Elsevier

The Lancet

Volume 374, Issue 9691, 29 August–4 September 2009, Pages 695-703
The Lancet

Articles
Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials

https://doi.org/10.1016/S0140-6736(09)61252-6Get rights and content

Summary

Background

Patients with chronic obstructive pulmonary disease (COPD) have few options for treatment. The efficacy and safety of the phosphodiesterase-4 inhibitor roflumilast have been investigated in studies of patients with moderate-to-severe COPD, but not in those concomitantly treated with longacting inhaled bronchodilators. The effect of roflumilast on lung function in patients with COPD that is moderate to severe who are already being treated with salmeterol or tiotropium was investigated.

Methods

In two double-blind, multicentre studies done in an outpatient setting, after a 4-week run-in, patients older than 40 years with moderate-to-severe COPD were randomly assigned to oral roflumilast 500 μg or placebo once a day for 24 weeks, in addition to salmeterol (M2-127 study) or tiotropium (M2-128 study). The primary endpoint was change in prebronchodilator forced expiratory volume in 1 s (FEV1). Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, number NCT00313209 for M2-127, and NCT00424268 for M2-128.

Findings

In the salmeterol plus roflumilast trial, 466 patients were assigned to and treated with roflumilast and 467 with placebo; in the tiotropium plus roflumilast trial, 371 patients were assigned to and treated with roflumilast and 372 with placebo. Compared with placebo, roflumilast consistently improved mean prebronchodilator FEV1 by 49 mL (p<0·0001) in patients treated with salmeterol, and 80 mL (p<0·0001) in those treated with tiotropium. Similar improvement in postbronchodilator FEV1 was noted in both groups. Furthermore, roflumilast had beneficial effects on other lung function measurements and on selected patient-reported outcomes in both groups. Nausea, diarrhoea, weight loss, and, to a lesser extent, headache were more frequent in patients in the roflumilast groups. These adverse events were associated with increased patient withdrawal.

Interpretation

Roflumilast improves lung function in patients with COPD treated with salmeterol or tiotropium, and could become an important treatment for these patients.

Funding

Nycomed.

Introduction

Pharmacotherapy for chronic obstructive pulmonary disease (COPD) improves lung function and reduces symptoms and exacerbations, but has limited clinical efficacy so that patients often remain symptomatic.1, 2, 3 Bronchodilator medications are important for the management of COPD. When required daily, regularly administered longacting inhaled bronchodilators are preferred to regularly administered shortacting bronchodilators, and are given to the patient to reduce and prevent symptoms and exacerbations. The principal longacting inhaled bronchodilators are β2 agonists (formoterol and salmeterol) and the anticholinergic drug tiotropium.1, 2, 3

Because regularly administered longacting bronchodilators have limited effects on symptoms and exacerbations,1, 2, 3, 4, 5, 6 many patients with COPD need additional treatment. The combination of one of the two longacting β2 agonists and tiotropium is recommended for patients with COPD that is moderate to very severe who remain symptomatic despite regular treatment with a single longacting bronchodilator.1, 2, 3 Similarly, theophylline is recommended as a second-choice treatment to supplement longacting bronchodilators, even though this recommendation is supported by results from only one small randomised clinical trial.7 The addition of inhaled glucocorticosteroids to longacting β2 agonists (combination with tiotropium has not been adequately assessed) further reduces symptoms and exacerbations, and improves lung function, particularly in patients with severe or very severe COPD.4, 8, 9, 10 Thus, inhaled glucocorticosteroids are recommended in combination with longacting bronchodilators for patients with COPD that is severe to very severe who have recurrent exacerbations.1, 2, 3 However, inhaled glucocorticosteroids have limited effect in these patients, and their long-term use is associated with a small but significant increase in the risk of pneumonia that is of clinical concern.4, 11, 12 Apart from improvements in bronchodilators and inhaled glucocorticosteroids, no novel treatment for COPD is expected to become available for several years.5, 13

Phosphodiesterase-4 (PDE4) inhibitors are a new class of anti-inflammatory drugs that have shown efficacy and acceptable tolerability in preclinical and clinical studies in patients with COPD.14, 15 A second-generation PDE4 inhibitor roflumilast has been shown to provide effective inhibition of chemotaxis, leucocyte activation, and cytokine production in vitro and in animal models of COPD,15 and reduce the number of neutrophils and eosinophils in the sputum of patients with COPD.16 In two large, randomised clinical studies undertaken in patients with COPD that was moderate to severe17 or severe to very severe,18 roflumilast consistently improved lung function. By contrast, the positive effect of roflumilast on exacerbations in moderate-to-severe disease17 was not noted in patients with severe disease, though subgroup analysis did show a reduction in exacerbation rate in patients with very severe COPD.18 In two randomised trials in symptomatic patients with severe COPD and a history of exacerbations, Calverley and colleagues19 confirmed after 1 year the positive effects of roflumilast on both lung function and exacerbations independent of the patient's smoking status or use of concomitant medication such as inhaled longacting β2 agonists.

To find out whether roflumilast provides benefit to patients who are regularly treated with longacting inhaled bronchodilators, we investigated its effects in patients with COPD who were regularly treated with salmeterol or tiotropium.

Section snippets

Setting

The salmeterol plus roflumilast (M2-127) trial was done in 135 centres in ten countries, whereas the tiotropium plus roflumilast (M2-128) trial was done in 85 centres in seven countries.

Patients

We recruited patients with moderate-to-severe COPD, which was defined spirometrically,1, 2, 3 from an outpatient setting to investigate the effect of roflumilast concomitantly with salmeterol or tiotropium. The main inclusion criteria were age older than 40 years, current or former smokers (≥1 year of smoking

Results

The studies started in April, 2006 (first patient enrolled), and ended in January, 2008 (last assessment completed). In the salmeterol plus roflumilast trial, 933 patients were randomly assigned and treated; 744 patients completed the study (figure 1A). In the tiotropium plus roflumilast trial, 743 patients were randomly assigned and treated, and 642 completed the study (figure 1B). Table 1 shows the demographic and baseline characteristics of the two intention-to-treat study populations.

The

Discussion

In patients with moderate-to-severe COPD treated with salmeterol or tiotropium, roflumilast improves lung function and some clinically relevant symptomatic outcomes. These results confirm the conclusions drawn from the findings of previous randomised clinical trials in which roflumilast was efficacious in patients with severe COPD who were not regularly treated with longacting bronchodilators.17, 18, 19 Additionally, our results show that roflumilast maintains its clinical efficacy in patients

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