Statmind Statistical and Mathematical Modelling, Innovation and Design AB, Lund, Sweden.
AstraZeneca R&D, Gothenburg, Sweden.
Contemp Clin Trials. 2018 Apr;67:87-90. doi: 10.1016/j.cct.2018.02.008. Epub 2018 Feb 21.
A planned change from Bricanyl® (terbutaline) Turbuhaler® M2 to M3 device required a pharmacodynamic study to evaluate therapeutic equivalence of the two devices. Because of the flat dose-response curve for this type of agent over this dose range when assessing bronchodilation, a bronchoprotection study was considered more feasible. In this double-blind, double-dummy, multicentre, single-dose, two-factor, crossover study, patients with stable mild-to-moderate asthma were randomised to 0.5 or 1.5 mg terbutaline via Turbuhaler® M2 or Turbuhaler® M3 followed by a methacholine challenge test. Primary outcome variable: concentration of methacholine causing a 20% fall in FEV (PC). Pairwise contrasts were constructed with 95% CIs to determine assay sensitivity for M2 and M3 devices and therapeutic equivalence at each dose level (95% CI for M3:M2 devices within pre-specified limit [0.67-1.50]) and the relative dose-potency (RDP) between M3 and M2 determined with 90% CI. Sixty patients were randomised and all completed the study. Between-device ratios of PC (M3:M2) were 0.92 (95% CI: 0.75-1.13) for 0.5 mg and 0.88 (95% CI 0.72-1.08) for 1.5 mg and estimated RDP was 1.20 (0.96-1.53). In conclusion, a methacholine provocation study (PC primary variable) is a useful alternative to the standard bronchodilation study when assessing therapeutic equivalence of a bronchodilator.
从 Bricanyl®（特布他林）Turbuhaler® M2 装置改为 M3 装置需要进行药效学研究，以评估两种装置的治疗等效性。由于在评估支气管扩张时，对于这种类型的药物在该剂量范围内，剂量反应曲线是平坦的，因此认为支气管保护研究更可行。在这项双盲、双模拟、多中心、单剂量、两因素、交叉研究中，稳定的轻度至中度哮喘患者被随机分配至 0.5 或 1.5mg 特布他林，通过 Turbuhaler® M2 或 Turbuhaler® M3 给药，然后进行乙酰甲胆碱挑战测试。主要结局变量：引起 FEV 下降 20%的乙酰甲胆碱浓度（PC）。构建了两两对比，并构建了 95%置信区间，以确定 M2 和 M3 装置的检测灵敏度，以及每个剂量水平的治疗等效性（M3：M2 装置在预设范围内的 95%置信区间 [0.67-1.50]）和 M3 与 M2 之间的相对剂量效价（RDP），90%置信区间确定。60 名患者被随机分组，所有患者均完成了研究。PC（M3：M2）的设备间比值为 0.5mg 时为 0.92（95%CI：0.75-1.13），1.5mg 时为 0.88（95%CI 0.72-1.08），估计 RDP 为 1.20（0.96-1.53）。总之，当评估支气管扩张剂的治疗等效性时，乙酰甲胆碱激发研究（PC 主要变量）是标准支气管扩张研究的有用替代方法。
