通过不同都保装置对硫酸特布他林在轻至中度哮喘患者中进行治疗等效性的乙酰甲胆碱激发试验：四交叉设计的评估

Methacholine challenge tests to demonstrate therapeutic equivalence of terbutaline sulfate via different Turbuhaler devices in patients with mild to moderate asthma: Appraisal of a four-way crossover design.

作者信息

Bjermer Leif, Gauvreau Gail M, Postma Dirkje S, O'Byrne Paul M, van den Berge Maarten, Boulet Louis-Philippe, Beckman Ola, Persson Tore, Román Jonas, Carlholm Marie, Schützer Kajs-Marie, Eckerwall Göran

机构信息

Department of Respiratory Medicine & Allergology, Skåne University Hospital, Lund, Sweden.

Michael G DeGroote School of Medicine, McMaster University, Hamilton, Canada.

出版信息

Pulm Pharmacol Ther. 2017 Jun;44:1-6. doi: 10.1016/j.pupt.2017.02.004. Epub 2017 Feb 20.

DOI:10.1016/j.pupt.2017.02.004

PMID:28232118

Abstract

BACKGROUND/OBJECTIVE: To demonstrate therapeutic equivalence of terbutaline via two different Turbuhaler devices by evaluating its protective effect against methacholine-induced bronchoconstriction in stable asthma.

METHODS

In this double-blind, double-dummy, multicentre, single-dose, 4-way crossover study, patients with stable mild-to-moderate asthma (FEV ≥80% predicted) were randomised to 0.5 or 1.5 mg terbutaline via either Turbuhaler M2 or Turbuhaler M3 followed by a methacholine challenge test. The primary outcome variable was the concentration of methacholine causing a 20% drop in FEV (PC). Patients had a PC methacholine <8 mg/mL that was reproducible after 2 weeks, and a stable baseline FEV at all visits (90-110% of enrolment value).

RESULTS

60 patients (mean age 31.1 years [range:18-64]; mean FEV 92.1% predicted normal [78.4-120.6%]) were randomised to treatment; all completed the study. There was a clear dose-response for both devices. The within-device ratios (1.5 mg:0.5 mg) were 1.79 and 1.87 for Turbuhaler M3 and M2, respectively (both p < 0.001). The between-device ratios (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. Both confidence intervals lie inside the interval 0.67-1.50, which was the pre-specified condition for equivalent effect.

CONCLUSIONS

Bronchoprotection using a standardised methacholine challenge model proved to be an effective design to elucidate therapeutic equivalence between devices in patients with mild-to-moderate asthma. The findings indicate that patients may switch from one type of Turbuhaler to the other without adjustment of therapy. Moreover, they show the robustness and utility of this study design and its suitability for investigating therapeutic equivalence.

EUDRACT NUMBER

2014-001457-16. CLINICALTRIALS.

GOV IDENTIFIER

NCT02322788.

摘要

背景/目的：通过评估特布他林对稳定期哮喘患者乙酰甲胆碱诱发的支气管收缩的保护作用，来证明两种不同都保装置吸入特布他林的治疗等效性。

方法

在这项双盲、双模拟、多中心、单剂量、4交叉试验研究中，将稳定期轻至中度哮喘患者（FEV≥预计值的80%）随机分为两组，分别通过都保M2或都保M3吸入0.5或1.5mg特布他林，随后进行乙酰甲胆碱激发试验。主要结局变量是使FEV下降20%的乙酰甲胆碱浓度（PC）。患者的乙酰甲胆碱PC<8mg/mL，且在2周后可重复，并且在所有访视时基线FEV稳定（为入组值的90%-110%）。

结果

60例患者（平均年龄31.1岁[范围：18-64岁]；平均FEV为预计正常值的92.1%[78.4%-120.6%]）被随机分配接受治疗；所有患者均完成了研究。两种装置均有明确的剂量反应。都保M3和都保M2的装置内比值（1.5mg:0.5mg）分别为1.79和1.87（均p<0.001）。0.5mg时装置间比值（M3:M2）为0.92（95%CI：0.75-1.13），1.5mg时为0.88（95%CI ：0.72-1.08）。两个置信区间均落在0.67-1.50区间内，这是预先设定的等效效应条件。