Abstract
RationaleThe long-acting β2-agonist/long-acting muscarinic antagonist combination indacaterol/glycopyrronium (IND/GLY) elicits bronchodilation, improves symptoms, and reduces exacerbations in COPD. Magnetic resonance imaging (MRI) of the lung with hyperpolarized gas and gadolinium contrast enhancement enables assessment of whole lung functional responses to IND/GLY.ObjectivesThe primary objective was assessment of effect of IND/GLY on global ventilated lung volume (%VV) versus placebo in COPD. Lung function, regional ventilation and perfusion in response to IND/GLY were also measured.MethodsThis double-blind, randomized, placebo-controlled, crossover study assessed %VV and pulmonary perfusion in patients with moderate-to-severe COPD after 8 days of once-daily IND/GLY treatment (110/50 µg) followed by 8 days of placebo, or vice versa, using inhaled hyperpolarized 3He gas and gadolinium contrast-enhanced MRI, respectively. Lung function measures including spirometry were performed for each treatment after 8 days.Measurements and main resultsOf 31 patients randomized, 29 completed both treatment periods. IND/GLY increased global %VV versus placebo (61.73% vs. 56.73%, respectively, least squares means treatment difference: 5.00% [90% CI 1.40 to 8.60]; P = 0.025). IND/GLY improved whole lung index of ventilation volume to perfusion volume (V/Q) ratio versus placebo; 94% (90% CI 83 to 105) versus 86% (90% CI 75 to 97; P = 0.047), respectively. IND/GLY showed a trend to improve diffusing capacity for carbon monoxide (DLCO) (+ 0.66 mL/min/mmHg; P = 0.082). By Day 8, forced expiratory volume in 1 s (FEV1) was increased by 0.32 L versus placebo (90% CI 0.26 to 0.38; P < 0.0001), substantiating earlier findings and providing evidence of assay sensitivity for this trial.ConclusionsIND/GLY improved lung ventilation assessed by 3He MRI after 1 week of treatment. This observation may provide mechanistic support for the symptomatic clinical benefit shown with IND/GLY in COPD.Clinical trial registered with www.clinicaltrials.gov (NCT02634983).
Highlights
In evaluating pharmacodynamic (PD) treatment effects, spirometry has limited sensitivity and cannot detect regional airway responses to elucidate therapeutic mechanisms [1]
A recent publication from the CLAIM study in chronic obstructive pulmonary disease (COPD) patients selected for hyperinflation described improved pulmonary microvascular blood flow and regional ventilation following 14-day treatment with indacaterol/glycopyrronium, as measured by dynamic gadolinium-enhanced 1H Magnetic resonance imaging (MRI) and phase-resolved functional lung (PREFUL)-MRI, respectively [7]
The mean (SD) predicted post-bronchodilator FEV1 of the participants at screening was 53.1% (11.68), and the mean (SD) % lung emphysema measured by High resolution computed tomography (HRCT) was 10.14% (7.35)
Summary
In evaluating pharmacodynamic (PD) treatment effects, spirometry has limited sensitivity and cannot detect regional airway responses to elucidate therapeutic mechanisms [1]. Singh et al Respiratory Research (2022) 23:26 can non-invasively measure both regional lung ventilation and perfusion, which cannot be obtained by traditional lung function tests [2]. This is relevant in the evaluation of novel therapies for chronic obstructive pulmonary disease (COPD), a complex, progressive lung condition classically associated with gas exchange impairment [3]. The fixed-dose combination of long-acting β2-agonist/long-acting muscarinic antagonist (LABA/LAMA) indacaterol/glycopyrronium (IND/GLY) elicits bronchodilation, improves symptoms, and prevents exacerbations in COPD [5, 6], the effects of long-acting bronchodilators on global ventilation and regional ventilation heterogeneity has not been fully elucidated. A recent publication from the CLAIM study in COPD patients selected for hyperinflation described improved pulmonary microvascular blood flow and regional ventilation following 14-day treatment with indacaterol/glycopyrronium, as measured by dynamic gadolinium-enhanced 1H MRI and phase-resolved functional lung (PREFUL)-MRI, respectively [7]
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