title: 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.
abstract: To demonstrate therapeutic equivalence of terbutaline via two different Turbuhaler®devices by evaluating its protective effect against methacholine-induced bronchoconstriction in stable asthma.
  
  
  
  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 PC20methacholine <8 mg/mL that was reproducible after 2 weeks, and a stable baseline FEV1at all visits (90-110% of enrolment value).
  
  
  
  60 patients (mean age 31.1 years [range:18-64]; mean FEV192.1% 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.
  
  
  
  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.
  
  
  
  2014-001457-16. CLINICALTRIALS.
  
  
  
  NCT02322788.
authors.affiliation: Department of Respiratory Medicine & Allergology, Skåne University Hospital, Lund, Sweden. Electronic address: leif.bjermer@med.lu.se.
authors.forename: Leif
authors.initials: L
authors.lastname: Bjermer
authors.affiliation: Michael G DeGroote School of Medicine, McMaster University, Hamilton, Canada.
authors.forename: Gail M
authors.initials: GM
authors.lastname: Gauvreau
authors.affiliation: University of Groningen, Department of Pulmonary Diseases, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: Michael G DeGroote School of Medicine, McMaster University, Hamilton, Canada.
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Byrne
authors.affiliation: University of Groningen, Department of Pulmonary Diseases, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: van den Berge
authors.affiliation: Quebec Heart and Lung Institute, Laval University, Quebec, Canada.
authors.forename: Louis-Philippe
authors.initials: LP
authors.lastname: Boulet
authors.affiliation: AstraZeneca R&D, Gothenburg, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Beckman
authors.affiliation: AstraZeneca R&D, Gothenburg, Sweden.
authors.forename: Tore
authors.initials: T
authors.lastname: Persson
authors.affiliation: AstraZeneca R&D, Gothenburg, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Román
authors.affiliation: AstraZeneca R&D, Gothenburg, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Carlholm
authors.affiliation: AstraZeneca R&D, Gothenburg, Sweden.
authors.forename: Kajs-Marie
authors.initials: KM
authors.lastname: Schützer
authors.affiliation: AstraZeneca R&D, Gothenburg, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Eckerwall
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000188:drug therapy*; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000494:pharmacology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004867:Equipment Design; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D016210:Methacholine Chloride / Q000008:administration & dosage / Q000494:pharmacology; D008875:Middle Aged; D009330:Nebulizers and Vaporizers; D013726:Terbutaline / Q000008:administration & dosage* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D016210:Methacholine Chloride; D013726:Terbutaline
keywords: Asthma; Equivalence; Methacholine challenge; Terbutaline; Turbuhaler(®)