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.
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 microg once per day) or placebo for 52 weeks. Primary endpoints were change in
prebronchodilator forced expiratory volume in 1 s (FEV(1)) 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.
Patients were assigned to treatment, stratified according to smoking status and treatment
with longacting beta(2) 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 FEV(1) 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.
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.
Nycomed.