Roflumilast combined with montelukast versus montelukast alone as add-on treatment in patients with moderate-to-severe asthma

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Roflumilast, a selective phosphodiesterase 4 inhibitor, has been shown to provide modest improvements in lung function in patients with mild-to-moderate asthma, but its efficacy in patients with moderate-to-severe asthma has not been assessed. We hypothesized that this drug might provide benefit if combined with montelukast, a leukotriene receptor antagonist, in patients whose symptoms are uncontrolled by inhaled corticosteroids and long-acting β-agonists.


We sought to examine the efficacy, safety, and mode of action of the addition of roflumilast and montelukast versus montelukast alone in patients with moderate-to-severe asthma.


In a phase 2, randomized, double-blind, placebo-controlled, multiple-dose, 2-sequence, crossover study, 64 patients were randomized to receive 500 μg of roflumilast plus montelukast followed by placebo plus 10 mg of montelukast (sequence AB) or placebo plus 10 mg of montelukast followed by 500 μg of roflumilast plus 10 mg of montelukast (sequence BA). All patients had a diagnosis of bronchial asthma inadequately controlled by at least a medium-dose inhaled corticosteroid plus a long-acting β-agonist.


The analysis of FEV1 change from baseline to week 4 showed a statistically significant and clinically meaningful treatment difference of 100 mL for roflumilast plus montelukast versus placebo plus montelukast. Also, improvements in patient-reported outcomes and a reduction in urinary leukotriene E4 levels were observed during roflumilast plus montelukast treatment compared with placebo plus montelukast treatment. Adverse events were consistent with the known safety profile of roflumilast.


The combination of roflumilast with montelukast compared with montelukast alone improved lung function and asthma control in patients with moderate-to-severe asthma and deserves further study for this indication.

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