ArticlesRoflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials
Introduction
Chronic obstructive pulmonary disease (COPD) is increasing in prevalence; it is associated with periodic exacerbations, resulting in patient anxiety,1 worsening health status, lung function decline, and increase in mortality rate.2, 3, 4 Effective management involves pharmacological and non-pharmacological treatments.5 Longacting inhaled bronchodilator drugs (β2 agonists and anticholinergic drugs) can improve health status and reduce the frequency of exacerbations, effects that are greater when longacting β2 agonists are used in combination with inhaled corticosteroids.6, 7, 8, 9 However, there is a need for further improvement of COPD therapy.
Phosphodiesterase-4 (PDE4) inhibition provides a novel approach to the treatment of COPD. Drugs that inhibit PDE4 have a wide range of anti-inflammatory actions in vitro and in vivo.10, 11, 12 Roflumilast, a new PDE4 inhibitor, reduces airway inflammation in COPD, as assessed with sputum neutrophil and eosinophil counts.13 However, although roflumilast improved lung function, it did not significantly reduce the frequency of exacerbations in unselected patients with severe COPD.14 The results of a post-hoc analysis of this study suggested that roflumilast reduced the rate of exacerbations in patients with severe airflow obstruction, frequent exacerbations, and those requiring oral steroids.13
To find out whether PDE4 inhibitors can have any effect on clinical outcomes in COPD, we tested the hypothesis that roflumilast reduces the rate of exacerbations requiring systemic corticosteroids in specific subsets of patients with COPD.
Section snippets
Setting
Study M2-124 was done in 246 centres in ten countries, and study M2-125 was done in 221 centres in eight countries (webappendix p 12).
Patients
For both studies, we recruited participants from an outpatient setting if they met inclusion criteria—ie, were former smokers or current smokers with at least a 20 pack-year history, older than 40 years, and had a clinical diagnosis of COPD (confirmed with a postbronchodilator [albuterol 400 μg] forced expiratory volume in 1 s [FEV1]/forced vital capacity [FVC]
Results
Patient recruitment began in February, 2006, and the studies ended in July, 2008. In the M2-124 study, 1523 patients were randomly assigned and treated (figure 1A). In M2-125, 1568 patients were randomly assigned and treated (figure 1B). Four patients in M2-124 and six in M2-125 were given roflumilast rather than placebo and are included in the treated group for the safety analysis. Table 1 shows the demographic and baseline characteristics of the patients who took at least one dose of study
Discussion
Roflumilast reduced exacerbation frequency and induced consistent and significant improvements in FEV1, both before and after bronchodilator use. Similar changes occurred in FVC and midexpiratory flow, suggesting a general improvement in operating lung volume. These changes were independent of the patient's smoking status or use of concomitant medication, such as inhaled longacting β2 agonists, and were similar to those reported in other patient populations with COPD.14, 19
PDE4 inhibition
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