Dose-finding evaluation of once-daily treatment with olodaterol, a novel long-acting β2-agonist, in patients with asthma: results of a parallel-group study and a crossover study.
BACKGROUND
Olodaterol is a novel, inhaled long-acting β2-agonist (LABA) with >24-hour duration of action investigated in asthma and chronic obstructive pulmonary disease.


METHODS
Two multicentre studies examined the efficacy and safety of 4 weeks' once-daily (QD) olodaterol (2, 5, 10 and 20 μg, with background inhaled corticosteroids) in patients with asthma. One randomised, double-blind, parallel-group study (1222.6; 296 patients) administered treatment in the morning. Pulmonary function tests (PFTs) were performed pre-dose (trough) and ≤3 hours post-dose (weeks 1 and 2), and ≤6 hours post-dose after 4 weeks; primary end point was trough forced expiratory volume in 1 second (FEV1) response (change from baseline mean FEV1) after 4 weeks. A second randomised, double-blind, placebo- and active-controlled (formoterol 12 μg twice-daily) incomplete-block crossover study (1222.27; 198 patients) administered QD treatments in the evening. PFTs were performed over a 24-hour dosing interval after 4 weeks; primary end point was FEV1 area under the curve from 0-24 hours (AUC0-24) response (change from study baseline [mean FEV1] after 4 weeks).


RESULTS
Study 1222.6 showed a statistically significant increase in trough FEV1 response with olodaterol 20 μg (0.147 L; 95 % confidence interval [CI]: 0.059, 0.234; p = 0.001) versus placebo, with more limited efficacy and no evidence of dose response compared to placebo across the other olodaterol doses (2, 5 and 10 μg). Study 1222.27 demonstrated increases in FEV1 AUC0-24 responses at 4 weeks with all active treatments (p < 0.0001); adjusted mean (95 % CI) differences from placebo were 0.140 (0.097, 0.182), 0.182 (0.140, 0.224), 0.205 (0.163, 0.248) and 0.229 (0.186, 0.272) L for olodaterol 2, 5, 10 and 20 μg, respectively, and 0.169 (0.126, 0.211) for formoterol, providing evidence of increased efficacy with higher olodaterol dose. Olodaterol was generally well tolerated, with a few events associated with known sympathomimetic effects, mainly with 20 μg.


CONCLUSIONS
The LABA olodaterol has >24-hour duration of action. In patients with asthma, evidence of bronchodilator efficacy was demonstrated with statistically and clinically significant improvements in the primary end point of trough FEV1 response measured in clinics over placebo for the highest administered dose of 20 μg in Study 1222.6, and statistically and clinically significant improvements versus placebo in FEV1 AUC0-24 responses at 4 weeks for all doses tested in Study 1222.27, which also exhibited a dose response. Bronchodilator efficacy was seen over placebo for all olodaterol doses for morning and evening peak expiratory flow in both studies. All doses were well tolerated.


BACKGROUND
NCT00467740 (1222.6) and NCT01013753 (1222.27).
Firestone Institute for Respiratory Health, and Department of Medicine, McMaster University Medical Centre, 1280 Main Street West, Room 3 W10, Hamilton, ON, L8S 4 K1, Canada. obyrnep@mcmaster.ca.
Paul M
PM
O'Byrne
Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada. tonydurzo@sympatico.ca.
Tony
T
D'Urzo
Institut für Gesundheitsförderung GmbH, Rüdersdorf, Germany. beck@ifg-forschung.de.
Ekkehard
E
Beck
Hospital Golnik, Clinical Department of Pulmonology and Allergy, Golnik, Slovenia. matjaz.flezar@klinika-golnik.si.
Matjaž
M
Fležar
Boehringer Ingelheim (Schweiz) GmbH, Basel, Switzerland. martina.gahlemann@boehringer-ingelheim.com.
Martina
M
Gahlemann
Boehringer Ingelheim Canada Ltd, Burlington, ON, Canada. lorna.hart@boehringer-ingelheim.com.
Lorna
L
Hart
Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria. zuzana.blahova@boehringer-ingelheim.com.
Zuzana
Z
Blahova
Boehringer Ingelheim Ltd, Bracknell, UK. robert.toorawa.ext@boehringer-ingelheim.com.
Robert
R
Toorawa
insaf Respiratory Research Institute, Wiesbaden, Germany. k.beeh@insaf-wi.de.
Kai-Michael
KM
Beeh
D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage*; D000328:Adult; D001249:Asthma / Q000175:diagnosis* / Q000188:drug therapy*; D048588:Benzoxazines / Q000008:administration & dosage*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
D058666:Adrenergic beta-2 Receptor Agonists; D048588:Benzoxazines; C549647:olodaterol