INTRODUCTION

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Recent asthma treatment guidelines define the goals of therapy: to achieve asthma control, i.e., near normal airway function, absence of asthma symptoms, no activity limitations, no episodes of worsening asthma, with an acceptable tolerability profile (1). However, many patients with persistent asthma cannot attain these treatment goals with a single controller medication even at high doses (2). Therefore, adding a second therapy with a complementary mechanism of action may provide more complete asthma control (2). Unfortunately, the use of multiple therapies complicates treatment regimens (3). For example, a previous report indicated that compliance with inhaled medications (30 to 60%) is less than with oral (70 to 80%) medications; multiple daily administration of any therapy also contributes to poor compliance (3). Therefore, an oral therapy administered once daily could potentially provide the clinical effectiveness desired in usual practice.

Montelukast, a new, specific leukotriene receptor antagonist (4) provides clinical benefit to patients with chronic asthma with a once daily, oral administration (5, 6). Subgroup analysis in previous short-term studies with crossover designs suggested that montelukast could provide additional clinical benefit to patients using concomitant inhaled corticosteroids (7, 8).

To prospectively determine whether concomitantly administered montelukast and inhaled corticosteroids cause additive clinical benefit, we performed a randomized, double-blind, double-dummy, clinical trial in patients with incompletely controlled asthma who were receiving inhaled beclomethasone 200 µg twice daily. At the time of random allocation, montelukast, 10 mg once daily at bedtime, was added to a treatment regiment of inhaled beclomethasone, 200 µg twice daily, and this treatment group was compared with a group of patients continuing this dose of inhaled beclomethasone alone. Blindly removing beclomethasone (switching to inhaled placebo in the presence of placebo tablets) determined whether patients enrolled in the trial benefitted clinically from inhaled corticosteroids. As a secondary objective, the study evaluated whether montelukast could be substituted for inhaled beclomethasone by blindly switching patients from beclomethasone to montelukast.

	METHODS

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This was a multicenter, randomized, parallel-group study consisting of a 4-wk, single-blind run-in period (Period 1) and a 16-wk, double-blind treatment period (Period 2) with four treatment groups. The visits in Period 1 and the first two visits in Period 2 were separated by 2 wk; subsequent visits were separated by approximately 3 wk. The study was conducted at 70 study centers, in 18 countries in North America, Europe, Africa, Australia, and Asia.

Written informed consent approved by the respective institutional review boards/ethical review committees and local regulatory agencies (where required) was obtained from each patient during or before the prestudy visit. Parental or guardian consent was obtained for patients younger than 18 yr of age.

Patients and Procedures

Healthy, nonsmoking, male and female patients (age 15 yr and older), with a history of at least 1 yr of intermittent or persistent asthma symptoms treated with inhaled corticosteroids for at least 6 wk before the prestudy visit were eligible for participation (the dose of inhaled corticosteroid 1 wk before the prestudy visit was either equal or comparable to 400 to 500 µg of beclomethasone). Patients were excluded if they had respiratory disorders other than asthma or had signs and symptoms of an upper respiratory infection within 3 wk of the prestudy visit. Female patients had a negative pregnancy test at the prestudy visit.

Antiasthma medications excluded before the prestudy visit were oral and parenteral corticosteroids within 1 mo; cromolyn and nedocromil within 2 wk; theophylline (oral and intravenous), -agonists (oral or long-acting inhaled), and anticholinergic agents within 1 wk. Antihistamines, except terfenadine (within 2 wk) and astemizole (within 3 mo), were permitted as needed during the study; immunotherapy was allowed at a constant monthly dose if initiated at least 6 mo before the prestudy visit. Patients used short-acting, inhaled -agonist on an "as needed" basis (via metered-dose inhalers of albuterol/salbutamol, 100 µg/actuation).

During the run-in period (Period 1) patients were dispensed two inhalers (morning and evening), in a blind manner, containing beclomethasone (Beclovent; Allen & Hanburys, Research Triangle Park, NC; 50 µg/actuation) and a bottle of placebo tablets. Patients were instructed to take 4 puffs (200 µg twice daily) and a tablet once daily at bedtime. Inhaled study medication was administered with an AeroChamber spacer device (Forest Pharmaceuticals, St. Louis, MO) throughout the study.

To be eligible for Period 2, patients were required to demonstrate, on at least two of the four visits in Period 1, an FEV₁ between 50 and 85% of the predicted value after withholding inhaled -agonist and antihistamine for at least 6 and 48 h, respectively, and to show at least a 15% increase in FEV₁ (absolute value) 20 to 30 min after inhaled -agonist administration. In addition, patients were required to have at least a minimum total daytime asthma symptom score (64 out of a possible 336 score) and daily average -agonist use (as needed) of at least 1 puff during the last 2 wk of Period 1. Eligible patients were randomly allocated in a double-blind double-dummy manner (both montelukast and beclomethasone and their respective placebos were allocated in a double-blind manner) to one of four treatment groups according to a computer-generated schedule (with a blocking factor of 6, non-U.S. study sites; 8, U.S. study sites) to receive (1) montelukast 10 mg once daily and inhaled beclomethasone 200 µg twice daily (montelukast plus beclomethasone group); (2) placebo tablets once daily and inhaled beclomethasone 200 µg twice daily (beclomethasone group); (3) montelukast 10 mg once daily and inhaled placebo twice daily (after removal of beclomethasone) (montelukast group); or (4) placebo tablet once daily and inhaled placebo (after removal of beclomethasone) (placebo group). The latter two groups effectively received treatment for 12, rather than 16 wk because the removal of inhaled beclomethasone was performed blindly by replacing the morning and evening beclomethasone inhalers with placebo inhalers 2 and 4 wk, respectively, after randomization. Only patients at the U.S. study sites were enrolled in the fourth treatment arm (placebo group).

Patient compliance was determined by weighing the beclomethasone/placebo canisters and by tablet counts (percent of tablets that should have been taken; percent of total weight that should have been used).

Spirometry was collected at each clinic visit between 6:00 and 9:00 A.M. using a standard spirometer (Puritan Bennett PB100/PB110; Nellcor, Kansas City, KS); at least three spirometry maneuvers were performed and the highest FEV₁ was recorded. The data were transmitted weekly to a spirometry quality control center for rigorous review of data quality (9) and adherence to spirometry inclusion criteria.

Daily asthma symptoms score and nocturnal awakenings were recorded on a diary card using validated measurement scales (10). On the diary card, patients recorded their peak expiratory flow rate (PEFR), measured in the morning upon awakening and evening before evening dose of study medication, and daily as needed use of short-acting inhaled -agonist. Physicians' and patients' global evaluations, using a seven-point scale (0 = very much better, 6 = very much worse) (6), and the self-administered Asthma Quality of Life Questionnaire (11) were also used. The diary card and patients' questionnaires were translated from English to the appropriate local languages and adjusted for linguistic equivalence and cultural differences (12).

FEV₁ and patient-reported daytime asthma symptoms were the prespecified primary efficacy endpoints. Other prespecified endpoints were changes in daily, "as needed," inhaled -agonist use, morning and evening PEFR, nocturnal awakenings with asthma, and peripheral blood eosinophil counts. Prespecified asthma outcomes included percent days with asthma exacerbations and percent patients with asthma attacks. An asthma-exacerbation day was defined as a day when any one of the following occurred: a decrease of > 20% from baseline value in morning PEFR; PEFR < 180 L/min; an increase of > 70% from baseline value in -agonist use (a minimum increase of two puffs); an increase > 50% from baseline in symptom score; "awake all night" with asthma; or worsening asthma requiring oral corticosteroid rescue, visit to a doctor's office, or hospitalization. An asthma attack was defined as worsening asthma requiring an unscheduled visit, hospitalization, or treatment with oral corticosteroids (13).

The safety and tolerability profile was determined by adverse experiences reports, physical examination, and 12-lead electrocardiography (ECG). Laboratory safety tests (including hematology, serum biochemistry, and urinalysis) and blood eosinophil counts were analyzed by a central laboratory (Covance Central Laboratory Services, Inc., Indianapolis, IN).

Statistical Analysis

The prespecified primary comparison was between the additivity and beclomethasone groups. The placebo group was included to validate the clinical benefit from inhaled corticosteroid treatment; the comparison of the montelukast group with other treatment arms was a secondary objective and is described by means of summary statistics and confidence intervals (CI). Baseline values were calculated as the average of the last 2 wk of Period 1. The primary analysis for efficacy endpoints included all patients with either (if appropriate) a baseline and at least one treatment measurement. (All allocated patients were included in safety summaries.) Endpoints with baseline values were analyzed as change or percent change from baseline.

All endpoints were calculated as average treatment period values over the 16 wk of Period 2 (comparison of the additivity and the beclomethasone groups) or over the last 10 wk of Period 2 (comparison of the montelukast and placebo groups with the beclomethasone group). The comparison over the last 10 wk of Period 2 was performed to allow time for the beclomethasone withdrawal groups to approach a clinical steady state. An analysis of variance (ANOVA) model was used to estimate treatment group means and between-group differences and to construct the 95% CI for the least-square (LS) means and the differences in LS means (14). The model contained factors for treatment and study center. Robust ANOVA was used and found to corroborate the primary analyses. The 7-point global evaluation score was analyzed by the ANOVA model; the scores were also collapsed into three categoriesbetter (0, 1, 2), no change (3), and worse (4, 5, 6)and analyzed with a Cochran-Mantel-Haenszel (CMH) test to corroborate the ANOVA results (15). Fisher exact test was used to compare between-treatment group frequencies of asthma exacerbation and attacks, and adverse experiences. p Values were rounded to three decimal places; p  0.05 was considered statistically significant.

The study was designed to have 650 patients complete Period 2, 50 in the placebo and 200 in each of the other three treatment groups. This sample size allowed detection, with 95% power (at  = 0.05; two-sided test), of a 6.0 percentage point difference in FEV₁ (percent change from baseline) and a 10.0% difference in daytime symptoms score (change from baseline) between the additivity and beclomethasone treatment groups.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Patients

A total of 642 patients were randomly allocated: 193, 200, 201, and 48 to the montelukast plus beclomethasone, beclomethasone, montelukast, and placebo treatment, respectively. There were no clinically meaningful differences among the four treatment groups in any of the baseline characteristics (Table 1). A summary of patients discontinued after randomization is given in Table 2. Additionally, data from five patients (daytime symptom scores) and six patients (FEV₁) could not be included in the efficacy analysis because of the lack of baseline or treatment period values.

Effects on Asthma Control Endpoints

Effects of adding montelukast to inhaled corticosteroids. The addition of montelukast (10 mg) to inhaled beclomethasone (200 µg twice daily) resulted in improved asthma control compared with beclomethasone alone, by demonstrating significant improvement in the primary and secondary endpoints (FEV₁ [p < 0.001], daytime symptoms score [p = 0.041]), morning PEFR (p = 0.004), and nocturnal awakenings (p = 0.027) over the 16-wk treatment period (Figure 1 and Table 3). Furthermore, the group receiving montelukast in addition to beclomethasone also experienced fewer days with asthma exacerbations (25% decrease) and fewer asthma attacks compared with patients receiving beclomethasone alone (Table 3). Daily -agonist use and the evening PEFR showed trends favoring concomitant therapy.

View larger version (19K): [in this window] [in a new window]   Figure 1.   Mean (± SE) FEV1 mean percent change from baseline. Treatment groups: beclomethasone + montelukast (closed diamonds); beclomethasone (closed triangles); montelukast (closed circles); placebo (open squares). (See METHODS for explanation of treatment groups.) AM removal: morning beclomethasone inhaler was replaced with a placebo inhaler in the placebo and montelukast groups; PM removal: evening beclomethasone inhalers were replaced with placebo inhalers in placebo and montelukast groups.

The physicians' global evaluations demonstrated significant improvements in the additivity group compared with beclomethasone (Table 3); 68.4, 25.3, and 6.3% of the patients in the additivity group felt better, experienced no change, or felt worse, respectively, compared with 54.1, 31.1, and 14.8% of the patients in the beclomethasone group (p = 0.001 ANOVA and CMH test). Patients' global evaluations showed qualitatively similar results, although the difference did not reach statistical significance (p = 0.085) (Table 3).

Comparison between placebo and beclomethasone groups. The complete blind removal of beclomethasone resulted in a decline of asthma control, e.g., FEV₁ decreased over time (Figure 1); the mean percent change (95% CI) in FEV₁ from baseline value was 11.96 (16.28, 7.64) for the placebo group compared with 0.52 (1.48, 2.53) for the beclomethasone group. The mean change (95% CI) in daytime symptom score from baseline value was 0.31 (0.08, 0.54) score for the placebo group compared with 0.09 (0.20, 0.02) score for the beclomethasone group. Similar changes on other endpoints, including -agonist use (percent change) [placebo: 59.20% (25.77, 92.63); beclomethasone: 1.88% (13.79, 17.55)] and nocturnal awakenings (nights/week) [placebo: 0.44 (0.45, 1.33); beclomethasone: 0.8 (1.38, 0.36)] were observed.

Comparison between montelukast and beclomethasone groups. The complete removal of beclomethasone also resulted in a decline in asthma control which did not reach the levels of the placebo group (Figure 1). The removal of both doses of beclomethasone resulted in a change in FEV₁ of 5.31% (7.32, 3.30) for the montelukast group compared with 0.52% (1.48, 2.53) for the beclomethasone group. The removal of both doses of beclomethasone also affected other endpoints, e.g., daytime symptoms score which showed a mean change (95% CI) of 0.27 (0.17, 0.38) score for the montelukast group compared with 0.09 (0.20, 0.002) score for the beclomethasone group. In a post hoc analysis, the removal of just the morning dose of beclomethasone had little noticeable effect on the FEV₁ compared with the same maneuver in the placebo group (Figure 1).

Effect on Peripheral Blood Eosinophil Counts

The baseline eosinophil counts were comparable in the four treatment groups (Table 1). Over the 16-wk treatment period, there was a significant increase in the eosinophil counts in the beclomethasone group compared with the additivity group (p = 0.011) (Figure 2).

View larger version (13K): [in this window] [in a new window]   Figure 2.   Change from baseline values in peripheral blood eosinophil counts for each treatment group.

Compliance

The compliance (mean ± SD) with the inhaled study medication over the 16-wk treatment period was 96.5 ± 19.4, 94.0 ± 18.8, 92.4 ± 18.7, and 94.6 ± 16.3% for the placebo, montelukast, beclomethasone, and additivity groups, respectively. The compliance with oral medication was 99.0 ± 0.7, 98.7 ± 1.1, 98.7 ± 0.7, and 98.6 ± 1.7% for the placebo, montelukast, beclomethasone, and additivity groups, respectively.

Safety Results

Clinical adverse experiences that occurred in at least 6% of patients in any of the four treatment groups are summarized in Table 4. The most commonly reported adverse experiences were upper respiratory tract infection, worsening asthma, and headache. Laboratory adverse experiences occurred with similar frequency across the four treatment groups. There were no patients who discontinued because of a laboratory abnormality. The incidence of elevated alanine aminotransaminase (ALT) and aspartame aminotransaminase (AST) were similar among the treatment groups; changes were generally transient and self-limited while continuing study medication.

	DISCUSSION

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This study demonstrated that montelukast, 10 mg once daily, provided additional clinical benefit in patients incompletely controlled on a commonly used starting dose of inhaled beclomethasone (200 µg twice daily). The treatment effect was consistently observed across the clinical endpoints including measurement of airways obstruction, patient-reported endpoints, and worsening asthma episodes. Concomitant inhaled beclomethasone and montelukast therapy provided additive clinical benefit consistent with the in vivo effects of corticosteroids on leukotriene biosynthesis (16). Although in vitro studies have suggested that corticosteroids inhibit the production of the cysteinyl leukotrienes, in vivo studies in asthmatic patients have not demonstrated inhibiting effects. Specifically, cysteinyl leukotrienes can be recovered from the airways of asthmatic patients despite high-dose oral corticosteroid therapy (16); therefore, it is proposed that corticosteroids and leukotriene receptor antagonists may have complementary actions.

The conclusion that montelukast provided effects in addition to inhaled beclomethasone therapy was validated by demonstrating that the removal of inhaled beclomethasone (placebo group) caused worsening asthma control. The decrease in asthma control showed that patients enrolled in this study, although incompletely controlled, received clinical benefit from inhaled corticosteroid therapy. This prospective study also confirmed previous post hoc observations from previous trials, that leukotriene receptor antagonists provide additional clinical benefit to patients using constant doses of inhaled corticosteroids but with incomplete asthma control (5). Such additive clinical benefit of leukotriene receptor antagonists and inhaled corticosteroids has also been demonstrated in stable patients on high-dose inhaled corticosteroid therapy (17, 18). One of these trials (17) showed that inhaled corticosteroids can be tapered when a leukotriene receptor antagonist was given concomitantly.

In addition to the complementary clinical benefit, we showed that the two therapies had additive effects on peripheral blood eosinophil counts. The eosinophil is believed to be an important effector inflammatory cell in asthma (19). A decrease in peripheral blood eosinophil counts has been observed previously with leukotriene receptor antagonists (20) and inhaled corticosteroids (21), as has decrease in airway eosinophils (22, 23). Although the mechanisms of these actions are not completely understood, it has been hypothesized that corticosteroids shorten eosinophil survival by increasing the rate of apoptosis (24), whereas leukotriene receptor antagonists may retard bone marrow eosinophil maturation by inhibiting synergistic effects of the cysteinyl leukotrienes with peptide growth factors on eosinophil/basophil stem cell maturation (25).

In some clinical trials, adding a second agent including long-acting -agonists (2, 26, 27) or theophylline (28, 29) has been shown to be more beneficial than doubling the dose of inhaled corticosteroids. Because increasing the dose of inhaled corticosteroids may not result in additional, clinically important benefit (30), the addition of another agent may be preferred (26, 27). Oral leukotriene receptor antagonists may play a role in this challenging patient population. Future head-to-head studies will need to compare the relative merits of the different agents used concomitantly to achieve better asthma control.

This study also suggested that the blind removal of inhaled beclomethasone from concomitant montelukast therapy resulted in loss of asthma control in some patients. If the dose of inhaled corticosteroids is to be lowered when administered concomitantly with a leukotriene receptor antagonist, it may make more clinical sense to slowly taper rather than rapidly remove this agent.

An interesting post hoc observation from this study was the maintenance of the treatment effect in the montelukast group after the blind removal of half the 400-µg beclomethasone dose. (Figure 1, AM removal) Although 2 wk is probably insufficient to assess the long-term effects, it is interesting to hypothesize that a leukotriene receptor antagonist and a low, once daily dose of inhaled corticosteroids might provide similar asthma control as high doses of inhaled corticosteroids (providing less long-term exposure to inhaled corticosteroids). This hypothesis needs to be tested in specifically designed, prospective, clinical trials.

In this trial, all study therapies were generally well tolerated; the frequencies of adverse events were comparable among all treatment groups (including placebo). Specifically, the combination of montelukast and inhaled beclomethasone was not associated with new clinical and laboratory adverse events.

In conclusion, montelukast, a leukotriene receptor antagonist, provided additional asthma control to patients benefiting from, but incompletely controlled on inhaled beclomethasone. The combination of these agents provided both complementary and additive actions on peripheral blood eosinophils, a parameter of asthmatic inflammation.