A randomized study using functional respiratory imaging to characterize bronchodilator effects of glycopyrrolate/formoterol fumarate delivered by a metered dose inhaler using co-suspension delivery technology in patients with COPD

Wilfried De Backer, Jan De Backer, Wim Vos, Ilse Verlinden, Cedric Van Holsbeke, Johan Clukers, Bita Hajian, Shahid Siddiqui, Martin Jenkins, Colin Reisner, Ubaldo J Martin, Wilfried De Backer, Jan De Backer, Wim Vos, Ilse Verlinden, Cedric Van Holsbeke, Johan Clukers, Bita Hajian, Shahid Siddiqui, Martin Jenkins, Colin Reisner, Ubaldo J Martin

Abstract

Background: Functional respiratory imaging (FRI) uses high-resolution computed tomography (HRCT) scans to assess changes in airway volume and resistance.

Patients and methods: In this randomized, double-blind, 2-week, crossover, Phase IIIB study, patients with moderate-to-severe COPD received twice-daily glycopyrrolate/formoterol fumarate delivered by a metered dose inhaler (GFF MDI, 18/9.6 μg) and placebo MDI, formulated using innovative co-suspension delivery technology. Co-primary endpoints included the following: specific image-based airway volume (siVaw) and specific image-based airway resistance (siRaw) at Day 15, measured using FRI. Secondary and other endpoints included the following: change from baseline in post-dose forced expiratory volume in 1 second (FEV1) and inspiratory capacity (IC; spirometry) and ratio to baseline in post-dose functional residual capacity (FRC) and residual volume (RV; body plethysmography).

Results: Twenty patients (46-78 years of age) were randomized and treated; of whom 19 completed the study. GFF MDI treatment increased siVaw by 75% and reduced siRaw by 71% vs placebo MDI (both P<0.0001). Image-based airway volume (iVaw) and image-based airway resistance (iRaw), without adjusting for lobe volume, demonstrated corresponding findings to the co-primary endpoint, as lobe volumes did not change with either treatment. Approximately 48% of the delivered dose of glycopyrronium and formoterol fumarate was estimated to be deposited in the lungs. Compared with placebo, GFF MDI treatment improved post-dose FEV1 and IC (443 mL and 454 mL, respectively; both P<0.001) and reduced FRC and RV (13% and 22%, respectively; both P<0.0001). There were no significant safety findings.

Conclusion: GFF MDI demonstrated significant, clinically meaningful benefits on FRI-based airway volume and resistance in patients with moderate-to-severe COPD. Benefits were associated with improvements in FEV1, IC, and hyperinflation.

Clinical trial registration: ClinicalTrials.gov: NCT02643082.

Keywords: GFF MDI; LAMA/LABA; airway resistance; airway volume; hyperinflation; inspiratory capacity.

Conflict of interest statement

Disclosure WDB, JC, and BH have no real or perceived conflicts of interest that relate to this manuscript. WDB’s department has received grants from AstraZeneca, Chiesi, and GlaxoSmithKline. JDB is the Chief Executive Officer and founder of FLUIDDA and holds shares in the company. WV is an employee of FLUIDDA and holds shares in the company. IV and CVH are employees of FLUIDDA. SS, MJ, and UJM are employees of AstraZeneca. CR is the Chief Executive Officer of Pearl – a member of the AstraZeneca Group – and an employee of AstraZeneca. All Pearl and AstraZeneca employees own AstraZeneca stocks. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Patient disposition diagram. Abbreviations: GFF, glycopyrrolate/formoterol fumarate; h, hours; MDI, metered dose inhaler.
Figure 2
Figure 2
Study design. Abbreviations: GFF, glycopyrrolate/formoterol fumarate; TP, treatment period; MDI, metered dose inhaler; HRCT, high-resolution computed tomography.
Figure 3
Figure 3
Functional respiratory imaging co-primary endpoint: siVaw at TLC on Day 15 (mL/L; intent-to-treat population). Note: Images from one representative patient. Abbreviations: GFF, glycopyrrolate/formoterol fumarate; LSM, least squares mean; MDI, metered dose inhaler; siVaw, specific image-based airway volume; TLC, total lung capacity.
Figure 4
Figure 4
Functional respiratory imaging co-primary endpoint: siRaw at TLC on Day 15 (kPa⋅s; intent-to-treat population). Note: Images from one representative patient. Abbreviations: GFF, glycopyrrolate/formoterol fumarate; LSM, least squares mean; MDI, metered dose inhaler; siRaw, specific image-based airway resistance; TLC, total lung capacity.
Figure 5
Figure 5
Spirometry endpoints on Day 15: change from baseline in post-dose FEV1, IC, and FVC (intent-to-treat population). Note: Error bars and parentheses represent 95% CIs. Abbreviations: FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GFF, glycopyrrolate/formoterol fumarate; IC, inspiratory capacity; LSM, least squares mean; MDI, metered dose inhaler.
Figure 6
Figure 6
Scatter plot comparison of change from baseline in siVaw (A) and siRaw (B) with change from baseline in FEV1 at Day 15. Abbreviations: FEV1, forced expiratory volume in 1 second; GFF, glycopyrrolate/formoterol fumarate; MDI, metered dose inhaler; siRaw, specific image-based airway resistance; siVaw, specific image-based airway volume.
Figure 7
Figure 7
Body plethysmography endpoints on Day 15: ratio to baseline in post-dose FRC, RV, and TLC (intent-to-treat population). Note: Error bars and parentheses represent 95% CIs. Abbreviations: FRC, functional residual capacity; GFF, glycopyrrolate/formoterol fumarate; LSM, least squares mean; MDI, metered dose inhaler; RV, residual volume; TLC, total lung capacity.

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