Randomized, Double-Blind, Dose-Finding Study for Tiotropium when Added to Olodaterol, Administered via the Respimat® Inhaler in Patients with Chronic Obstructive Pulmonary Disease

René Aalbers, M Reza Maleki-Yazdi, Alan Hamilton, Stella Waitere-Wijker, Yihua Zhao, Valeria C Amatto, Olaf Schmidt, Leif Bjermer, René Aalbers, M Reza Maleki-Yazdi, Alan Hamilton, Stella Waitere-Wijker, Yihua Zhao, Valeria C Amatto, Olaf Schmidt, Leif Bjermer

Abstract

Introduction: Combining long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs) is beneficial in chronic obstructive pulmonary disease (COPD), as the two classes of bronchodilator have complementary modes of action. The optimal dose for the fixed-dose combination of the LAMA tiotropium and the LABA olodaterol needed to be determined. In this phase II trial, the dose response of tiotropium on top of olodaterol was investigated in a free-dose combination, while other phase II studies have explored different doses of olodaterol on top of tiotropium, with both drugs delivered using the Respimat(®) inhaler.

Methods: This was a double-blind incomplete crossover trial in which 233 patients with moderate or severe COPD were randomized to receive four out of eight free-dose combinations of olodaterol (5 or 10 µg) and tiotropium (1.25, 2.5, or 5 µg) or placebo for 4 weeks each. Primary end point was trough forced expiratory volume in 1 s (FEV1) change from baseline (response) after 4 weeks.

Results: Addition of tiotropium 1.25, 2.5, and 5 µg to olodaterol 5 µg increased mean trough FEV1 response by 0.054, 0.065, and 0.084 L, respectively; addition of tiotropium 1.25, 2.5, and 5 µg to olodaterol 10 µg increased mean trough FEV1 response by 0.051, 0.083, and 0.080 L, respectively. All treatments were well tolerated and incidence of adverse events was similar with all treatments.

Conclusions: Overall, a dose response for tiotropium on top of both doses of olodaterol was observed, with increasing improvements in trough FEV1 compared to olodaterol alone as the tiotropium dose was increased.

Funding: Boehringer Ingelheim.

Trial registration: ClinicalTrials.gov number, NCT01040403.

Keywords: Bronchodilator; Chronic obstructive pulmonary disease; Dose finding; Long-acting muscarinic antagonists; Long-acting β2-agonists; Olodaterol; Tiotropium.

Figures

Fig. 1
Fig. 1
Trial design
Fig. 2
Fig. 2
Patient disposition
Fig. 3
Fig. 3
FEV1 profiles after 4 weeks of treatment with tiotropium 1.25, 2.5, 5 μg, and placebo on top of olodaterol 5 μg (a) and 10 μg (b). −1:00 value is mean of 1 h pre-treatment and 10 min pre-treatment values. P < 0.05 for all tiotropium + olodaterol versus olodaterol 5 µg in (a) and versus olodaterol 10 µg in (b). FEV1 forced expiratory volume in 1 s
Fig. 4
Fig. 4
FVC profiles after 4 weeks of treatment with tiotropium 1.25, 2.5, 5 μg, and placebo on top of olodaterol 5 μg (a) and 10 μg (b). −1:00 value is mean of 1 h pre-treatment and 10 min pre-treatment values. P < 0.05 for all tiotropium + olodaterol versus olodaterol 5 µg in (a) and versus olodaterol 10 µg in (b). FVC forced vital capacity

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Source: PubMed

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