Abstract
BackgroundAs chronic obstructive pulmonary disease (COPD) is a heterogeneous disease it is unlikely that all patients will benefit equally from a given therapy. Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, has been shown to improve lung function in moderate and severe COPD but its effect on exacerbations in unselected populations was inconclusive. This led to the question of whether a responsive subset existed that could be investigated further.MethodsThe datasets of two previous replicate, randomized, double-blind, placebo-controlled, parallel-group studies (oral roflumilast 500 μg or placebo once daily for 52 weeks) that were inconclusive regarding exacerbations were combined in a post-hoc, pooled analysis to determine whether roflumilast reduced exacerbations in a more precisely defined patient subset.ResultsThe pooled analysis included 2686 randomized patients. Roflumilast significantly decreased exacerbations by 14.3% compared with placebo (p = 0.026). Features associated with this reduction were: presence of chronic bronchitis with or without emphysema (26.2% decrease, p = 0.001), presence of cough (20.9% decrease, p = 0.006), presence of sputum (17.8% decrease, p = 0.03), and concurrent use of inhaled corticosteroids (ICS; 18.8% decrease, p = 0.014). The incidence of adverse events was similar with roflumilast and placebo (81.5% vs 80.1%), but more patients in the roflumilast group had events assessed as likely or definitely related to the study drug (21.5% vs 8.3%).ConclusionsThis post-hoc, pooled analysis showed that roflumilast reduced exacerbation frequency in a subset of COPD patients whose characteristics included chronic bronchitis with/without concurrent ICS. These observations aided the design of subsequent phase 3 studies that prospectively confirmed the reduction in exacerbations with roflumilast treatment.Trials registrationClinicalTrials.gov identifiers: NCT00076089 and NCT00430729.
Highlights
As chronic obstructive pulmonary disease (COPD) is a heterogeneous disease it is unlikely that all patients will benefit from a given therapy
In two previous 12-month studies, in patients with severe-to-very-severe COPD, roflumilast improved lung function, neither study demonstrated a significant effect on exacerbations [10]
This post-hoc, pooled analysis of two large-scale trials in patients with severe and very severe COPD showed a significant reduction in exacerbations with roflumilast treatment and identified a subgroup of patients who are most likely to benefit from treatment with roflumilast, namely those patients with chronic bronchitis
Summary
As chronic obstructive pulmonary disease (COPD) is a heterogeneous disease it is unlikely that all patients will benefit from a given therapy. Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, has been shown to improve lung function in moderate and severe COPD but its effect on exacerbations in unselected populations was inconclusive. This led to the question of whether a responsive subset existed that could be investigated further. In a 6-month study in patients with moderate-to-severe COPD (post-bronchodilator mean forced expiratory volume in 1 second [FEV1] 54% predicted [8]), the PDE4 inhibitor roflumilast improved lung function and reduced exacerbations [9]. Neither study demonstrated a significant effect on exacerbations, which was a co-primary endpoint, a trend towards lower overall exacerbation rates with roflumilast was seen in each study
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