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

Stephen I. Rennard, Peter M.A. Calverley, Udo M. Goehring, Dirk Bredenbröker, Fernando J. Martinez

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number18
JournalRespiratory Research
Volume12
DOIs
StatePublished - Jan 27 2011

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Phosphodiesterase 4 Inhibitors
Chronic Obstructive Pulmonary Disease
Placebos
Chronic Bronchitis
Roflumilast
Emphysema
Sputum
Cough
Adrenal Cortex Hormones
Lung

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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Reduction of exacerbations by the PDE4 inhibitor roflumilast - the importance of defining different subsets of patients with COPD. / Rennard, Stephen I.; Calverley, Peter M.A.; Goehring, Udo M.; Bredenbröker, Dirk; Martinez, Fernando J.

In: Respiratory Research, Vol. 12, 18, 27.01.2011.

Research output: Contribution to journalArticle

Rennard, Stephen I. ; Calverley, Peter M.A. ; Goehring, Udo M. ; Bredenbröker, Dirk ; Martinez, Fernando J. / Reduction of exacerbations by the PDE4 inhibitor roflumilast - the importance of defining different subsets of patients with COPD. In: Respiratory Research. 2011 ; Vol. 12.
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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.",
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