The use of methacholine provocation when assessing therapeutic equivalence between two inhalers in asthmatic patients

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 FEV1 (PC20). 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 PC20 (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 (PC20 primary variable) is a useful alternative to the standard bronchodilation study when assessing therapeutic equivalence of a bronchodilator.