Reduction of exacerbations by the PDE4 inhibitor roflumilast--the importance of defining different subsets of patients with COPD

Abstract

Background: As 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.

Methods: The 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.

Results: The 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%).

Conclusions: This 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 registration: ClinicalTrials.gov identifiers: NCT00076089 and NCT00430729.

Figures

Figure 1

Trial profiles of M2-111 and M2-112. Percentages are based on the number of randomized patients in a treatment group.

Figure 2

Rate ratios and 95% CIs for reduction in COPD exacerbations with roflumilast by patient subgroup. Error bars represent 95% CIs.

Figure 3

Differences and 95% CIs between roflumilast and placebo for increase in pre-bronchodilator FEV1 (L) by patient subgroup. Error bars represent 95% CIs.

Figure 4

Differences and 95% confidence intervals between roflumilast and placebo for changes in St George's Respiratory Questionnaire (SGRQ) total score by patient subgroup. Error bars represent 95% CIs.