Functional respiratory imaging assessment of budesonide/glycopyrrolate/formoterol fumarate and glycopyrrolate/formoterol fumarate metered dose inhalers in patients with COPD: the value of inhaled corticosteroids

Maarten van den Berge, Jan De Backer, Cedric Van Holsbeke, Wilfried De Backer, Roopa Trivedi, Martin Jenkins, Paul Dorinsky, Magnus Aurivillius, Maarten van den Berge, Jan De Backer, Cedric Van Holsbeke, Wilfried De Backer, Roopa Trivedi, Martin Jenkins, Paul Dorinsky, Magnus Aurivillius

Abstract

Background: For patients with chronic obstructive pulmonary disease (COPD), greater improvements in lung function have been demonstrated for triple versus dual inhaled therapies in traditional spirometry studies. This study was the first to use functional respiratory imaging (FRI), known for increased sensitivity to airway changes versus spirometry, to assess the effect of the inhaled corticosteroid (ICS) component (budesonide) on lung function in patients with moderate-to-severe COPD and a blood eosinophil count > 150 cells/mm3.

Methods: Patients in this Phase IIIb (NCT03836677), randomized, double-blind, crossover study received twice-daily budesonide/glycopyrrolate/formoterol fumarate (BGF) 320/18/9.6 μg fixed-dose triple therapy and glycopyrrolate/formoterol fumarate (GFF) 18/9.6 μg fixed-dose dual therapy over 4 weeks, each delivered via a single metered dose Aerosphere inhaler. Primary endpoints were the improvements from baseline for each treatment in specific (i.e. corrected for lobar volume) image-based airway volume (siVaw) and resistance (siRaw) measured via FRI taken at total lung capacity (Day 29). Secondary outcomes included spirometry and body plethysmography. Adverse events were monitored throughout the study.

Results: A total of 23 patients were randomized and included in the intent-to-treat analysis (mean age 64.9 years, 78.3% males, 43.5% current smokers, mean predicted post-bronchodilator forced expiratory volume in 1 s [FEV1] 63.6%). BGF and GFF both statistically significantly increased siVaw from baseline at Day 29 (geometric mean ratio [GM], 95% confidence interval [CI]: 1.72 [1.38, 2.13] and 1.53 [1.28, 1.83], respectively, both p < 0.0001), with a greater increase observed for BGF versus GFF (GM, 95% CI 1.09 [1.03, 1.16], p = 0.0061). Statistically significant reductions in siRaw were also observed with both BGF and GFF (GM, 95% CI 0.50 [0.39, 0.63] and 0.52 [0.40, 0.67], respectively, both p < 0.0001). Additionally, significant improvements from baseline in post-dose FEV1 were observed with BGF and GFF (mean 346 mL, p = 0.0003 and 273 mL, p = 0.0004, respectively). Safety findings were consistent with the known profiles of BGF and GFF.

Conclusions: As observed using FRI, triple therapy with BGF resulted in greater increases in airway volume, and reductions in airway resistance versus long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) dual therapy with GFF, reflecting the ICS component's contribution in patients with moderate-to-severe COPD.

Trial registration: ClinicalTrials.gov, NCT03836677. Registered 11 February 2019, https://ichgcp.net/clinical-trials-registry/NCT03836677.

Keywords: Budesonide; COPD; Formoterol fumarate; Functional respiratory imaging; Glycopyrrolate; Triple therapy.

Conflict of interest statement

MvdB reports research grants paid to his institution from AstraZeneca, Chiesi, GlaxoSmithKline, and TEVA Pharma. JDB is the Chief Executive Officer and founder of FLUIDDA and holds shares in the company. CVH is an employee of FLUIDDA. WDB has no real or perceived conflicts of interest that relate to this manuscript. His department has received grants from AstraZeneca, Chiesi, and GlaxoSmithKline. RT, MJ, PD, and MA are employees of AstraZeneca and hold stock and/or stock options in the company.

Figures

Fig. 1
Fig. 1
Study design. BGF budesonide/glycopyrrolate/formoterol fumarate, BID twice-daily, GFF glycopyrrolate/formoterol fumarate
Fig. 2
Fig. 2
Geometric mean ratio to baseline: a siVaw and b siRaw at Day 29. ****p ≤ 0.0001, **p < 0.01. Error bars show 95% CI. BGF budesonide/glycopyrrolate/formoterol fumarate, CI confidence interval, GFF glycopyrrolate/formoterol fumarate, siRaw specific image-based airway resistance, siVaw specific image-based airway volume
Fig. 3
Fig. 3
Percent change from baseline to Day 29 in a siVaw and b siRaw. Images show one representative patient’s data for siVaw (mL/L) and siRaw (kPa·s) percent change from baseline to Day 29 at TLC. Green coloring represents a an increase in airways volume and b a decrease in airway resistance. Orange coloring indicates the converse. BGF budesonide/glycopyrrolate/formoterol fumarate, GFF glycopyrrolate/formoterol fumarate, siRaw specific image-based airway resistance, siVaw specific image-based airway volume, TLC total lung capacity

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