title: Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials.
abstract: 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 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Nycomed.
authors.affiliation: School of Clinical Sciences, Liverpool, UK. pmacal@liverpool.ac.uk
authors.forename: Peter M A
authors.initials: PM
authors.lastname: Calverley
authors.forename: Klaus F
authors.initials: KF
authors.lastname: Rabe
authors.forename: Udo-Michael
authors.initials: UM
authors.lastname: Goehring
authors.forename: Søren
authors.initials: S
authors.lastname: Kristiansen
authors.forename: Leonardo M
authors.initials: LM
authors.lastname: Fabbri
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Martinez
mesh_terms: D000284:Administration, Oral; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use; D000368:Aged; D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use*; D000704:Analysis of Variance; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D018680:Cholinergic Antagonists / Q000627:therapeutic use; D003521:Cyclopropanes / Q000494:pharmacology / Q000627:therapeutic use; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology; D012044:Regression Analysis; D012720:Severity of Illness Index; D012907:Smoking / Q000453:epidemiology; D016896:Treatment Outcome; D014797:Vital Capacity / Q000187:drug effects
chemical_list: D000318:Adrenergic beta-Agonists; D000631:Aminopyridines; D001549:Benzamides; D018680:Cholinergic Antagonists; D003521:Cyclopropanes; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; C424423:Roflumilast