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

Kai-Michael Beeh, Craig LaForce, Martina Gahlemann, Arne Wenz, Robert Toorawa, Matjaž Fležar, Kai-Michael Beeh, Craig LaForce, Martina Gahlemann, Arne Wenz, Robert Toorawa, Matjaž Fležar

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.

Trial registration: ClinicalTrials.gov NCT01311661.

Figures

Fig. 1
Fig. 1
Study design. All patients received three dose regimens; each was separated by a 2-week washout period. Patients in the 5 μg total daily dose group received one of six possible sequences of olodaterol 2.5 μg BID, 5 μg QD and placebo. Patients in the 10 μg total daily dose group received one of six possible sequences of olodaterol 5 μg BID, 10 μg QD and placebo. Patients continued taking ICS throughout the study, with posology determined by former use. If administration of ICS and study treatment coincided, patients were to take study treatment followed by ICS
Fig. 2
Fig. 2
CONSORT diagram illustrating participant flow. Since this was a crossover trial and every patient was supposed to receive three treatments, the total number of patients is not the sum of the number of each patient on each treatment. Of the seven patients who discontinued prematurely, the most frequent reason was non-compliance with the trial protocol (three patients). BID: twice daily; QD: once daily; AE: adverse event
Fig. 3
Fig. 3
Adjusted mean FEV1: individual time points from 0 to 24 h at 3 weeks. Analysis with imputation, full analysis set. BID: twice daily; QD: once daily; FEV1: forced expiratory volume in 1 s
Fig. 4
Fig. 4
Difference versus placebo at 3 weeks of adjusted mean FEV1 AUC0–12 (a) and AUC12–24 (b). FEV1: forced expiratory volume in 1 s; AUC0–12: area under the curve from 0 to 12 h; SE: standard error; BID: twice daily; QD: once daily; AUC12–24: area under the curve from 12 to 24 h
Fig. 5
Fig. 5
Adjusted mean FVC AUC0–24 at 3 weeks. FVC: forced vital capacity; AUC0–24: area under the curve from 0 to 24 h; SE: standard error; BID: twice daily; QD: once daily

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