Background Pressurised metered dose inhalers (pMDIs) contain a hydrofluorocarbon propellant, such as
hydrofluoroalkane-134a (HFA-134a), which is known to have global warming potential (GWP). Transitioning pMDIs to propellants with lower GWP will reduce the environmental impact of pMDIs. This study assessed the safety of a near-zero GWP propellant, hydrofluoroolefin-1234ze (HFO-1234ze), compared with HFA-134a when used in the delivery of budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) in participants with chronic
obstructive pulmonary disease (COPD). The results of this study advance our understanding of the safety of
HFO-1234ze compared with HFA-134a.

Methods This phase 3, double-blind, parallel-group study (ClinicalTrials.gov NCT05573464) across 9 countries (Argentina, Bulgaria, Canada, Germany, Mexico, Poland, Turkey, the United Kingdom, the United States) included participants (aged 40–80 years) with physician-diagnosed COPD using dual or triple inhaled
maintenance therapies, COPD Assessment Test score ≥10, ≥10 pack-years smoking history, and no comorbid
diagnosis of asthma or other clinically significant diseases impacting study outcomes. Participants were
randomised (1:1) to receive either BGF HFO-1234ze or BGF HFA-134a (two inhalations of 160/7⋅2/5⋅0 μg twice
daily) for 12 weeks in the main safety analysis set (or 52 weeks [first 120 participants per treatment]). Safety
endpoints included the incidence of adverse events (AEs), measures of vital signs, clinical laboratory tests, and electrocardiograms.

Findings Participants were recruited between 27 September 2022 and 19 May 2023. A total of 874 participants were screened. Of 558 treated participants (mean [standard deviation] age, 67⋅0 [7⋅4] years; male, 315 [56⋅5%]) in the 12-week safety analysis set, 280 received BGF HFO-1234ze, and 278 received BGF HFA-134a. The AE incidence was balanced between formulations in the 12-week (HFO-1234ze, 124 [44⋅3%]; HFA-134a, 114 [41⋅0%]) and 52-week (HFO-1234ze, 80 [66⋅7%]; HFA-134a, 94 [78⋅3%]) safety analysis sets.