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The effect of glycopyrronium and indacaterol, as monotherapy and in combination, on the methacholine dose-response curve of mild asthmatics: a randomized three-way crossover study.
Respir Res. 2017 08 02; 18(1):146.RR

Abstract

BACKGROUND

Methacholine dose-response curves illustrate pharmacologic bronchoprotection against methacholine-induced airway hyperresponsiveness and can be used to quantitate changes in airway sensitivity (position), reactivity (slope), and maximal responsiveness following drug administration. Our objective was to determine the influence of single-dose glycopyrronium (long-acting muscarinic antagonist) and indacaterol (ultra-long acting β2 agonist), as monotherapy and in combination, on the methacholine dose-response curve of mild asthmatics and to compare these findings with a non-asthmatic control curve.

METHODS

This was a randomized, double blind, double dummy, three-way crossover study. For asthmatic participants (n = 14), each treatment arm included a baseline methacholine challenge, drug administration, and repeat methacholine challenges at 1, 24, and 48 h. Non-asthmatic control participants (n = 15) underwent a single methacholine challenge and did not receive any study treatment. Methacholine dose-response curves were graphed as the percent fall in forced expiratory volume in 1 s (FEV1) for each methacholine concentration administered. Best-fit curves were then generated. Differences in airway reactivity were calculated through linear regression. Changes in airway sensitivity were assessed as the shift in the provocative concentration of methacholine causing a 20% fall in FEV1.

RESULTS

Compared to baseline, all treatments significantly reduced airway sensitivity to methacholine at 1 h post-dose (indacaterol ~1.5 doubling concentrations; glycopyrronium ~5 doubling concentrations; combination ~5 doubling concentrations). Bronchoprotection at 24 and 48 h remained significant with glycopyrronium and combination therapy only. Airway reactivity was not influenced by indacaterol whereas glycopyrronium significantly reduced airway reactivity at all time-points (p = 0.003-0.027). The combination significantly decreased slope at 1 (p = 0.021) and 24 (p = 0.039) hours only. The non-asthmatic control and 1-h glycopyrronium curves are nearly identical. Only the non-asthmatic control and 1-h post-combination therapy curves appeared to generate a true response plateau (three data points within 5%), which occurred at a 14% fall in FEV1.

CONCLUSIONS

Methacholine dose-response curves differentiate the bronchoprotective mechanisms triggered by different classes of asthma medications. Assessment of bronchoprotection using methacholine dose-response curves may be useful during clinical development of respiratory medications when performing superiority, equivalence, or non-inferiority trials.

TRIAL REGISTRATION

clinicaltrials.gov (NCT02953041). Retrospectively registered on October 24th 2016.

Authors+Show Affiliations

Department of Physiology College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada.Department of Physiology College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada. Department of Medicine, Division of Respirology, Critical Care and Sleep Medicine, University of Saskatchewan, College of Medicine, 103 Hospital Drive 5th Floor, Saskatoon, SK, S7N 0W8, Canada.Department of Physiology College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada. don.cockcroft@usask.ca. Department of Medicine, Division of Respirology, Critical Care and Sleep Medicine, University of Saskatchewan, College of Medicine, 103 Hospital Drive 5th Floor, Saskatoon, SK, S7N 0W8, Canada. don.cockcroft@usask.ca.

Pub Type(s)

Comparative Study
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28768531

Citation

Blais, Christianne M., et al. "The Effect of Glycopyrronium and Indacaterol, as Monotherapy and in Combination, On the Methacholine Dose-response Curve of Mild Asthmatics: a Randomized Three-way Crossover Study." Respiratory Research, vol. 18, no. 1, 2017, p. 146.
Blais CM, Davis BE, Cockcroft DW. The effect of glycopyrronium and indacaterol, as monotherapy and in combination, on the methacholine dose-response curve of mild asthmatics: a randomized three-way crossover study. Respir Res. 2017;18(1):146.
Blais, C. M., Davis, B. E., & Cockcroft, D. W. (2017). The effect of glycopyrronium and indacaterol, as monotherapy and in combination, on the methacholine dose-response curve of mild asthmatics: a randomized three-way crossover study. Respiratory Research, 18(1), 146. https://doi.org/10.1186/s12931-017-0628-4
Blais CM, Davis BE, Cockcroft DW. The Effect of Glycopyrronium and Indacaterol, as Monotherapy and in Combination, On the Methacholine Dose-response Curve of Mild Asthmatics: a Randomized Three-way Crossover Study. Respir Res. 2017 08 2;18(1):146. PubMed PMID: 28768531.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The effect of glycopyrronium and indacaterol, as monotherapy and in combination, on the methacholine dose-response curve of mild asthmatics: a randomized three-way crossover study. AU - Blais,Christianne M, AU - Davis,Beth E, AU - Cockcroft,Donald W, Y1 - 2017/08/02/ PY - 2017/04/12/received PY - 2017/07/24/accepted PY - 2017/8/4/entrez PY - 2017/8/5/pubmed PY - 2018/5/8/medline KW - Combination therapy KW - Long-acting muscarinic antagonist KW - Ultra-long acting β2 agonist SP - 146 EP - 146 JF - Respiratory research JO - Respir. Res. VL - 18 IS - 1 N2 - BACKGROUND: Methacholine dose-response curves illustrate pharmacologic bronchoprotection against methacholine-induced airway hyperresponsiveness and can be used to quantitate changes in airway sensitivity (position), reactivity (slope), and maximal responsiveness following drug administration. Our objective was to determine the influence of single-dose glycopyrronium (long-acting muscarinic antagonist) and indacaterol (ultra-long acting β2 agonist), as monotherapy and in combination, on the methacholine dose-response curve of mild asthmatics and to compare these findings with a non-asthmatic control curve. METHODS: This was a randomized, double blind, double dummy, three-way crossover study. For asthmatic participants (n = 14), each treatment arm included a baseline methacholine challenge, drug administration, and repeat methacholine challenges at 1, 24, and 48 h. Non-asthmatic control participants (n = 15) underwent a single methacholine challenge and did not receive any study treatment. Methacholine dose-response curves were graphed as the percent fall in forced expiratory volume in 1 s (FEV1) for each methacholine concentration administered. Best-fit curves were then generated. Differences in airway reactivity were calculated through linear regression. Changes in airway sensitivity were assessed as the shift in the provocative concentration of methacholine causing a 20% fall in FEV1. RESULTS: Compared to baseline, all treatments significantly reduced airway sensitivity to methacholine at 1 h post-dose (indacaterol ~1.5 doubling concentrations; glycopyrronium ~5 doubling concentrations; combination ~5 doubling concentrations). Bronchoprotection at 24 and 48 h remained significant with glycopyrronium and combination therapy only. Airway reactivity was not influenced by indacaterol whereas glycopyrronium significantly reduced airway reactivity at all time-points (p = 0.003-0.027). The combination significantly decreased slope at 1 (p = 0.021) and 24 (p = 0.039) hours only. The non-asthmatic control and 1-h glycopyrronium curves are nearly identical. Only the non-asthmatic control and 1-h post-combination therapy curves appeared to generate a true response plateau (three data points within 5%), which occurred at a 14% fall in FEV1. CONCLUSIONS: Methacholine dose-response curves differentiate the bronchoprotective mechanisms triggered by different classes of asthma medications. Assessment of bronchoprotection using methacholine dose-response curves may be useful during clinical development of respiratory medications when performing superiority, equivalence, or non-inferiority trials. TRIAL REGISTRATION: clinicaltrials.gov (NCT02953041). Retrospectively registered on October 24th 2016. SN - 1465-993X UR - https://www.unboundmedicine.com/medline/citation/28768531/The_effect_of_glycopyrronium_and_indacaterol_as_monotherapy_and_in_combination_on_the_methacholine_dose_response_curve_of_mild_asthmatics:_a_randomized_three_way_crossover_study_ L2 - https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-017-0628-4 DB - PRIME DP - Unbound Medicine ER -