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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

Bjermer, Leif LU ; Gauvreau, Gail M; Postma, Dirkje S; O'Byrne, Paul M.; van den Berge, Maarten; Boulet, Louis Philippe; Beckman, Ola; Persson, Tore; Román, Jonas and Carlholm, Marie, et al. (2017) In Pulmonary Pharmacology and Therapeutics 44. p.1-6
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 (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... (More)

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.

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publication status
published
subject
keywords
Asthma, Equivalence, Methacholine challenge, Terbutaline, Turbuhaler
in
Pulmonary Pharmacology and Therapeutics
volume
44
pages
6 pages
publisher
Elsevier
external identifiers
  • scopus:85014487285
ISSN
1094-5539
DOI
10.1016/j.pupt.2017.02.004
language
English
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no
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d91eb039-3df1-42c5-a437-183972e5a186
date added to LUP
2017-03-16 10:53:11
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2018-01-14 04:31:02
@article{d91eb039-3df1-42c5-a437-183972e5a186,
  abstract     = {<p>Background/Objective To demonstrate therapeutic equivalence of terbutaline via two different Turbuhaler<sup>®</sup> 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<sub>1</sub> ≥80% predicted) were randomised to 0.5 or 1.5 mg terbutaline via either Turbuhaler<sup>®</sup> M2 or Turbuhaler<sup>®</sup> M3 followed by a methacholine challenge test. The primary outcome variable was the concentration of methacholine causing a 20% drop in FEV<sub>1</sub> (PC<sub>20</sub>). Patients had a PC<sub>20</sub> methacholine &lt;8 mg/mL that was reproducible after 2 weeks, and a stable baseline FEV<sub>1</sub> at all visits (90–110% of enrolment value). Results 60 patients (mean age 31.1 years [range:18–64]; mean FEV<sub>1</sub> 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<sup>®</sup> M3 and M2, respectively (both p &lt; 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<sup>®</sup> 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.</p>},
  author       = {Bjermer, Leif and Gauvreau, Gail M and Postma, Dirkje S and O'Byrne, Paul M. and van den Berge, Maarten and Boulet, Louis Philippe and Beckman, Ola and Persson, Tore and Román, Jonas and Carlholm, Marie and Schützer, Kajs Marie and Eckerwall, Göran},
  issn         = {1094-5539},
  keyword      = {Asthma,Equivalence,Methacholine challenge,Terbutaline,Turbuhaler},
  language     = {eng},
  month        = {06},
  pages        = {1--6},
  publisher    = {Elsevier},
  series       = {Pulmonary Pharmacology and Therapeutics},
  title        = {Methacholine challenge tests to demonstrate therapeutic equivalence of terbutaline sulfate via different Turbuhaler<sup>®</sup> devices in patients with mild to moderate asthma : Appraisal of a four-way crossover design},
  url          = {http://dx.doi.org/10.1016/j.pupt.2017.02.004},
  volume       = {44},
  year         = {2017},
}