title: Randomised, double-blind, placebo-controlled crossover study to investigate different dosing regimens of olodaterol delivered via Respimat® in patients with moderate to severe persistent asthma.
abstract: BACKGROUND
  A Phase II, multicentre, randomised, double-blind, placebo-controlled, crossover trial comparing the 24-h forced expiratory volume in 1 s (FEV1) time profile after 3 weeks' treatment with once-daily (QD) or twice-daily (BID) olodaterol (at the same total daily dose) versus placebo delivered via Respimat® in patients with moderate to severe asthma.
  
  
  METHODS
  Patients were randomised to different sequences of olodaterol with 2-week washout, either as a total daily dose of 5 μg (5 μg QD [AM] or 2.5 μg BID) or placebo, or 10 μg (10 μg QD [AM] or 5 μg BID) or placebo. Primary end point was FEV1 area under the curve from 0 to 24 h (AUC0-24) response (defined as change from study baseline FEV1) after 3 weeks. Key secondary end points were FEV1 AUC0-12 and AUC12-24 responses.
  
  
  RESULTS
  Two hundred and six patients received treatment. All olodaterol treatments demonstrated statistically significant improvements in FEV1 AUC0-24 response at 3 weeks versus placebo (p < 0.0001); adjusted mean treatment difference versus placebo was 0.191 L for olodaterol 2.5 μg BID (95 % confidence interval [CI] 0.152, 0.229), 0.150 L for 5 μg QD (95 % CI 0.111, 0.189), 0.228 L for 5 μg BID (95 % CI 0.190, 0.266) and 0.209 L for 10 μg QD (95 % CI 0.170, 0.247). These results were supported by the key secondary end points. Olodaterol 5 μg QD provided numerically lower mean values for 24-h bronchodilation than olodaterol 2.5 μg BID (p = 0.0465), with no statistically significant difference between treatment with olodaterol 10 μg QD and 5 μg BID. No relevant differences in morning and evening peak expiratory flow or Asthma Control Questionnaire scores at 3 weeks were observed between different doses and regimens. Adverse events were generally mild to moderate and comparable between groups.
  
  
  CONCLUSIONS
  All doses and dose frequencies provided adequate 24-h bronchodilation superior to placebo. Based on the results of this study, it would be reasonable to include both posologies of 5 μg olodaterol daily (5 μg QD or 2.5 μg BID, both delivered in two puffs per dose from the Respimat® inhaler) in subsequent studies. Further studies are necessary to confirm the optimum dosing regimen in asthma. No safety concerns were identified.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01311661.
authors.affiliation: Insaf GmbH Institut für Atemwegsforschung, Biebricher Allee 34, D-65187, Wiesbaden, Germany. k.beeh@insaf-wi.de.
authors.forename: Kai-Michael
authors.initials: KM
authors.lastname: Beeh
authors.affiliation: North Carolina Clinical Research, Raleigh, NC, USA. claforce@nccr.com.
authors.forename: Craig
authors.initials: C
authors.lastname: LaForce
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany. martina.gahlemann@boehringer-ingelheim.com.
authors.forename: Martina
authors.initials: M
authors.lastname: Gahlemann
authors.affiliation: Boehringer Ingelheim (Schweiz) GmbH, Basel, Switzerland. arne.wenz.ext@boehringer-ingelheim.com.
authors.forename: Arne
authors.initials: A
authors.lastname: Wenz
authors.affiliation: Boehringer Ingelheim Ltd, Bracknell, Berkshire, UK. robert.toorawa.ext@boehringer-ingelheim.com.
authors.forename: Robert
authors.initials: R
authors.lastname: Toorawa
authors.affiliation: University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia. matjaz.flezar@klinika-golnik.si.
authors.forename: Matjaž
authors.initials: M
authors.lastname: Fležar
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D000068600:Albuterol, Ipratropium Drug Combination / Q000008:administration & dosage*; D001249:Asthma / Q000175:diagnosis* / Q000188:drug therapy*; D048588:Benzoxazines / Q000008:administration & dosage*; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index
chemical_list: D000068600:Albuterol, Ipratropium Drug Combination; D048588:Benzoxazines; D001993:Bronchodilator Agents; C549647:olodaterol