Advertisement

Advances in Therapy

, Volume 36, Issue 9, pp 2434–2449 | Cite as

A Randomized, Double-Blind, Double-Dummy Study of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Relative to Umeclidinium/Vilanterol Dry Powder Inhaler in COPD

  • François MaltaisEmail author
  • Gary T. Ferguson
  • Gregory J. Feldman
  • Gaëtan Deslee
  • Arnaud Bourdin
  • Harald Fjällbrant
  • Agnieszka Siwek-Posłuszna
  • Martin A. Jenkins
  • Ubaldo J. Martin
Original Research

Abstract

Introduction

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).

Methods

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.

Results

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.

Conclusions

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.

Trial registration

NCT03162055 (Clinicaltrials.gov)

Funding

AstraZeneca

Keywords

Bronchodilators Chronic obstructive pulmonary disease LABA LAMA Respiratory 

Notes

Acknowledgements

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.

Funding

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.

Authorship

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 [32].

Disclosures

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 Availability

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.

Supplementary material

12325_2019_1015_MOESM1_ESM.docx (39 kb)
Supplementary material 1 (DOCX 39 kb)

References

  1. 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. 2.
    AstraZeneca Pharmaceuticals LP. Bevespi Aerosphere™ prescribing information. 2017. http://www.azpicentral.com/bevespi/bevespi_pi.pdf. Accessed Apr 11, 2019.
  3. 3.
    Boehringer Ingelheim Ltd. Spiolto Respimat summary of product characteristics. 2017. https://www.medicines.org.uk/emc/medicine/30495. Accessed Apr 11, 2019.
  4. 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. 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. 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.
  7. 7.
    Doty A, Schroeder J, Vang K, et al. Drug delivery from an innovative LAMA/LABA co-suspension delivery technology fixed-dose combination MDI: evidence of consistency, robustness, and reliability. AAPS PharmSciTech. 2018;19(2):837–44.CrossRefGoogle Scholar
  8. 8.
    Taylor G, Warren S, Dwivedi S, et al. Gamma scintigraphic pulmonary deposition study of glycopyrronium/formoterol metered dose inhaler formulated using co-suspension delivery technology. Eur J Pharm Sci. 2018;111:450–7.CrossRefGoogle Scholar
  9. 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
  10. 10.
    Martinez FJ, Rabe KF, Ferguson GT, et al. Efficacy and safety of glycopyrrolate/formoterol metered dose inhaler formulated using co-suspension delivery technology in patients with COPD. Chest. 2017;151(2):340–57.CrossRefGoogle Scholar
  11. 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
  12. 12.
    Martinez FJ, Fabbri LM, Ferguson GT, et al. Baseline symptom score impact on benefits of glycopyrrolate/formoterol metered dose inhaler in COPD. Chest. 2017;152(6):1169–78.CrossRefGoogle Scholar
  13. 13.
    Hanania NA, Tashkin DP, Kerwin EM, et al. Long-term safety and efficacy of glycopyrrolate/formoterol metered dose inhaler using novel Co-Suspension™ Delivery Technology in patients with chronic obstructive pulmonary disease. Respir Med. 2017;126:105–15.CrossRefGoogle Scholar
  14. 14.
    Donohue JF, Maleki-Yazdi MR, Kilbride S, Mehta R, Kalberg C, Church A. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med. 2013;107(10):1538–46.CrossRefGoogle Scholar
  15. 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
  16. 16.
    Donohue JF. Minimal clinically important differences in COPD lung function. COPD. 2005;2(1):111–24.CrossRefGoogle Scholar
  17. 17.
    Chapman KR, Beeh KM, Beier J, et al. A blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 study. BMC Pulm Med. 2014;14:4.CrossRefGoogle Scholar
  18. 18.
    Kalberg C, O’Dell D, Galkin D, Newlands A, Fahy WA. Dual bronchodilator therapy with umeclidinium/vilanterol versus tiotropium plus indacaterol in chronic obstructive pulmonary disease: a randomized controlled trial. Drugs R D. 2016;16(2):217–27.CrossRefGoogle Scholar
  19. 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
  20. 20.
    Maleki-Yazdi MR, Kaelin T, Richard N, Zvarich M, Church A. Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial. Respir Med. 2014;108(12):1752–60.CrossRefGoogle Scholar
  21. 21.
    Zheng J, Zhong N, Newlands A, Church A, Goh AH. Efficacy and safety of once-daily inhaled umeclidinium/vilanterol in Asian patients with COPD: results from a randomized, placebo-controlled study. Int J Chron Obstruct Pulmon Dis. 2015;10:1753–67.CrossRefGoogle Scholar
  22. 22.
    Agusti A, Calverley PM, Celli B, et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res. 2010;11:122.CrossRefGoogle Scholar
  23. 23.
    Mahler DA, Witek TJ Jr. The MCID of the Transition Dyspnea Index is a total score of one unit. COPD. 2005;2(1):99–103.CrossRefGoogle Scholar
  24. 24.
    Kon SS, Canavan JL, Jones SE, et al. Minimum clinically important difference for the COPD Assessment Test: a prospective analysis. Lancet Respir Med. 2014;2(3):195–203.CrossRefGoogle Scholar
  25. 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. 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
  27. 27.
    Feldman GJ, Sousa AR, Lipson DA, et al. Comparative efficacy of once-daily umeclidinium/vilanterol and tiotropium/olodaterol therapy in symptomatic chronic obstructive pulmonary disease: a randomized study. Adv Ther. 2017;34(11):2518–33.CrossRefGoogle Scholar
  28. 28.
    Bosnic-Anticevich S, Chrystyn H, Costello RW, et al. The use of multiple respiratory inhalers requiring different inhalation techniques has an adverse effect on COPD outcomes. Int J Chron Obstruct Pulmon Dis. 2017;12:59–71.CrossRefGoogle Scholar
  29. 29.
    Price D, Chrystyn H, Kaplan A, et al. Effectiveness of same versus mixed asthma inhaler devices: a retrospective observational study in primary care. Allergy Asthma Immunol Res. 2012;4(4):184–91.CrossRefGoogle Scholar
  30. 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
  31. 31.
    Lavorini F, Fontana GA. Targeting drugs to the airways: the role of spacer devices. Expert Opin Drug Deliv. 2009;6(1):91–102.CrossRefGoogle Scholar
  32. 32.
    Battisti WP, Wager E, Baltzer L, et al. Good Publication Practice for communicating company-sponsored medical research: GPP3. Ann Intern Med. 2015;163(6):461–4.CrossRefGoogle Scholar

Copyright information

© Springer Healthcare Ltd., part of Springer Nature 2019

Authors and Affiliations

  • François Maltais
    • 1
    Email author
  • Gary T. Ferguson
    • 2
  • Gregory J. Feldman
    • 3
  • Gaëtan Deslee
    • 4
  • Arnaud Bourdin
    • 5
  • Harald Fjällbrant
    • 6
  • Agnieszka Siwek-Posłuszna
    • 7
  • Martin A. Jenkins
    • 8
  • Ubaldo J. Martin
    • 9
  1. 1.Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de QuébecUniversité LavalQuébecCanada
  2. 2.Pulmonary Research Institute of Southeast MichiganFarmington HillsUSA
  3. 3.S. Carolina Pharmaceutical ResearchSpartanburgUSA
  4. 4.Hôpital Maison Blanche, INSERM U1250, Service des Maladies RespiratoiresCHU de ReimsReimsFrance
  5. 5.CHU Montpellier, PhyMedExp, INSERM, CNRSUniversité de MontpellierMontpellierFrance
  6. 6.AstraZeneca GothenburgMölndalSweden
  7. 7.AstraZenecaWarsawPoland
  8. 8.AstraZenecaCambridgeUK
  9. 9.AstraZenecaGaithersburgUSA

Personalised recommendations