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

Background/Objective: To demonstrate therapeutic equivalence of terbutaline via two different Turbuhaler((R)) 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 (FEV1 >= 80% predicted) were randomised to 0.5 or 1.5 mg terbutaline via either Turbuhaler((R)) M2 or Turbuhaler((R)) M3 followed by a methacholine challenge test. The primary outcome variable was the concentration of methacholine causing a 20% drop in FEV1 (PC20). Patients had a PC20 methacholine <8 mg/mL that was reproducible after 2 weeks, and a stable baseline FEV1 at all visits (90-110% of enrolment value).Results: 60 patients (mean age 31.1 years [range:18-64]; mean FEV1 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((R)) 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((R)) 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. (c) 2017 Elsevier Ltd. All rights reserved.