title: The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease.
abstract: BACKGROUND
  This study investigated the effects on 24-h lung function and lung volume of a once-daily fixed-dose combination (FDC) of the long-acting muscarinic antagonist tiotropium and the long-acting β2-agonist olodaterol in patients with chronic obstructive pulmonary disease.
  
  
  METHODS
  This was a randomised, double-blind, placebo-controlled, Phase III trial with an incomplete crossover design. Patients received four of the following six treatment options for 6 weeks each: placebo, olodaterol 5 μg, tiotropium 2.5 μg, tiotropium 5 μg, tiotropium + olodaterol FDC 2.5/5 μg and tiotropium + olodaterol FDC 5/5 μg, all delivered via the Respimat(®) inhaler. The primary end point was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 24 h (AUC0-24) response after 6 weeks of treatment; key secondary end points were FEV1 AUC from 0 to 12 h and AUC from 12 to 24 h, and further end points included lung-volume parameters measured using body plethysmography (subset of patients), measures of peak and trough FEV1, and incidence of adverse events.
  
  
  RESULTS
  A significant improvement in FEV1 AUC0-24 response was observed with tiotropium + olodaterol 5/5 μg and 2.5/5 μg versus placebo and monotherapies after 6 weeks of treatment; mean response with tiotropium + olodaterol 5/5 μg versus placebo was 0.280 L (p < 0.0001). Differences to monotherapies with tiotropium + olodaterol 5/5 μg were 0.115 L versus olodaterol 5 μg, 0.127 L versus tiotropium 2.5 μg and 0.110 L versus tiotropium 5 μg (p < 0.0001 for all comparisons). Secondary end points supported these data. No safety concerns were identified.
  
  
  CONCLUSIONS
  Overall, this study demonstrated improvements in lung function over 24 h with an FDC of tiotropium + olodaterol over tiotropium or olodaterol alone, with no observed difference in tolerability. ClinicalTrials.gov number: NCT01559116.
authors.affiliation: Insaf GmbH Institut für Atemwegsforschung, Wiesbaden, Germany. Electronic address: k.beeh@insaf-wi.de.
authors.forename: Kai-Michael
authors.initials: KM
authors.lastname: Beeh
authors.affiliation: Pulmonary and Sleep Associates of Jasper, Jasper, AL, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Westerman
authors.affiliation: Pulmonary Research Institute at LungClinic Grosshansdorf GmbH, Airway Research Center North, Grosshansdorf, Germany.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Kirsten
authors.affiliation: Centre de Recherche Appliquée en Allergie de Québec, Québec, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Hébert
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Grönke
authors.affiliation: Boehringer Ingelheim, Burlington, Ontario, Canada.
authors.forename: Alan
authors.initials: A
authors.lastname: Hamilton
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; Department of Sports Medicine, Medical Clinic V, University of Tübingen, Tübingen, Germany.
authors.forename: Kay
authors.initials: K
authors.lastname: Tetzlaff
authors.affiliation: Ghent University Hospital, Ghent, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Derom
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000368:Aged; D048588:Benzoxazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000503:physiopathology; D012129:Respiratory Function Tests; D013997:Time Factors; D000069447:Tiotropium Bromide / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D048588:Benzoxazines; D001993:Bronchodilator Agents; D004338:Drug Combinations; D018727:Muscarinic Antagonists; C549647:olodaterol; D000069447:Tiotropium Bromide
keywords: Chronic obstructive pulmonary disease; Combination therapy; Olodaterol; Tiotropium