The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease

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 beta(2)-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 mu g, tiotropium 2.5 mu g, tiotropium 5 mu g, tiotropium + olodaterol FDC 2.5/5 mu g and tiotropium + olodaterol FDC 5/5 mu g, all delivered via the Respimat (R) inhaler. The primary end point was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 24 h (AUC(0-24)) 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 AUC(0-24) response was observed with tiotropium + olodaterol 5/5 mu g and 2.5/5 mu g versus placebo and monotherapies after 6 weeks of treatment; mean response with tiotropium + olodaterol 5/5 mu g versus placebo was 0.280 L (p < 0.0001). Differences to monotherapies with tiotropium + olodaterol 5/5 mu g were 0.115 L versus olodaterol 5 mu g, 0.127 L versus tiotropium 2.5 mu g and 0.110 L versus tiotropium 5 mu g (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