Relieving exertional dyspnea during the 3-min constant speed shuttle test in patients with COPD with indacaterol/glycopyrronium versus tiotropium: the RED trial

Jessie Beaulieu, Dennis Jensen, Denis E O'Donnell, Cynthia Brouillard, Lauren Tracey, Sandra Vincent, Éric Nadreau, Emmanuelle Bernard, Sarah Bernard, François Maltais, Jessie Beaulieu, Dennis Jensen, Denis E O'Donnell, Cynthia Brouillard, Lauren Tracey, Sandra Vincent, Éric Nadreau, Emmanuelle Bernard, Sarah Bernard, François Maltais

Abstract

Background: Exertional dyspnea is a cardinal feature of chronic obstructive pulmonary disease (COPD) and a major cause of activity limitation. Although dual bronchodilation is more effective than bronchodilator monotherapy at improving resting pulmonary function, it is unclear to which extent this translates into superior relief of exertional dyspnea.

Methods: We conducted a randomized controlled, double-blind, cross-over trial comparing indacaterol 110 µg/glycopyrronium 50 µg once daily (OD) with tiotropium 50 µg OD in patients with moderate to severe COPD and resting hyperinflation (functional residual capacity >120% of predicted value). The primary outcome was Borg dyspnea score at the end of a 3-min constant speed shuttle test after 3 weeks of treatment. Secondary outcomes included changes in Borg dyspnea score after the first dose of study medication, expiratory flows and lung volumes. Statistical analysis was conducted using a cross-over analysis of variance model with repeated measurements.

Results: A total of 50 patients with COPD and a mean forced expiratory volume in 1 s of 54 ± 11% (mean ± SEM) predicted participated in the cross-over phase of the trial. Compared with baseline, there was a decrease in dyspnea after the first dose of medication with indacaterol/glycopyrronium [mean -1.00, 95% confidence interval (CI) -1.49 to -0.52] but not with tiotropium alone (mean -0.36, 95% CI -0.81 to 0.08). The reduction in dyspnea after the first dose was statistically significant between the two treatments (mean difference of -0.64, 95% CI -1.11 to -0.17). Despite indacaterol/glycopyrronium providing further bronchodilation and lung deflation throughout the trial, the reduction in dyspnea was not sustained at 3 weeks of treatment (mean between-treatment difference at 3 weeks of 0.09, 95% CI -0.44 to 0.61).

Conclusion: In comparison with bronchodilator monotherapy, indacaterol/glycopyrronium provided greater immediate exertional dyspnea relief, although this difference was not sustained after 3 weeks of therapy despite evidence of further bronchodilation and lung deflation.The reviews of this paper are available via the supplemental material section.

Keywords: COPD; COPD pharmacology; bronchodilation; dyspnea; exercise.

Conflict of interest statement

Conflict of interest statement: DJ reports grants from Boehringer Ingelheim and Novartis during the conduct of this study; grants and personal fees from AstraZeneca, and grants from Tilray outside the submitted work. DEO reports grants from AstraZeneca and Boehringer Ingelheim during the conduct of this study; and personal fees for serving on speaker bureaus, consultation panels and advisory boards from Almirall, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis and Pfizer outside the submitted work. FM reports grants from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Sanofi, and Novartis during the conduct of this study, and personal fees for serving on speaker bureaus and consultation panels from Boehringer Ingelheim, Grifols and Novartis outside the submitted work.

Figures

Figure 1.
Figure 1.
Study design. CSST, constant speed shuttle test; ICF, informed consent form; ISWT, incremental shuttle walking test; PFT, pulmonary function tests.
Figure 2.
Figure 2.
Flow chart. COPD, chronic obstructive pulmonary disease; ICF, informed consent form; SAE, severe adverse event.
Figure 3.
Figure 3.
Borg dyspnea scores at the end of the 3-min constant speed shuttle test after 3 weeks of treatment (a), and after the first dose of study medication (b). Data are mean ± SEM. Numbers over the brackets indicate mean between-treatment differences. *Indicates statistical significance (p < 0.05). Ind/Gly, indacaterol/glycopyrronium; Tio, tiotropium.
Figure 4.
Figure 4.
Changes from baseline in slow vital capacity (SVC), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), inspiratory capacity (IC), functional residual capacity (FRC) and residual volume (RV) after the first dose ((a) and (c)) or after 3 weeks of therapy ((b) and (d)) of either indacaterol/glycopyrronium or tiotropium alone. Results are expressed in L ((a) and (b)) and in percentage change from baseline ((c) and (d)). *Indicates statistical significance (p < 0.05).
Figure 5.
Figure 5.
Breathing frequency (Bf), tidal volume (VT) and minute ventilation (VE) during the 3-min constant speed shuttle test after the first dose of study medication ((a), (c), and (e)) and after 3 weeks of treatment ((b), (d) and (f)). Data are mean ± SEM. *Indicates statistical significance (p < 0.05).

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Source: PubMed

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