Research Center, Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec City, Québec, Canada.
Boehringer Ingelheim (Canada) Ltd., Burlington, ON, Canada.
Adv Ther. 2019 Apr;36(4):962-968. doi: 10.1007/s12325-019-00911-y. Epub 2019 Mar 6.
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 μg, and compare it with the dose response of olodaterol monotherapy.
In this double-blind, parallel-group trial, patients were randomized to receive either tiotropium 5 μg or a fixed-dose combination of tiotropium 5 μg with olodaterol 2 μg, 5 μg, or 10 μg, delivered once daily via the Respimat for 4 weeks (NCT00696020). Patients had a diagnosis of chronic obstructive pulmonary disease and post-bronchodilator forced expiratory volume in 1 s (FEV) ≥ 30 and < 80% of predicted normal. The primary endpoint was trough FEV response (change from baseline) after 4 weeks. Secondary endpoints included FEV and forced vital capacity (FVC) over 6 h after dosing.
Compared with tiotropium 5 μg, mean (standard error) trough FEV increased with the addition of olodaterol 2 μg by 0.024 L (0.027), olodaterol 5 μg by 0.033 L (0.027), and olodaterol 10 μg by 0.057 L (0.027). Statistically significant improvements in FEV versus tiotropium were seen across all timepoints up to 6 h with all doses of tiotropium/olodaterol. Similar results were observed for FVC.
There was a benefit of tiotropium/olodaterol compared with tiotropium monotherapy in FEV and FVC. There was a dose-response relationship for olodaterol on top of tiotropium for FEV 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.
Boehringer Ingelheim International GmbH.
在药物固定剂量组合的临床开发过程中，最好进行剂量探索研究以确定每个成分的最佳剂量。这项 II 期剂量探索研究的目的是确认添加奥达特罗对噻托溴铵的肺功能益处，描述奥达特罗与噻托溴铵 5μg 联合用药的剂量反应关系，并与奥达特罗单药治疗的剂量反应进行比较。
在这项双盲、平行分组试验中，患者被随机分配接受噻托溴铵 5μg 或噻托溴铵 5μg 与奥达特罗 2μg、5μg 或 10μg 的固定剂量组合，每天一次通过 Respimat 给药，持续 4 周（NCT00696020）。患者患有慢性阻塞性肺疾病，支气管扩张剂后 1 秒用力呼气量（FEV）≥30%且<80%预计正常。主要终点是 4 周后的谷值 FEV 反应（与基线相比的变化）。次要终点包括给药后 6 小时的 FEV 和用力肺活量（FVC）。
与噻托溴铵 5μg 相比，奥达特罗 2μg 增加的平均（标准误差）谷值 FEV 为 0.024L（0.027），奥达特罗 5μg 为 0.033L（0.027），奥达特罗 10μg 为 0.057L（0.027）。在所有时间点，所有剂量的噻托溴铵/奥达特罗与噻托溴铵相比，FEV 均有统计学意义上的显著改善，直至 6 小时。FVC 也观察到类似的结果。
与噻托溴铵单药治疗相比，噻托溴铵/奥达特罗在 FEV 和 FVC 方面具有优势。奥达特罗在噻托溴铵的基础上具有剂量反应关系，与奥达特罗单药治疗的剂量反应相似。这些结果与一项研究噻托溴铵在奥达特罗基础上的剂量反应的研究结果一起，有助于为 III 期研究选择剂量。
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