Objectives

This randomized, placebo-controlled, crossover study on subjects with moderate asthma, compares the clinical efficacy of regular treatment with the combination of leukotriene receptor antagonists (LTRAs) montelukast and the long-acting β-agonists (LABAs) salmeterol to determine whether the combination montelukast and salmeterol could provide an effective therapeutic strategy for asthma.

Background

Previous asthma studies suggest that the most robust clinical effect of LABAs, which is lung function, is distinct from that of the LTRAs, which provides protection against exacerbations. The efficacy of combination therapy of LTRAS and LABAs, as compared against the usual combination of LABAs and an inhaled corticosteroid (ICS), is unknown.

Participants

The patients consisted of male and female, ages 12 to 65 years old, with a history of physician diagnosed asthma at the Asthma Clinical Research Network centers. At enrollment, the subjects were required to have FEV1 ≥ 40% of the predicted value and demonstrate hyperresponsiveness to methacholine(PC20 ≤8 mg/ml) or a 12% or greater improvement in FEV1 after the administration of a β-agonist bronchodilator (if FEV1 was <55% of predicted at enrollment). Subjects not using an ICS or LTRA at the time of enrollment were required to have an FEV1 ≤ 80% of the predicted value. No smoking was allowed for 1 year before enrollment, and cumulative exposure was less than 10 pack-years. Subjects with respiratory tract infection, or asthma exacerbation (i.e., the need for oral corticosteroid or urgent care visit) within the previous 6 weeks were also excluded.

Design

192 subjects were enrolled in this study. They were subjected to a 36-week randomized, double-blind, placebo-controlled cross-over trial. During an initial 4-week run-in period, all subjects received single-blind treatment with beclomethasone hydrofluoroalkane (HFA) (80 µg twice daily) and montelukast (10 mg by mouth at bedtime), as well as “as needed” albuterol. The physiologic and symptom measurements recorded during the 4 week period provided baseline data used in defining subsequent asthma treatment failures. The treatment regimen included both ICS and an LTRA during this run- in period and those with the capacity to achieve reasonable asthma control were enrolled in the study. Subjects without any treatment failure criteria and an FEV1 ≥ 55% of predicted at the conclusion of the 4-week run-in period were randomized to receive double-blind treatment with either the combination of beclomethasone HFA and salmeterol and placebo LTRA or the combination of montelukast and placebo beclomethasone HFA for 14 weeks of active treatment. The subjects then underwent a 4-week "run-out" period during which patients received beclomethasone HFA 80 µg twice daily in addition to 10 mg montelukast by mouth at bedtime. Subjects then crossed over to the alternate combination therapy as compared with that which they had received in the first active treatment and completed the second active treatment period over the subsequent 14 weeks.

Conclusions

In patients with moderate asthma, the combination therapy of LTRAS and LABAs is inferior to the combination of ICS and LABA as judged by protection against asthma treatment failures, lung function, and markers of inflammation and airway reactivity. The researchers recommended that patients similar to those in the study should not substitute the combination therapy of LTRAS and LABAs for the ICS and LABA combination therapy.

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