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

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 (FEV₁ ≥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 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^® 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.