title: Roflumilast and dyspnea in patients with moderate to very severe chronic obstructive pulmonary disease: a pooled analysis of four clinical trials.
abstract: OBJECTIVE
  Breathlessness is a predominant symptom of chronic obstructive pulmonary disease (COPD), making it a valuable outcome in addition to lung function to assess treatment benefit. The phosphodiesterase-4 inhibitor roflumilast has been shown to provide small but significant improvements in dyspnea, as measured by the transition dyspnea index (TDI), in two 1-year studies in patients with severe to very severe COPD.
  
  
  METHODS
  To provide a more comprehensive assessment of the impact of roflumilast on dyspnea, post hoc analyses of four 1-year roflumilast studies (M2-111, M2-112, M2-124, and M2-125) in patients with moderate to very severe COPD were conducted.
  
  
  RESULTS
  In this pooled analysis (N=5,595), roflumilast significantly improved TDI focal scores versus placebo at week 52 (treatment difference, 0.327; P<0.0001). Roflumilast was associated with significantly greater TDI responders and significantly fewer TDI deteriorators (≥1-unit increase or decrease from baseline, respectively) versus placebo at week 52 (P<0.01, both); these significant differences were apparent by week 8 and maintained until study end (P<0.05, all). At study end, the postbronchodilator forced expiratory volume in 1 second improvement in TDI responders was significantly greater with roflumilast versus placebo (P<0.05). Similar to the overall population, improvements in TDI focal scores at week 52 were small but consistently significant over placebo in patients with chronic bronchitis, regardless of exacerbation history, concomitant treatment with short-acting muscarinic antagonists or long-acting β2-agonists, or pretreatment with inhaled corticosteroids.
  
  
  CONCLUSIONS
  This analysis shows that patients treated with roflumilast to reduce exacerbation risk may also experience small but significant improvements in dyspnea, with accompanying improvements in lung function.
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
authors.affiliation: Forest Research Institute, Jersey City, NJ, USA.
authors.forename: Shawn X
authors.initials: SX
authors.lastname: Sun
authors.affiliation: Forest Research Institute, Jersey City, NJ, USA.
authors.forename: Stavros
authors.initials: S
authors.lastname: Tourkodimitris
authors.affiliation: Forest Research Institute, Jersey City, NJ, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Rowe
authors.affiliation: Takeda Pharmaceuticals International GmbH, Zurich, Switzerland.
authors.forename: Udo M
authors.initials: UM
authors.lastname: Goehring
authors.affiliation: Takeda Pharmaceuticals International GmbH, Zurich, Switzerland.
authors.forename: Dirk
authors.initials: D
authors.lastname: Bredenbröker
authors.affiliation: Department of Clinical Science, University of Liverpool, Liverpool, UK.
authors.forename: Peter M A
authors.initials: PM
authors.lastname: Calverley
mesh_terms: D000368:Aged; D000631:Aminopyridines / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides / Q000009:adverse effects / Q000627:therapeutic use*; D003521:Cyclopropanes / Q000009:adverse effects / Q000627:therapeutic use; D004417:Dyspnea / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D058988:Phosphodiesterase 4 Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D016032:Randomized Controlled Trials as Topic; D020127:Recovery of Function; D012307:Risk Factors; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D058988:Phosphodiesterase 4 Inhibitors; C424423:Roflumilast
keywords: breathlessness; lung function; phosphodiesterase-4 inhibitor; subgroup analyses