Effect of indacaterol/glycopyrronium on ventilation and perfusion in COPD: a randomized trial

Abstract

Rationale: The 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.

Objectives: The 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.

Methods: This 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 results: Of 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 (DL_CO) (+ 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.

Conclusions: IND/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).

Keywords: Chronic obstructive pulmonary disease; Hyperpolarized 3He gas magnetic resonance imaging; Indacaterol/glycopyrronium; V/Q index; Ventilation volume and perfusion volume; Ventilation/perfusion ratio.

Fig. 1

A Study design. This was a randomized, double-blind, placebo-controlled, two-period crossover study of approximately 8 weeks and consisted of 7 periods. B Study disposition. A total of 122 patients were screened, of whom 31 were randomized to one of two treatment sequences. Two patients did not complete both treatment period I and II due to SAEs (one atrial fibrillation and one femoral neck fracture). Screen failures relating to inclusion/exclusion criteria primarily included clinically significant electrocardiogram abnormalities, abnormal computed tomography scan, ineligible pulmonary function test results, or COPD exacerbation. IND/GLY indacaterol/glycopyrronium, MRI magnetic resonance imaging, PD pharmacodynamics, SAE serious adverse event

Fig. 2

Distribution of ³He within the lung by MRI: quantitative percentage ventilated lung volume assessment for sample Patient 1 (additional images and video are available in Additional file 1: Fig. S1). Shown are example ³He MRI image segmentations of the lungs acquired during the placebo and treatment periods from a patient demonstrating the effect of IND/GLY compared with placebo. Upper panels: Source images showing the distribution of hyperpolarized ³He gas within the lung. 2D coronal slices from back to front (upper left to lower right) were acquired for volumetric assessment after 7 days of placebo and IND/GLY treatment in the respective treatment periods. Center panels: Image segmentations with ventilated lung shown in blue and unventilated lung shown in brown (2D slices). Lower panels: 3D volume rendering of the image segmentations. IND/GLY indacaterol/glycopyrronium, MRI magnetic resonance imaging

Fig. 3

Effect of indacaterol/glycopyrronium treatment on measurements of lung ventilation and perfusion—PD set. Absolute difference in MRI-derived A % VV, B pulmonary perfusion (mL/100 g_{lung tissue}/min) and C V/Q after 1 week of treatment compared with placebo in the PD analysis set. Parameters were calculated using a mixed-effects model including crossover sequence, period, and treatment as fixed factors, and patient as a random effect. Data are presented as LS mean treatment differences ± 90% CI compared with placebo. CI confidence interval, LS least squares, PD pharmacodynamics, VV ventilated lung volume, V/Q ventilation volume/perfusion volume

Fig. 4

Effect of IND/GLY treatment on lung function—PD set. Analysis of IND/GLY treatment on A FEV₁ and B FEF_25–75% over time. Measurements were obtained 0.75 and 0.25 h pre-dose, and 0.25, 1 and 2 h post-dose on Day 1, and 0.75 and 0.25 h pre-dose and 0.25, 1 and 2 h post-dose on Day 8. C The effects of 8 days of IND/GLY versus placebo treatment on residual volume and inspiratory capacity are shown. Data were analyzed using a mixed-effects model including crossover sequence, period, treatment, and time as fixed factors, and patients as a random effect. *P < 0.0001. FEV₁ forced expiratory volume in 1 s, FEF forced expiratory flow, IND/GLY indacaterol/glycopyrronium, SE standard error