INTRODUCTION

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Asthma is a chronic disease with two main components: inflammation and bronchoconstriction. It is also a complex disease involving many cells and mediators (1). Historically, no single medication has been available to effectively treat both the underlying inflammation and the smooth muscle dysfunction (e.g., bronchoconstriction) associated with asthma. The introduction of a combination product (Advair Diskus; GlaxoWellcome, Research Triangle Park, NC) containing an inhaled corticosteroid, fluticasone propionate (FP), and an inhaled long-acting inhaled ₂-agonist, salmeterol, has provided patients with a single, effective, and convenient medication that treats the two main components of the disease. The combination product has been shown to be an effective treatment for patients with persistent asthma that was inadequately controlled while receiving salmeterol alone or low to high doses of inhaled corticosteroids alone (2).

Montelukast is a leukotriene receptor antagonist that has been shown to improve some clinical outcomes compared with placebo in patients previously treated with inhaled ₂-agonists alone (5). In a patient population similar to that in the current study, low doses of FP and beclomethasone dipropionate (BDP), 200 µg twice daily provided greater improvements in pulmonary function (FEV₁ and peak expiratory flow [PEF]), daytime asthma symptom scores, rescue albuterol use, and nighttime awakenings compared with montelukast, 10 mg once daily (6, 7). Thus, the exact role of leukotriene modifiers as initial maintenance treatment of persistent asthma has not been established.

This is the first study to compare the efficacy and safety of the combination product, fluticasone propionate (100 µg) and salmeterol (50 µg), with that of oral montelukast (10 mg) as initial maintenance therapy in patients with persistent asthma who were uncontrolled on short-acting ₂-agonists alone.

	METHODS

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Patient Selection

Male and female patients aged 15 yr and older were eligible if they had asthma for at least 6 mo and had been treated with an oral or inhaled short-acting ₂-agonist on a scheduled or as-needed basis for at least 6 wk before screening. At the screening visit, all patients were required to have an FEV₁ between 50 and 80% of the predicted normal value (Crapo or Polgar standards, race adjusted for black patients) and an increase in FEV₁ of at least 12% within 30 min of the inhalation of two puffs (180 µg) of albuterol (8, 9).

Study Design and Intervention

This multicenter, double-blind, double-dummy, parallel group study was conducted at 56 sites in the United States. An institutional review board approved the study protocol and all patients signed a written informed consent document before enrollment.

Eligible patients entered an 8 to 14-d screening period. Before this period, all oral and inhaled short-acting ₂-agonists were replaced with inhaled albuterol (Ventolin inhalation aerosol; GlaxoWellcome). Baseline information related to asthma control was obtained during the screening period. Patients were considered symptomatic and, thus, eligible for randomization, if they required rescue albuterol on five or more days during the 7 d preceding randomization or if they had a diary card symptom score of  2 on three or more days for chest tightness, wheezing, or shortness of breath. At randomization, patients were also required to have an FEV₁ between 50 and 80% of the predicted normal value and to be within ± 15% of the best FEV₁ at screening. Symptom scores were based on a 0 to 5-point Likert scale of 0 (no symptoms) to 5 (symptoms causing discomfort and preventing normal daily activities).

Patients were then randomly assigned to receive either the combination product, FP at 100 µg and salmeterol at 50 µg (FSC), twice daily via the Diskus device (Advair Diskus; GlaxoWellcome) plus placebo montelukast capsules once daily or montelukast at 10 mg (overencapsulated Singulair tablets; Merck & Co., West Point, PA) once daily plus placebo FSC twice daily.

An asthma exacerbation was defined as any requirement for additional asthma medications other than those permitted by the protocol. Therefore, any requirement for supplemental oral or parenteral corticosteroids, as determined by each investigator, was considered an exacerbation. Patients were withdrawn from the study in the event of an asthma exacerbation.

Statistical Methods

The primary efficacy measure was change from baseline in morning predose FEV₁ at end point. All analyses for efficacy and safety were conducted with the intent-to-treat population, defined as all randomized patients. All data from patients who were withdrawn from the study early were included in the analyses using data available up to the time of study discontinuation. The end-point assessments compared the last available data values for all patients, regardless of the duration of participation.

	RESULTS

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One thousand two hundred and seventeen patients were screened for participation. Four hundred and twenty-three patients met the inclusion criteria and were randomly assigned to treatment. Randomization resulted in comparable treatment groups at baseline with respect to patient demographics and pulmonary function. The characteristics of the patients in the two treatment groups are reported in Table 1. Compliance with the Diskus device and with the oral capsules was similar between treatment groups and was approximately 98% with the Diskus device and 99% with the capsules.

Efficacy

Table 2 reports baseline values and the changes at end point for the various efficacy measures evaluated in this study.

Pulmonary function. Treatment with FSC resulted in significantly greater improvements in FEV₁ compared with montelukast (Figure 1). At Week 1 (first treatment assessment), Week 4, Week 8, Week 12, and at end point, treatment with FSC resulted in increases in FEV₁ of 0.45 ± 0.03, 0.52 ± 0.03, 0.57 ± 0.03, 0.56 ± 0.03, and 0.54 ± 0.03 L from baseline, respectively, compared with increases of 0.21 ± 0.02, 0.27 ± 0.03, 0.31 ± 0.04, 0.29 ± 0.03, and 0.27 ± 0.03 L, respectively, with montelukast (p < 0.001 vs. montelukast at all assessments; Figure 1). These improvements in FEV₁ at end point represented a 23% increase from baseline with FSC compared with an 11% increase with montelukast (p < 0.001). Greater improvements in FEF_25-75 at end point were also noted with FSC compared with montelukast (0.80 ± 0.05 vs. 0.33 ± 0.04 L/s, p < 0.001), representing a 53 and 23% change from baseline, respectively.

View larger version (14K): [in this window] [in a new window]   Figure 1.   Mean change from baseline in FEV1 over 12 wk and at end point. *p < 0.001, combination product versus montelukast at all time points.

Greater improvements in morning PEF (Figure 2) and evening PEF were observed with FSC compared with montelukast. The combination product produced significantly greater improvements in morning PEF after the first treatment day compared with montelukast and greater improvements were maintained throughout the study, showing no diminution of effect (Figure 2; p < 0.001). Similar results were observed for evening PEF.

View larger version (20K): [in this window] [in a new window]   Figure 2.   Mean change from baseline in daily morning PEF. *p < 0.001, combination product versus montelukast at all time points.

After treatment with FSC, morning PEF increased by 43.7 ± 4.4 L/min from baseline on the first treatment day compared with 10.0 ± 3.2 L/min with montelukast (p < 0.001). In addition, improvement in morning PEF from baseline was below 40 L/min on more than 90% of the treatment days (75 of 83) and below 43 L/min on all treatment days in patients treated with montelukast. By contrast, improvements from baseline in morning PEF exceeded 43 L/min on all treatment days and was above 80 L/min on 71% of days (59 of 83) in patients treated with FSC.

After 1 wk of treatment, improvements in morning PEF of 52.1 ± 4.7 versus 17.9 ± 2.7 L/min were found in the FSC and montelukast groups, respectively (p < 0.001) and after 12 wk, increases of 95.3 ± 7.2 and 35.9 ± 5.3 L/min were observed (p < 0.001). The mean change from baseline at end point in morning PEF stratified by severity of airway obstruction showed that treatment with FSC resulted in significantly greater increases in morning PEF at end point in patients with a mean FEV₁ < 70% at study entry (97.2 ± 9.8 L/min [n = 109] vs. 33.3 ± 6.2 L/min [n = 136]) and in patients with a mean FEV₁  70% at study entry (82.1 ± 9.2 L/min [n = 102] vs. 35.9 ± 7.3 L/min [n = 75]) compared with montelukast (p  0.003).

Asthma symptoms and nighttime awakenings. The number of days in which patients reported no symptoms (i.e., a symptom score of 0) was used to determine the percentage of symptom-free days during treatment with FSC or montelukast. At baseline, patients in both treatment groups reported a low number of symptom-free days (3.9 ± 0.7 and 5.8 ± 1.0% of days for the FSC and montelukast groups, respectively). Treatment with FSC resulted in a significantly greater improvement in the mean percentage of symptom-free days compared with montelukast (Figure 3). Statistically significant differences in favor of FSC were noted by Week 1 (p < 0.001). Likewise, a significantly greater decrease in the combined asthma symptom score for symptoms of chest tightness, wheeze, and shortness of breath was observed after the first week of treatment with FSC compared with montelukast and continued throughout the study (p < 0.001 at all time points).

View larger version (18K): [in this window] [in a new window]   Figure 3.   The percentage of symptom-free days over 12 wk of treatment and at end point. *p < 0.001, combination product versus montelukast at all time points.

At baseline, FSC and montelukast groups reported 66.7 ± 2.6 and 62.4 ± 2.6% of nights with no awakenings, respectively. Treatment with FSC significantly increased the percentage of nights with no awakenings at end point (mean change, 23.0 ± 2.5%) compared with montelukast (mean change, 15.5 ± 2.4%; p < 0.001). At end point, patients treated with FSC had a mean of 89.8 ± 1.7% of nights with no awakenings due to asthma compared with 78.0 ± 2.4% in patients treated with montelukast. In patients who had at least two nights with awakenings at baseline, treatment with FSC significantly increased the percentage of nights with no awakenings at end point (mean change, 49.2 ± 4.0 vs. 31.4 ± 3.3%; p = 0.001).

Rescue albuterol use. Significant differences in rescue albuterol use were noted in favor of FSC by Week 1 and continued throughout the study (p < 0.001; Figure 4). Similarly, treatment with FSC resulted in a significantly greater percentage of rescue-free days at end point (mean change, 53.0 ± 2.8%; p < 0.001) compared with montelukast (mean change, 26.2 ± 2.5%).

View larger version (19K): [in this window] [in a new window]   Figure 4.   Rescue albuterol use over 12 wk of treatment and at end point. *p < 0.001, combination product versus montelukast at all time points.

Patient satisfaction scores. Significantly more patients treated with FSC (81%) reported that they were satisfied or very satisfied (overall satisfaction) with their study medication compared with 58% of patients treated with montelukast (p < 0.001). Likewise, compared with montelukast, more patients treated with FSC were satisfied or very satisfied with how well the medication worked (83 vs. 59%, p < 0.001).

Safety

Asthma exacerbations. Fewer patients treated with FSC (n = 0) had an exacerbation compared with patients treated with montelukast (n = 11, 5%; p < 0.001).

Adverse events. The overall incidence of adverse events was similar between groups (61% with FSC and 62% with montelukast). Twenty-five (12%) patients treated with FSC and 17 (8%) patients treated with montelukast experienced at least one adverse event during the study that was considered by the investigator to be potentially related to treatment ("drug related"). The most commonly reported drug-related adverse events ( 1% in any group) were headache (2% in both treatment groups) and hoarseness (2% with FSC). Four patients treated with FSC withdrew because of adverse events potentially related to treatment (nausea, heartburn/stomach pains, abdominal pain/diarrhea, itchiness/skin rash). Five patients treated with montelukast withdrew because of adverse events potentially related to treatment (heart palpitations/insomnia, rash, asthma exacerbations/bronchitis, diarrhea, headache). One patient treated with montelukast experienced a serious adverse event that was considered by the investigator to be potentially related to treatment and that resulted in withdrawal (asthma exacerbation/bronchitis).

	DISCUSSION

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In this study, initiating therapy with FSC twice daily was superior to montelukast (10 mg once daily) in improving pulmonary function and asthma symptoms, reducing rescue albuterol use, and reducing the number of exacerbations in patients who were symptomatic while taking ₂-agonists alone and who required long-term maintenance treatment of their asthma. These significant differences were not restricted to patients with more severe asthma as indicated by baseline lung function impairment. Rather, even patients with milder asthma as assessed by an FEV₁% predicted greater than 70% at study entry had significantly greater improvements in lung function, symptoms, and rescue-free days than patients treated with montelukast. These data indicate that treatment with the FP (100 µg)-salmeterol (50 µg) combination product was more effective than montelukast in treating the inflammation and bronchoconstriction associated with asthma.

The combination product resulted in a greater change from baseline in morning PEF than montelukast by Day 1 and these improvements continued to be observed throughout the 12-wk study. This difference in onset of effect may be especially important to patients who are initiating maintenance therapy. For example, the presence or absence of perceptible clinical benefits may impact adherence to a maintenance regimen. The present study was not designed to directly address this question. Moreover, it should be recognized that asthma treatments do not replace ongoing asthma education, an important component of management for all patients with asthma (10). Nevertheless, it is important to note that patient satisfaction questionnaires from the present study indicated that significantly more patients treated with FSC were satisfied or very satisfied with how well their medication worked compared with patients treated with montelukast.

Combination treatment with a long-acting ₂-agonist and an inhaled corticosteroid addresses the two main components of asthma: inflammation and bronchoconstriction. However, salmeterol has a number of nonbronchodilator properties that may contribute to its observed clinical benefits. Specifically, salmeterol inhibits vascular permeability and inhibits platelet-activating factor-induced eosinophil accumulation into the lung (11). In addition, in vitro studies have shown that salmeterol inhibits release of mast cell mediators such as histamine, leukotrienes, and prostaglandin D₂ from human lung (11). More recently, salmeterol has been shown to be capable of priming the glucocorticoid receptor for activation by corticosteroids (12). However, the clinical relevance of these in vitro observations is unclear. Nonetheless, previous studies have demonstrated that use of a long-acting ₂-agonist with inhaled corticosteroid therapy compared with treatment with higher doses of inhaled corticosteroids alone is associated with comparable control of airway inflammation as assessed by bronchial biopsy in patients with asthma (13, 14). These studies, along with other studies that demonstrated reduced airway hyperresponsiveness and reduced exacerbation rates (without altering the ability to detect worsening asthma), indicate that inhaled long-acting ₂ agonists do not mask worsening asthma (15). Rather, it is clear that using an inhaled corticosteroid with an inhaled long-acting ₂-agonist has a broader scope of activity in the treatment of asthma than a single-mediator antagonist.

A clinical question raised by this study is whether initial maintenance treatment of patients with asthma with a combination product is necessary or whether monotherapy with a single maintenance product may be sufficient. Although the role of leukotriene-modifying drugs in the stepwise management of asthma is not fully established (1), previous studies have demonstrated the clinical superiority of low doses of inhaled corticosteroids compared with leukotriene receptor antagonists (6, 7, 18) when used as initial maintenance therapy. Studies comparing the concurrent use of an inhaled long-acting ₂-agonist and an inhaled corticosteroid with an inhaled corticosteroid alone as initial maintenance therapy are limited. However, an initial report by Pearlman and coworkers demonstrated that FP (88 µg twice daily) plus salmeterol administered via separate inhalers over 4 wk resulted in greater improvements in measures of pulmonary function and symptom control compared with FP (88 or 220 µg twice daily) alone (19). These data and the data from the current study support the combined use of FP and salmeterol as initial maintenance therapy, a position that is consistent with current treatment guidelines, provided that the severity of asthma is appropriate (1, 20).

Clearly, there are patients with mild persistent asthma for whom monotherapy with a single maintenance treatment such as a low dose of an inhaled corticosteroid would be sufficient. However, it must be recognized that many patients with persistent asthma greatly underestimate the severity of their disease. In a survey, more than 60% of patients with symptoms consistent with moderate persistent asthma thought that their asthma was well controlled (21). Similarly, in an investigation of deaths from asthma in Australia over a 3-yr period, Robertson and colleagues demonstrated that one-third of patients who died had mild persistent asthma (based on reported symptoms, exercise capacity, medication requirements, and previous asthma attacks) (22). These statistics, coupled with the fact that patients with asthma are not routinely made to undergo lung function tests, suggest that the patients in this study are representative of the type of patient for whom initial maintenance treatment decisions are routinely made. The results of this study indicate that, for these patients, treatment of both the inflammation and bronchoconstriction associated with asthma was a more effective strategy than treatment with a single-mediator antagonist.

In summary, this is the first study to compare the efficacy and safety of the combination product, FP at 100 µg and salmeterol at 50 µg, administered twice daily, with that of montelukast, 10 mg administered once daily, as initial maintenance therapy for the treatment of persistent asthma in patients previously treated with ₂-agonists alone. Statistically and clinically significant differences between treatment groups in favor of the combination product were observed in pulmonary function, asthma symptoms, rescue albuterol use, number of asthma exacerbations, and patient satisfaction scores. These data suggest that the initiation of initial maintenance therapy with FP and salmeterol combined in a single product helps control bronchoconstriction and inflammation in persistent asthma and is a more effective treatment strategy than treatment with a single-mediator antagonist.