title: Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials.
abstract: 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 microg 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 (FEV(1)). Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, number NCT00313209 for M2-127, and NCT00424268 for M2-128.
  
  
  RESULTS
  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 FEV(1) 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 FEV(1) 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.
  
  
  CONCLUSIONS
  Roflumilast improves lung function in patients with COPD treated with salmeterol or tiotropium, and could become an important treatment for these patients.
  
  
  BACKGROUND
  Nycomed.
authors.affiliation: University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Leonardo M
authors.initials: LM
authors.lastname: Fabbri
authors.forename: Peter M A
authors.initials: PM
authors.lastname: Calverley
authors.forename: José Luis
authors.initials: JL
authors.lastname: Izquierdo-Alonso
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Bundschuh
authors.forename: Manja
authors.initials: M
authors.lastname: Brose
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Martinez
authors.forename: Klaus F
authors.initials: KF
authors.lastname: Rabe
mesh_terms: D000280:Administration, Inhalation; D000284:Administration, Oral; D000368:Aged; D000420:Albuterol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000631:Aminopyridines / Q000627:therapeutic use*; D000704:Analysis of Variance; D001549:Benzamides / Q000627:therapeutic use*; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D003521:Cyclopropanes / 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 / Q000627:therapeutic use*; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology; D012044:Regression Analysis; D000068299:Salmeterol Xinafoate; D012602:Scopolamine Derivatives / Q000627:therapeutic use*; D012720:Severity of Illness Index; D012907:Smoking / Q000453:epidemiology; D000069447:Tiotropium Bromide; D016896:Treatment Outcome; D014797:Vital Capacity / Q000187:drug effects
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D001993:Bronchodilator Agents; D003521:Cyclopropanes; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D012602:Scopolamine Derivatives; C424423:Roflumilast; D000068299:Salmeterol Xinafoate; D000420:Albuterol; D000069447:Tiotropium Bromide