Efficacy of Nebulized Glycopyrrolate on Lung Hyperinflation in Patients with COPD

Abstract

Introduction: Lung hyperinflation in chronic obstructive pulmonary disease (COPD) is associated with activity limitation, impaired cardiac output, and mortality. Several studies have demonstrated that long-acting muscarinic antagonists (LAMAs) delivered by dry powder inhalers can promote lung deflation; however, the potential of nebulized LAMAs on improving hyperinflation in COPD is currently unknown.

Methods: This single-center, randomized, double-blind, two-way crossover study (NCT04155047) evaluated the efficacy of a single dose of nebulized LAMA [glycopyrrolate (GLY) 25 µg] versus placebo in patients with COPD and lung hyperinflation. Patients with moderate-to-severe COPD and a residual volume (RV) ≥ 130% of predicted normal were included. The primary endpoint was changed from baseline in RV at 6 h post-treatment. Other endpoints included changes from baseline in spirometric and plethysmographic measures up to 6 h post-treatment.

Results: A total of 22 patients (mean pre-bronchodilator RV, 153.7% of predicted normal) were included. The primary objective of the study was not met; the placebo-adjusted least squares (LS) mean [95% confidence interval (CI) change from baseline in RV with GLY at 6 h post-treatment was - 0.323 l (- 0.711 to 0.066); p = 0.0987]. A post hoc evaluation of the primary analysis was conducted after excluding a single statistical outlier; substantial improvements in RV with GLY compared with placebo was observed after exclusion of this outlier [placebo-adjusted LS mean change from baseline (95% CI) in RV was - 0.446 l (- 0.741 to - 0.150)]. Improvements from baseline were also observed with GLY compared with placebo in spirometric and plethysmographic measures up to 6 h post-treatment. GLY was generally safe, and no new safety signals were detected.

Conclusions: This is the first study to evaluate the effect of nebulized GLY on lung deflation. Nebulized GLY resulted in marked improvements in RV up to 6 h post-treatment, compared with placebo. Improvements were also observed with GLY in spirometric and plethysmographic parameters of lung function.

Trial registration: ClinicalTrials.gov identifier, NCT04155047.

Keywords: Body plethysmography; COPD; Hyperinflation; Lung deflation; Nebulized glycopyrrolate; Residual volume.

© 2021. The Author(s).

Figures

Fig. 1

SUN101-402 double-blind, two-way crossover study design. GLY glycopyrrolate

Fig. 2

Patient disposition in the SUN101-402 phase IV study. Treatment sequence AB involved administration of GLY 25 µg in treatment period 1, and placebo in treatment period 2. Treatment sequence BA involved administration of placebo in treatment period 1, and GLY 25 µg in treatment period 2. AE adverse event, GLY glycopyrrolate

Fig. 3

Change from baseline in residual volume a with treatment time in the efficacy population, b at the primary endpoint in either the efficacy population or after exclusion of the outlier, and for individual patients treated with c GLY or d placebo. *p < 0.05; **p < 0.01 vs. placebo. CI confidence interval, GLY nebulized glycopyrrolate, LS least squares, RV residual volume

Fig. 4

Change from baseline in spirometric (a), plethysmographic (b) endpoints, specific airway resistance (c), and airways resistance (d) at 6-h post-treatment, in the efficacy population. *p < 0.05 vs. placebo. CI confidence interval, ERV expiratory reserve volume, FEV1 forced expiratory volume in 1 s, FRC functional residual capacity, FVC forced vital capacity, GLY glycopyrrolate, IC inspiratory capacity, l liter(s), LS least squares, Raw airway resistance, RV residual volume, sRaw specific airway resistance, TLC total lung capacity