Beeh Kai-Michael, Westerman Jan, Kirsten Anne-Marie, Hébert Jacques, Grönke Lars, Hamilton Alan, Tetzlaff Kay, Derom Eric
Insaf GmbH Institut für Atemwegsforschung, Wiesbaden, Germany.
Pulmonary and Sleep Associates of Jasper, Jasper, AL, USA.
Pulm Pharmacol Ther. 2015 Jun;32:53-9. doi: 10.1016/j.pupt.2015.04.002. Epub 2015 May 6.
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 β2-agonist olodaterol in patients with chronic obstructive pulmonary disease.
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 μg, tiotropium 2.5 μg, tiotropium 5 μg, tiotropium + olodaterol FDC 2.5/5 μg and tiotropium + olodaterol FDC 5/5 μg, all delivered via the Respimat(®) inhaler. The primary end point was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 24 h (AUC0-24) 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.
A significant improvement in FEV1 AUC0-24 response was observed with tiotropium + olodaterol 5/5 μg and 2.5/5 μg versus placebo and monotherapies after 6 weeks of treatment; mean response with tiotropium + olodaterol 5/5 μg versus placebo was 0.280 L (p < 0.0001). Differences to monotherapies with tiotropium + olodaterol 5/5 μg were 0.115 L versus olodaterol 5 μg, 0.127 L versus tiotropium 2.5 μg and 0.110 L versus tiotropium 5 μg (p < 0.0001 for all comparisons). Secondary end points supported these data. No safety concerns were identified.
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.
本研究调查了长效毒蕈碱拮抗剂噻托溴铵与长效β2受体激动剂奥达特罗每日一次固定剂量联合用药（FDC）对慢性阻塞性肺疾病患者24小时肺功能和肺容量的影响。
这是一项随机、双盲、安慰剂对照的III期试验，采用不完全交叉设计。患者接受以下六种治疗方案中的四种，每种治疗6周：安慰剂、奥达特罗5μg、噻托溴铵2.5μg、噻托溴铵5μg、噻托溴铵+奥达特罗FDC 2.5/5μg和噻托溴铵+奥达特罗FDC 5/5μg，均通过Respimat(®)吸入器给药。主要终点是治疗6周后0至24小时曲线下的1秒用力呼气容积（FEV1）面积（AUC0-24）反应；关键次要终点是0至12小时的FEV1 AUC和12至24小时的AUC，进一步的终点包括使用体描仪测量的肺容量参数（患者亚组）、FEV1峰谷值测量以及不良事件发生率。
治疗6周后，与安慰剂和单药治疗相比，噻托溴铵+奥达特罗5/5μg和2.5/5μg的FEV1 AUC0-24反应有显著改善；噻托溴铵+奥达特罗5/5μg与安慰剂相比的平均反应为0.280L（p<0.0001）。噻托溴铵+奥达特罗5/5μg与单药治疗的差异分别为：与奥达特罗5μg相比为0.115L，与噻托溴铵2.5μg相比为0.127L，与噻托溴铵5μg相比为0.110L（所有比较p<0.0001）。次要终点支持这些数据。未发现安全问题。
总体而言，本研究表明，与单独使用噻托溴铵或奥达特罗相比，噻托溴铵+奥达特罗FDC在24小时内可改善肺功能，耐受性无差异。ClinicalTrials.gov编号：NCT01559116。
