Elsevier

The Lancet

Volume 374, Issue 9691, 29 August–4 September 2009, Pages 685-694
The Lancet

Articles
Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials

https://doi.org/10.1016/S0140-6736(09)61255-1Get rights and content

Summary

Background

The phosphodiesterase-4 inhibitor roflumilast can improve lung function and prevent exacerbations in certain patients with chronic obstructive pulmonary disease (COPD). We therefore investigated whether roflumilast would reduce the frequency of exacerbations requiring corticosteroids in patients with COPD.

Methods

In two placebo-controlled, double-blind, multicentre trials (M2-124 and M2-125) with identical design that were done in two different populations in an outpatient setting, patients with COPD older than 40 years, with severe airflow limitation, bronchitic symptoms, and a history of exacerbations were randomly assigned to oral roflumilast (500 μg once per day) or placebo for 52 weeks. Primary endpoints were change in prebronchodilator forced expiratory volume in 1 s (FEV1) and the rate of exacerbations that were moderate (glucocorticosteroid-treated) or severe. Analysis was by intention to treat. The trials are registered with ClinicalTrials.gov, number NCT00297102 for M2-124, and NCT00297115 for M2-125.

Findings

Patients were assigned to treatment, stratified according to smoking status and treatment with longacting β2 agonists, and given roflumilast (n=1537) or placebo (n=1554). In both studies, the prespecified primary endpoints were achieved and were similar in magnitude. In a pooled analysis, prebronchodilator FEV1 increased by 48 mL with roflumilast compared with placebo (p<0·0001). The rate of exacerbations that were moderate or severe per patient per year was 1·14 with roflumilast and 1·37 with placebo (reduction 17% [95% CI 8–25], p<0·0003). Adverse events were more common with roflumilast (1040 [67%]) than with placebo (963 [62%]); 219 (14%) patients in the roflumilast group and 177 (12%) in the placebo group discontinued because of adverse events. In the pooled analysis, the difference in weight change during the study between the roflumilast and placebo groups was −2·17 kg.

Interpretation

Since different subsets of patients exist within the broad spectrum of COPD, targeted specific therapies could improve disease management. This possibility should be explored further in prospective studies.

Funding

Nycomed.

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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    Last authors

    Investigators are listed in webappendix (p 2)

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