Journal Article

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

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

2011

Overview

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 .

• Publisher: BioMed Central,BioMed Central Ltd,Nature Publishing Group,BMC
• Subject: Acquisitions & mergers / Administration, Oral / Aged / Agonists / Aminopyridines - administration & dosage / Aminopyridines - adverse effects / Aminopyridines - therapeutic use / Analysis / Analysis of covariance / Anti-Inflammatory Agents - administration & dosage / Anti-Inflammatory Agents - adverse effects / Anti-Inflammatory Agents - therapeutic use / Anticholinergics / Benzamides - administration & dosage / Benzamides - adverse effects / Benzamides - therapeutic use / Bronchitis / Bronchodilators / Care and treatment / Chronic obstructive pulmonary disease / Clinical medicine / Clinical trials / Clinical Trials, Phase III as Topic / Complications and side effects / Corticoids / Corticosteroids / Cough / Cyclopropanes - administration & dosage / Cyclopropanes - adverse effects / Cyclopropanes - therapeutic use / Dosage and administration / Double-Blind Method / Drug Administration Schedule / Drug therapy / Emphysema / Female / Forced Expiratory Volume / Hospitalization / Hospitals / Humans / Hypotheses / Inhibitors / Lung - drug effects / Lung - enzymology / Lung - physiopathology / Lung diseases / Lung diseases, Obstructive / Male / Medicine / Medicine & Public Health / Middle Aged / Mortality / Multicenter Studies as Topic / Patient outcomes / Patient Selection / Patients / Phosphodiesterase / Phosphodiesterase 4 Inhibitors - administration & dosage / Phosphodiesterase 4 Inhibitors - adverse effects / Phosphodiesterase 4 Inhibitors - therapeutic use / Phosphodiesterase IV / Placebos / Pneumology/Respiratory System / Proportional Hazards Models / Pulmonary Disease, Chronic Obstructive - drug therapy / Pulmonary Disease, Chronic Obstructive - enzymology / Pulmonary Disease, Chronic Obstructive - physiopathology / Randomized Controlled Trials as Topic / Regression analysis / Research Design / Respiratory function / Risk Assessment / Risk Factors / Roflumilast / Sputum / Standard deviation / Statistical analysis / Steroids / Studies / Treatment Outcome