency depart-ment within 1 month, hospitalized forasthma within 3 months, or having unre-solved symptoms and signs of upper res-piratory tract infection within 3 weekswere excluded. Excluded medicationsincluded any form of corticosteroidswithin 1 month; cromolyn, nedocromil,or leukotriene-receptor antagonistswithin 2 weeks; theophylline, oral orlong-acting b-agonists, or inhaled anti-cholinergics within 1 week; or terfena-dine, fexofenadine, loratadine, orcetirizine within 48 hours of the firstvisit. Patients starting immunotherapywithin 6 months were excluded; howev-er, a patient taking immunotherapylonger than 6 months prior to entrycould be included if dosage was consis-tent throughout the duration of thestudy.

EvaluationsThe primary endpoint was the compari-

son of the effect of 12 weeks of treat-ment with oral montelukast on the per-centage of asthma-free days. Anasthma-free day was defined as any dayin which the patient had normal pul-monary function (PEF at least 80% ofpredicted), no symptoms (a score of 0 or1 out of a possible 6 on the diary cardquestion), no use of rescue medication(short-acting b-agonists or other), nonocturnal awakenings, and no unsched-uled doctor visits. Results with mon-telukast were compared with those forpatients taking fluticasone.

Secondary endpoints included “as-needed” b-agonist use, percentage ofdays with b-agonist use, days with symp-toms, percentage of asthma rescue med-ication-free days, asthma-specific qualityof life, FEV1, morning (AM) PEF, asth-ma attacks, nocturnal awakenings,patients’ global assessment of asthma,blood eosinophil count, percentage ofasthma rescue medication-free days inpatients with normal lung function, andsafety and tolerability over the 12-weekperiod. Also evaluated was the treat-ment effect of oral montelukast andinhaled fluticasone over the 36-weekopen-label treatment period (Period 3)and the maintenance of treatment effectfrom Period 2 to Period 3.

A day with symptoms was any daywith a symptom score of 2 or greater onthe diary card question. An asthma res-cue medication-free day was defined asany day a patient had no b-agonist orcorticosteroid use and no asthma-relatedhealth care resource use, such as anunscheduled office visit, an urgent oremergency care visit, or hospitalization.An asthma attack was defined as anunscheduled visit to the doctor’s office,emergency room, or hospital or treat-ment with oral, intravenous, or intramus-cular corticosteroids. Patients withnormal lung function were defined asthose with an AM PEF at least 80% ofpredicted.



Patients were instructed how to usethe daily diary card which containeddaytime asthma symptoms and night-time awakening scales that had beenpreviously shown to have acceptableevaluative measurement properties.22

Daytime asthma symptoms were record-ed in the evening before taking studymedication and included an assessmentof the daily asthma symptoms, such as,but not limited to, chest discomfort(tightness), wheezing, shortness ofbreath (breathlessness), and cough ratedon a 7-point scale from 0 (symptomsnone of the time) to 6 (symptoms all ofthe time). Patients recorded the totalnumber of puffs of “as-needed” b-ago-nist used since arising. Nighttime symp-toms were recorded in the morningupon arising, before taking any medica-tion. Patients recorded whether theywoke up during the night with symp-toms of asthma and the total number ofb-agonist puffs taken since going to bed.Patients also recorded the use of oralcorticosteroid rescue medications andvisits to the physician’s office or hospitalfor episodes of worsening asthma.Patients measured PEF (best of 3 meas-urements) in the morning on arisingusing a commercial flow meter.

At the completion of the 12-weekperiod, patients evaluated the change inasthma (global evaluation) by selectingthe most appropriate response on a 7-point scale (very much better, moderate-ly better, a little better, unchanged, alittle worse, moderately worse, verymuch worse). An asthma-specific quali-ty-of-life questionnaire was completedprior to randomization and at the end ofthe 12-week and 36-week periods orupon discontinuation of the trial.23

Statistical MethodsThe primary analysis was a modifiedintention-to-treat approach in that allpatients who have been treated for 1day with at least one baseline measure-

ment were included in the analysis. Toassess whether montelukast was similarto fluticasone for the primary endpoint,it was determined that the two-sided95% CI of the treatment difference(average percentage of asthma-free dayson fluticasone minus the average per-centage of asthma-free days on mon-telukast) for the 12-week double-blindperiod and the 36-week open-label peri-od should lie below 10% (3 days permonth). The 95% CI was constructedusing the least-squares (LS) means froman analysis of covariance (ANCOVA)model with effects for treatment andcenter, using baseline asthma-free daysas covariate. Treatment differences forsecondary endpoints were exploredusing 95% CIs constructed using LSmeans. In addition, the treatment differ-ence for secondary endpoints was testedusing an analysis of variance (ANOVA)or ANCOVA models with effects fortreatment and center using baseline ascovariate (if available). Maintenance oftreatment effect was explored forpatients remaining on the same treat-ment throughout the whole 48 weekactive treatment duration (90% ofpatients).

The safety profile of montelukastand fluticasone was compared by statis-tical and clinical assessments of frequen-cy of adverse experiences during thetreatment periods.

Power and Sample SizeThe study was designed with a samplesize of 166 patients in each treatmentgroup in order to provide 90% power toaccurately assess the primary endpointof asthma-free days during the 12-weekperiod. A limit of 10% corresponds to atreatment difference of 3 days/month. Alarger number of patients was recruitedto ensure that there was a sufficientnumber of patients with mild asthmaand whose symptoms corresponded toStep II of the GINA guidelines.

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RESULTSPatientsSix hundred forty-five patients enteredthe 12-week double-blind treatmentperiod; 325 were allocated to the oral

montelukast group and 320 to theinhaled fluticasone group (Figure 1).The demographic characteristics of thepatients were essentially and statisticallysimilar between the two groups

Figure 1. Study design for evaluation of oral montelukast 10 mg and inhaled fluticasone 100 µgtwice daily in patients with mild persistent asthma

†Other includes patient did not follow up on visit; many infections; private reasons; patient did not tolerate fluticasone spray; patient uncooperative.

‡Primary endpoint.



(Table 1). Patients continuing into theopen-label phase were generally similarto those not continuing into the open-label phase.

Of the 645 patients, 30 (13 in themontelukast group and 17 in the flutica-sone group) were excluded from themodified intention-to-treat analysis forthe primary endpoint of asthma-freedays. Three patients were excluded fromall efficacy analyses due to protocol vio-lations, and 27 were excluded due to a

lack of a valid baseline or treatment-period measurements. A total of 602patients entered the open-label 36-weekphase; 300 patients in the montelukastgroup and 302 in the fluticasone group(Figure 1).

Efficacy EvaluationsAsthma-Free DaysThroughout the trial, both montelukastand fluticasone significantly improvedthe primary endpoint asthma-free days

Table 1. Demographic and Baseline Characteristics of Randomized Patients with Asthma Treated with Oral Montelukast 10 mg Once Daily at Bedtime or Inhaled Fluticasone 100 µgTwice Daily

Characteristic Montelukast Fluticasonen=325 n=320

Age, yr 35.9 ± 14.3 36.6 ± 13.8Gender, n (%)

Male 126 (38.8) 113 (35.3)Female 199 (61.2) 207 (64.7)

Race, n (%)Caucasian 208 (64.0) 196 (61.3)Black 2 (0.6) 3 (0.9)Asian 37 (11.4) 38 (11.9)Hispanic 58 (17.8) 63 (19.7)Other 20 (6.2) 20 (6.3)

Height (cm) 167.3 ± 10.1 165.9 ± 10.0Weight (kg) 71.4 ± 15.6 69.3 ± 13.7History of allergic rhinitis, n (%) 194 (59.7) 179 (56.1) History of atopic dermatitis, n (%) 42 (12.9) 45 (14.1)FEV1, L (n) 3.14 ± 0.85 (324) 2.99 ± 0.81 (318) FEV1, % of predicted, (n*) 90.5 ± 12.2 (324) 88.2 ± 12.2 (318) AM PEFR, L/min, (n*) 397.7 ± 102.2 (323) 390.7 ± 108.8 (314) Asthma-free days, %, (n*) 22.6 ± 23.2 (320) 22.8 ± 23.6 (308) b-agonist, puffs/day, (n*) 1.28 ± 1.1 (305) 1.38 ± 1.3 (301) Days with symptoms, % (n*) 47.0 ± 22.2 (324) 48.6 ± 21.6 (313)Asthma rescue medication free days,† %, (n*) 45.3 ± 22.2 (311) 44.7 ± 23.0 (303)Quality of life score, pooled domains, (n*) 4.98 ± 1.00 (324) 4.97 ± 0.95 (318)Nocturnal awakenings, % (n*) 21.3 ± 26.5 (321) 23.1 ± 27.1 (309)Blood eosinophils, 103/µL (n*) 0.29 ± 0.24 (319) 0.28 ± 0.22 (315)

*Number of patients with available information in this category.†Defined as a day without b-agonist use or other asthma-related medication or resource use and AMPEF at least 80% of predicted.F E V1 = forced expiratory volume in 1 second; AM PEF = peak expiratory flow measured in the morning.Data are mean ± standard deviation unless otherwise specified.



from baseline (P £ 0.001) (Figure 2). At12 and 36 weeks, the number of asthma-free days was significantly greater forpatients treated with fluticasone thanfor those treated with montelukast. TheLS mean treatment difference was6.44% in favor of fluticasone at 12weeks (P=0.003) and 5.38% in favor offluticasone at 36 weeks (P=0.047) (Table2).

The maintenance of treatmenteffect was evaluated by slope analysis ofthe weekly measurements over the 12-and 36-week periods. There was a signif-icant increase in asthma-free days rela-tive to baseline for both montelukastand fluticasone (P=0.031). The differ-ence in slopes (–0.11 [95% CI –0.24,0.02]) between montelukast and fluticas-one over the entire 48 weeks was notsignificant (P=0.094).

The subgroup analysis by gender,

age, race, baseline b-agonist use, andyears since diagnosis of asthma showedno significant treatment ¥ subgroupeffect except for evaluation by baselineb-agonist use. No treatment differencewas evident in patients with low b-agonist use at baseline compared withthe median (<0.92 puffs/day). In patientswith high b-agonist use at baseline (> 0.92 puffs/day), a higher percentageof asthma-free days was seen forpatients taking fluticasone comparedwith values at baseline (P=0.031).

Secondary EndpointsBoth montelukast and fluticasone signif-icantly reduced average daily “as need-ed” b-agonist use in patients who had atleast 0.5 puffs/day of b-agonist use atbaseline (P=0.002) (Figure 3). At 12weeks, patients on fluticasone had a sig-nificantly greater decrease in puffs/day

Table 2. Treatment Differences in Efficacy Endpoints for Oral Montelukast 10 mg and Inhaled Fluticasone 100 µg Twice Daily in Patients With Mild Persistent Asthma

Treatment Differences in the 12-Week Double-Blind Period TreatmEnd Point Montelukast Fluticasone LS Mean Treatment Monte

n* Mean (SD) n* Mean (SD) Difference (95% CI)† n* MAsthma-free days (%) 278 46.1 (36.1) 284 49.5 (37.0) 5.38 (0.07,10.69) 312 3“As needed” b-agonist use‡§ 218 –42.6 (79.4) 235 –52.5 (77.9) –9.78 (–24.62, 5.06) 247 –Days with b-agonist use (%) 268 28.6 (28.9) 281 24.9 (31.1) –4.95 (–9.56, –3.4) 303 3Days with symptoms (%) 280 23.9 (27.7) 290 19.2 (27.0) –5.10 (–9.26, –0.94) 316 2Asthma rescue medication- 268 71.2 (29.1) 281 74.8 (31.1) 5.07 (0.42, 9.72) 303 6

free days (%)Asthma rescue medication- 278 50.2 (36.6) 285 52.8 (37.3) 4.83 (–0.45, 10.10) 312 4

free days with normal lungfunction (%)

FEV1 (L, % change) 277 –2.04 (10.36) 284 1.52 (10.57) 3.14 (1.43, 4.85) 314 –FEV1 (% of predicted)‡§ 277 –2.02 (9.27) 284 1.25 (9.20) 2.83 (1.33, 4.32) 314 –AM PEF (L/min)‡§ 279 22.8 (55.4) 291 32.4 (49.2) 9.35 (1.01, 17.68) 315 1Nocturnal awakenings (%) 279 9.9 (18.3) 288 8.0 (15.8) –2.73 (–5.33, –0.13) 313 1Asthma specific Quality of 208 0.66 (0.97) 237 0.83 (1.06) 0.11 (–0.04, 0.27) 246 0

Life scoreEosinophil count (103/µL)‡§ 275 –0.04 (0.20) 285 –0.04 (0.20) 0.01 (–0.02, 0.03) 275 –*Number of patients with data available in this category.†Treatment difference = montelukast value – fluticasone value.‡Includes only patients with baseline b-agonist use ≥ 0.5 puffs/day.§Change from baseline.CI = confidence interval, LS = least squares; SD = standard deviation.



of b-agonist than did patients takingmontelukast (P=0.001), but the differ-ence was not significant in the 36-weekperiod (P=0.196) (Table 2). Montelukastand fluticasone also significantlyreduced the percentage of days with b-agonist use during the 12- and 36-weektreatment periods (P<0.001). Treatmentfavored the fluticasone group at 12weeks (P<0.001) and at 36 weeks(P=0.035) (Table 2). Both treatmentssignificantly increased the percentage ofasthma rescue medication-free days dur-ing both time periods for all patientsand for patients with normal lung func-tion (P £ 0.001). For percentage of asth-ma rescue medication-free days in allpatients, treatment favored the fluticas-one group at 12 weeks (P<0.001) and at36 weeks (P=0.033). In patients withnormal lung function, treatment favoredfluticasone at 12 weeks (P=0.001) but

not at 36 weeks (P=0.073) (Table 2).Montelukast and fluticasone signifi-

cantly reduced the percentage of dayswith symptoms relative to baseline(P<0.001). Treatment favored fluticas-one at the 12-week (P<0.001) and 36-week (P=0.016) periods (Table 2).Montelukast did not change FEV1 dur-ing either treatment period but did sig-nificantly improve AM PEF from valuesat baseline during both periods. Thechange from baseline in AM PEF duringthe 12-week double-blind period was16.88 L/min for the montelukast treat-ment group and 23.66 L/min for the flu-ticasone treatment group, (P=0.047). At36 weeks, AM PEF change from base-line was 22.80 L/min for the montelukasttreatment group and 32.36 L/min for thefluticasone treatment group (P=0.028)(Table 2).

There was no significant difference

haled

d Treatment Differences in the 36-Week Open-Label Periodreatment Montelukast Fluticasone LS Mean Treatment (95% CI)† n* Mean (SD) n* Mean (SD) Difference (95% CI)†

0.69) 312 37.5 (32.6) 303 43.7 (34.8) 6.44 (2.24, 10.64) 62, 5.06) 247 –27.4 (70.2) 244 –46.9 (57.6) –18.84 (–30.09, –7.59) 6, –3.4) 303 36.8 (28.3) 296 30.8 (28.6) –7.13 (–10.92, –-3.34) 6, –0.94) 316 29.5 (27.8) 308 23.6 (26.4) –7.34 (–11.03, –3.65)9.72) 303 62.9 (28.5) 296 69.2 (28.6) 7.11 (3.31, 10.90)

10.10) 312 41.2 (33.2) 303 47.9 (35.2) 7.32 (3.17, 11.47)

4.85) 314 –0.33 (9.81) 309 2.73 (11.38) 2.60 (0.98, 4.22)4.32) 314 –0.55 (8.70) 309 2.15 (8.92) 2.17 (0.83, 3.51)17.68) 315 16.9 (42.3) 309 23.7 (39.9) 6.31 (0.08, 12.55)3, –0.13) 313 14.8 (22.2) 304 9.9 (15.8) –5.73 (–8.28, –3.17) 0.27) 246 0.47 (0.85) 247 0.70 (0.92) 0.24 (0.11, 0.37)

0.03) 275 –0.05 (0.23) 277 –0.04 (0.19) –0.00 (–0.03, 0.03)



between montelukast and fluticasoneduring either period for the proportionof patients having an asthma attack.During the 12-week double-blind peri-od, 7.7% of the patients in the mon-telukast group and 4.4% for the

fluticasone group reported having anasthma attack (odds ratio 1.82; 95% CI0.93, 3.56; P=0.083). During the 36-weekperiod, 16.7% of the patients in themontelukast group and 14.5% in the flu-ticasone group reported an asthma

Figure 2. Percentage of asthma-free days for patients taking oral montelukast or inhaled fluticas-one during the 12-week double-blind and 36-week open-label periods. Both treatment groupssignificantly increased the percentage of asthma-free days from baseline for the 48-week treat-ment period. The percent of asthma-free days was greater in the fluticasone group than in themontelukast group at both time periods

Figure 3. “As needed” b-agonist use in patients taking oral montelukast or inhaled fluticasone forthe 12-week double-blind and 36-week open-label periods. Both treatment groups significantlyreduced average daily b-agonist use over the 48-week active treatment period. Reduction in“as needed” b-agonists was greater in the fluticasone group than in the montelukast group dur-ing the 12-week period but not during the 36-week open-label period.



attack (odds ratio 1.18; 95% CI 0.75,1.84; P=0.474).

Montelukast and fluticasone signifi-cantly reduced nocturnal awakeningscompared with baseline values duringthe 12- and 36-week trial periods(P<0.001). The percentage of nights withawakenings due to asthma during the12-week period was 14.83% for themontelukast group and 9.93% for thefluticasone group. During the 36-weektreatment period, the mean percentageof nocturnal awakenings was 9.88% inthe montelukast group and 8.00% in thefluticasone group. Patients taking fluti-casone had fewer nights with awaken-ings in the 12-week (P<0.001) and36-week time periods (P=0.040) com-pared with those taking montelukast(Table 2).

Both montelukast and fluticasonesignificantly improved overall quality oflife and individual domains of activity,symptoms, emotional function, and envi-ronmental stimuli (P<0.001). The treat-ment effect for overall quality of lifefavored fluticasone at 12 weeks (P £0.01), but the difference between thetreatments was not significant at 36weeks (P=0.150). For the global evalua-tion, 29.8% in the montelukast groupand 32.1% in the fluticasone groupreported feeling moderately better, and30.1% on montelukast and 39.4% onfluticasone reported feeling very muchbetter than when they entered the study.The treatment difference was significant(P<0.001).

Montelukast and fluticasone signifi-cantly reduced peripheral bloodeosinophil counts from baseline duringboth periods (P<0.001); the treatmentdifference was not significant duringeither period (P=0.894) (Table 2).

SafetyDuring the 12-week period, adverseexperiences determined by the investi-gator to be possibly, probably, or defi-

nitely drug related occurred in 24(7.4%) and 12 (3.8%) of patients in themontelukast and fluticasone groups,respectively. The most common clinicaladverse experiences were asthma, whichoccurred in 4 (1.2%) patients takingmontelukast and 1 (0.3%) patient takingfluticasone, and headache in 4 (1.2%)patients taking montelukast and 2(0.6%) patients taking fluticasone.Eleven (1.7%) of the 645 patients dis-continued therapy due to a clinicaladverse experience: 7 (2.2%) in themontelukast group (including 2 patientswho discontinued due to pregnancy) and4 (1.3%) in the fluticasone group.

During the 36-week period, 19patients (6.3%) in both groups hadadverse experiences that were consid-ered drug related. The most commonadverse experiences were headache,reported by 3 (1.0%) patients takingmontelukast and 1 (0.3%) patient takingfluticasone, and asthma, reported by 5(1.7%) patients taking montelukast and3 (1.0%) taking fluticasone. A total of 16(2.7%) of 602 patients discontinuedtherapy due to pregnancy or a clinicaladverse experience during the 36-weekopen-label period. There were no clini-cally meaningful differences betweentreatment groups and no discontinua-tions due to laboratory adverse experi-ences over the 48 weeks of activetherapy.

DISCUSSIONIn this study, montelukast and fluticas-one significantly improved asthma-freedays, the primary endpoint, as well asmultiple parameters of asthma controlover the 48 weeks of the active treat-ment period. However, the study did notsupport the non-inferiority hypothesis ofmontelukast compared with fluticasonein asthma-free days during the 12-weekdouble-blind period. There was a statisti-cally significant difference in the per-centage of asthma-free days, favoring



fluticasone over montelukast. Althoughboth treatments significantly improvedb-agonist use and nocturnal awakenings,both of which are components of anasthma-free day, outcomes favored fluti-casone for these clinical endpoints.These results differ from the equivalentefficacy established for montelukastcompared with inhaled corticosteroids inprevious studies.17,20 The establishednon-inferiority boundary for mon-telukast was defined at a conservativelevel of no more than 3 days per monthfor the difference in asthma-free dayscompared with findings for fluticasone.However, since the 95% CIs includedthe boundary of 10%, the non-inferiorityof montelukast to fluticasone could notbe established. The mean difference inasthma-free days was less than 2 daysper month per patient between thetreatment groups.

The percentage of asthma rescuemedication-free days was significantlyi m p r o v e d , and asthma attacks were signif-icantly reduced by montelukast and fluti-casone during the 48-week activetreatment period. Patients taking eithermontelukast of fluticasone had more than75% of days per month with no symp-toms and approximately 70% of days permonth with no need for rescue medica-t i o n . Symptoms such as the intensity ofshortness of breath and use of rescuemedication in mild asthmatics have beenshown to correlate with quality of life,which was improved by both therapies.2 4

In a similar study, montelukast andfluticasone significantly improved asth-ma rescue-free days to the same degreein patients with an FEV1 >86% predict-ed.17 A similar analysis performed in thepresent study did not support this find-ing. The results of the previous studysuggest that montelukast is as effectiveas fluticasone in patients with very mildasthma. However, asthma is a variabledisease, and therapy will have to be tai-lored to the individual patient.

Goals of therapy are to preventrecurrent exacerbations of asthma andto minimize the need for emergencytreatment.1,2 Although this was a popula-tion of patients with mild asthma,attacks can occur in this subgroup, con-tributing significantly to the burden ofuncontrolled asthma. In this study, asth-ma attacks were significantly and simi-larly reduced by both montelukast andfluticasone over the duration of thestudy, confirming results from a previousclinical trial that demonstrated thatmontelukast and beclomethasonereduced asthma attacks to a similardegree in patients with mild to moderateasthma.20

The improvements in multipleindices of asthma seen with montelukastdid not correlate with FEV1 over theactive treatment periods. FEV1remained relatively unchanged inpatients taking montelukast for 48 con-secutive weeks; however, montelukastimproved FEV1 in other studies inadults with a broad range of asthmaseverities.8 A subgroup analysis of clini-cal trials evaluating the effect of mon-telukast in patients with mild asthmareported an average improvement of6.8% or greater in FEV1 in trials of vari-ous durations of treatment.25 Fluticasonesignificantly increased FEV1 in the pres-ent study (2.73% after 12 weeks and1.52% at 36 weeks). This level of changein FEV1, although statistically signifi-cant, may not be clinically relevant. AMPEF was significantly improved for bothmontelukast and fluticasone.

Airway inflammation is an estab-lished feature of asthma and it is recog-nized that the eosinophil is a keycellular mediator of the inflammationassociated with asthma.26 Results fromthe present study demonstrated thatmontelukast and fluticasone significantlyreduced peripheral blood eosinophils inmild asthmatic patients over the 48-week trial period. Reductions in periph-



eral blood eosinophils have been previ-ously demonstrated in adult and pedi-atric patients treated withmontelukast.9,10,13,27 Reductions inperipheral blood eosinophils have beenassociated with improved asthma con-trol and appear to be associated withimprovements in clinical indices of asth-ma control in the present study.28,29

Decreases in eosinophilia in the patientstreated with montelukast or fluticasonein the current study underscore theimportance of inflammation even in themildest forms of asthma.

In summary, this clinical trial com-paring once-daily oral montelukast totwice-daily inhaled fluticasone demon-strated that both treatments significantlyimproved the primary endpoint (asth-ma-free days) as well as other secondaryendpoints during the 12-week double-blind and 36-week open-label trial peri-ods. Both treatment approaches in thisstudy maintained significant control ofasthma symptoms, reduced asthmaattacks to a similar degree, improvedquality of life, reduced peripheral bloodeosinophils over the 48-week trial peri-od. Results from the 12-week trialfavored fluticasone in several indices,these differences tended to diminishduring the 36-week period.

ACKNOWLEDGMENTThis study was supported by a grantfrom Merck & Co., Inc.

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