Long-Term Safety and Efficacy of Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Formulated Using Co-Suspension Delivery Technology in Japanese Patients with COPD

Abstract

Background

Budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) is a triple fixed-dose combination for COPD. The long-term safety of triple therapy for COPD has not been investigated in Japanese patients. In this 28-week extension study (NCT3262012), we investigated the long-term safety and tolerability of BGF MDI in Japanese patients with moderate-to-very severe COPD who completed the 24-week Phase III randomized, double-blind, multicenter KRONOS study (NCT2497001).

Materials and methods

Patients randomized to BGF MDI 320/18/9.6 μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 μg twice-daily in KRONOS continued treatment for up to 28 additional weeks. Safety was evaluated over 52 weeks via adverse event (AE) monitoring, electrocardiograms, clinical laboratory testing, and vital sign measurements.

Results

The safety population included 416 patients who received BGF MDI (n=139), GFF MDI (n=138), BFF MDI (n=70), or BUD/FORM DPI (n=69). Treatment-emergent AE (TEAE) rates were similar across treatment groups (range: 82.6–82.9%). The most frequent TEAEs overall were nasopharyngitis (32.2%) and bronchitis (9.9%). The incidence of major adverse cardiovascular events was low across groups (range: 0.0–2.9%). Over 52 weeks, the incidence of confirmed pneumonia was 9.4% (BGF MDI), 3.6% (GFF MDI), 5.7% (BFF MDI), and 2.9% (BUD/FORM DPI); in the 28-week extension period, rates were comparable across groups (range: 2.9–5.7%). Six deaths were reported (0.7–2.2% per group); none were considered treatment-related. No clinically meaningful trends were observed in electrocardiograms, laboratory parameters, or vital signs over time in any of the treatment groups.

Conclusion

All treatments were well tolerated over 52 weeks, and the safety profile of BGF MDI was generally comparable to dual long-acting muscarinic antagonist (LAMA)/long-acting β₂-agonist (LABA) and inhaled corticosteroid (ICS)/LABA therapies. These findings support the long-term tolerability of BGF MDI in Japanese patients with COPD.

Keywords:

• co-suspension delivery technology
• ICS/LAMA/LABA
• inhaled corticosteroid
• long-acting muscarinic antagonist
• long-acting β₂-agonist
• Japan

Acknowledgments

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. 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 and was funded by AstraZeneca, Gaithersburg, USA, in accordance with Good Publication Practice (GPP3) guidelines.¹⁸

Abbreviations

AE, adverse event; AESI, adverse event of special interest; BFF, budesonide/formoterol fumarate; BGF, budesonide/glycopyrrolate/formoterol fumarate; BUD/FORM DPI, budesonide/formoterol dry powder inhaler; CEC, clinical endpoint committee; E-RS, Evaluating Respiratory Symptoms; FEV₁, forced expiratory volume in 1 s; GFF, glycopyrrolate/formoterol fumarate; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; LSM, least squares mean; MACE, major adverse cardiovascular events; MDI, metered dose inhaler; mITT, modified intent-to-treat; TEAE, treatment-emergent adverse event.

Ethics Approval and Informed Consent

Patients provided written informed consent prior to screening, and the study was conducted in accordance with Good Clinical Practice, including the Declaration of Helsinki and the International Council for Harmonisation. The protocol was approved by local institutional review boards (names and protocol numbers have been previously published).³ The names of all institutional review boards can be found in Supplementary Table 2.

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.

Author Contributions

HO, MT, EB, SB, KdA, PD, and CR contributed to the conception or design of the study; MI, YF, YI, OH, GTF, KFR, HO, MT, EB, KdA, and MA participated in the acquisition of reported data; NH and SB contributed to the statistical analysis of the data. All authors participated in the analysis and interpretation of data reported. All authors reviewed or critically revised the manuscript, provided the final approval of the version to be published, and agreed to be accountable for all aspects of the work.

Disclosure

MI reports personal fees from AstraZeneca, during the conduct of the study; and personal fees from Kyorin, Nippon Boehringer Ingelheim, and Novartis Pharma, outside of the submitted work. YI reports personal fees from GlaxoSmithKline, Nippon Boehringer Ingelheim, Nobelpharma, and Shionogi & Co. Ltd, outside of the submitted work. OH reports personal fees from AstraZeneca, Nippon Boehringer Ingelheim, and Novartis Pharma; and research funding from AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Nippon Boehringer Ingelheim, and Novartis Pharma. GTF 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. KFR reports personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi Pharmaceuticals, InterMune, Novartis, Sanofi, and Teva; and grants from the Ministry of Education and Science, Germany, outside of the submitted work. NH, HO, and MT are employees of AstraZeneca K.K., Japan. EB, SB, MA, CR, and PD are employees of AstraZeneca. KdA is a former employee of AstraZeneca. The authors report no other conflicts of interest in this work.