Dose Determination for a Fixed-Dose Drug Combination: A Phase II Randomized Controlled Trial for Tiotropium/Olodaterol Versus Tiotropium in Patients with COPD

Introduction: During the clinical development of a fixed-dose combination of drugs, it is best practice to conduct dose-finding studies to determine the optimal dose of each component. The aims of this phase II dose-finding study were to confirm the lung function benefit of adding olodaterol to tiotropium, describe the dose-response relationship of olodaterol in combination with tiotropium 5 mu g, and compare it with the dose response of olodaterol monotherapy. Methods: In this double-blind, parallel-group trial, patients were randomized to receive either tiotropium 5 mu g or a fixed-dose combination of tiotropium 5 mu g with olodaterol 2 mu g, 5 mu g, or 10 mu g, delivered once daily via the Respimat (R) for 4 weeks (NCT00696020). Patients had a diagnosis of chronic obstructive pulmonary disease and post-bronchodilator forced expiratory volume in 1s (FEV1) >= 30 and < 80% of predicted normal. The primary endpoint was trough FEV1 response (change from baseline) after 4 weeks. Secondary endpoints included FEV1 and forced vital capacity (FVC) over 6 h after dosing. Results: Compared with tiotropium 5 mu g, mean (standard error) trough FEV1 increased with the addition of olodaterol 2 mu g by 0.024 L (0.027), olodaterol 5 mu g by 0.033 L (0.027), and olodaterol 10 mu g by 0.057 L (0.027). Statistically significant improvements in FEV1 versus tiotropium were seen across all timepoints up to 6 h with all doses of tiotropium/olodaterol. Similar results were observed for FVC. Conclusion: There was a benefit of tiotropium/olodaterol compared with tiotropium monotherapy in FEV1 and FVC. There was a dose-response relationship for olodaterol on top of tiotropium for FEV1 and FVC similar to the dose response previously seen for olodaterol monotherapy. These results, together with the results of a study investigating the dose response of tiotropium on top of olodaterol, helped to inform the dose selection for the phase III studies.