A Randomized, Double-Blind, Double-Dummy Study of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Relative to Umeclidinium/Vilanterol Dry Powder Inhaler in COPD
Glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), formulated using co-suspension delivery technology, is the only approved fixed-dose combination long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) delivered via MDI. Direct comparisons of GFF MDI versus other LAMA/LABAs have not previously been performed. We assessed the efficacy and safety of GFF MDI relative to umeclidinium/vilanterol dry powder inhaler (UV DPI) in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD).
In this phase IIIb randomized, double-blind, double-dummy, multicenter, 24-week study, patients received GFF MDI 18/9.6 μg (equivalent to glycopyrronium/formoterol fumarate dihydrate 14.4/10 μg; two inhalations per dose, twice-daily; n = 559) or UV DPI 62.5/25 μg (one inhalation, once-daily; n = 560). Primary endpoints were change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) and peak change from baseline in FEV1 within 2 h post-dose, both over 24 weeks. Additional lung function, symptom and safety endpoints were also assessed.
For the primary endpoints, GFF MDI was non-inferior to UV DPI (using a margin of − 50 mL) for peak FEV1 (least squares mean [LSM] difference − 3.4 mL, 97.5% confidence interval [CI] − 32.8, 25.9) but not for trough FEV1 (LSM difference − 87.2 mL; − 117.0, − 57.4). GFF MDI was nominally superior to UV DPI for onset of action (p < 0.0001) and was nominally non-inferior to UV DPI for all symptom endpoints (Transition Dyspnea Index focal score, Early Morning/Night-Time Symptoms COPD instrument scores, and COPD Assessment Test score). Exacerbation and safety findings were similar between groups.
Over 24 weeks of treatment, GFF MDI was non-inferior to UV DPI for peak FEV1, but not for morning pre-dose trough FEV1. GFF MDI had a faster onset of action versus UV DPI. There were no clinically meaningful differences between treatments in symptom endpoints. Both treatments were well tolerated with similar safety profiles.
KeywordsBronchodilators Chronic obstructive pulmonary disease LABA LAMA Respiratory
The authors would like to thank all the patients and their families, and the team of investigators, research nurses, and operations staff involved in these studies.
This study, including the article processing charges, were supported by AstraZeneca. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Medical Writing and/or Editorial Assistance
Medical writing support, under the direction of the authors, was provided by Julia King, PhD, of CMC Connect, a division of McCann Health Medical Communications Ltd, Glasgow, UK, funded by AstraZeneca, Gaithersburg, USA, in accordance with Good Publication Practice (GPP3) guidelines .
François Maltais reports research support from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Grifols, and Novartis; advisory board participation for Boehringer Ingelheim and GlaxoSmithKline, and speaking engagements for Boehringer Ingelheim, Grifols, and Novartis. Gary T. Ferguson reports grants, personal fees, and non-financial support from AstraZeneca during the conduct of the study; grants, personal fees and non-financial support from AstraZeneca, Boehringer Ingelheim, Novartis, Pearl—a member of the AstraZeneca Group, and Sunovion; grants and personal fees from Theravance; and personal fees from Circassia, GlaxoSmithKline, Innoviva, Mylan, and Verona, outside of the submitted work. Gregory J. Feldman has nothing to disclose. Gaëtan Deslee reports fees or funding from BTG/PneumRx, AstraZeneca, Chiesi, Boehringer Ingelheim, Novartis, and Nuvaira. Arnaud Bourdin reports fees or funding from AstraZeneca, GSK, Chiesi Pharmaceuticals, Boehringer Ingelheim, Novartis, Roche, Sanofi/Regeneron, and TEVA for consulting activities, participation in scientific committees, and as an investigator of clinical trials. Harald Fjällbrant is an employee of AstraZeneca. Agnieszka Siwek-Posłuszna is an employee of AstraZeneca. Martin A. Jenkins is an employee of AstraZeneca. Ubaldo J. Martin is an employee of AstraZeneca.
Compliance with Ethics Guidelines
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (see the supplementary material for the full list of institutional review boards) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. The clinical study protocol and informed consent form were approved by appropriate independent ethics committees or institutional review boards. All patients gave informed consent before any study procedures.
Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
- 1.Global Initiative for Chronic Obstructive Lung Disease. 2019 Report: global strategy for prevention, diagnosis and management of COPD. 2019. http://www.goldcopd.org. Accessed Apr 11, 2019.
- 2.AstraZeneca Pharmaceuticals LP. Bevespi Aerosphere™ prescribing information. 2017. http://www.azpicentral.com/bevespi/bevespi_pi.pdf. Accessed Apr 11, 2019.
- 3.Boehringer Ingelheim Ltd. Spiolto Respimat summary of product characteristics. 2017. https://www.medicines.org.uk/emc/medicine/30495. Accessed Apr 11, 2019.
- 4.AstraZeneca AB. Duaklir Genuair summary of product characteristics. 2017. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003745/WC500178413.pdf. Accessed Apr 11, 2019.
- 5.Novartis Europharm Limited. Ultibro Breezhaler summary of product characteristics. 2017. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002679/WC500151255.pdf. Accessed Apr 11, 2019.
- 6.Glaxo Group Limited. Anoro Ellipta summary of product characteristics. 2017. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002751/WC500168424.pdf. Accessed Apr 11, 2019.
- 9.De Backer W, De Backer J, Vos W, et al. 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. Int J Chron Obstruct Pulmon Dis. 2018;13:2673–84.CrossRefGoogle Scholar
- 11.Lipworth BJ, Collier DJ, Gon Y, et al. Improved lung function and patient-reported outcomes with co-suspension delivery technology glycopyrrolate/formoterol fumarate metered dose inhaler in COPD: a randomized phase III study conducted in Asia, Europe, and the USA. Int J Chron Obstruct Pulmon Dis. 2018;13:2969–84.CrossRefGoogle Scholar
- 15.Decramer M, Anzueto A, Kerwin E, et al. Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials. Lancet Respir Med. 2014;2(6):472–86.CrossRefGoogle Scholar
- 19.Ferguson GT, Rabe KF, Martinez FJ, et al. Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial. Lancet Respir Med. 2018;6(10):747–58.CrossRefGoogle Scholar
- 25.Donohue JF, Niewoehner D, Brooks J, O’Dell D, Church A. Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomized, double-blind, placebo-controlled study. Respir Res. 2014;15:78.CrossRefGoogle Scholar
- 26.Kerwin E, Ferguson GT, Sanjar S, et al. Dual bronchodilation with indacaterol maleate/glycopyrronium bromide compared with umeclidinium bromide/vilanterol in patients with moderate-to-severe COPD: results from two randomized, controlled, cross-over studies. Lung. 2017;195(6):739–47.CrossRefGoogle Scholar
- 30.Fakih F, Spangenthal S, Sigal B, et al. Randomized study of the effects of Aerochamber Plus® Flow-Vu® on the efficacy, pharmacokinetics and safety of glycopyrronium/formoterol fumarate dihydrate metered dose inhaler in patients with chronic obstructive pulmonary disease. Respir Med. 2018;138:74–80.CrossRefGoogle Scholar