A Randomized, Double-Blind Crossover Study of Change in Post-Dose Lung Function with Hydrofluoroolefin-1234ze, a Next-Generation Propellant for Metered Dose Inhalers, in Participants with Asthma.

Abstract

Background: Pressurized metered dose inhalers (pMDIs) currently contain propellants with relatively high global warming potential (GWP), such as hydrofluoroalkane-134a (HFA-134a). Hyrofluoroolefin-1234ze (HFO-1234ze) is a near-zero GWP propellant in development for use in future pMDIs. Methods: This Phase IIIb, multicenter, randomized, double-blind, single-dose crossover study aimed to assess post-dose lung function and clinical manifestations of bronchospasm following single doses of HFA-134a and HFO-1234ze via pMDI (four inhalations with no active drugs) in participants with well or partially controlled asthma. The primary endpoint was change from baseline in forced expiratory volume in one second area under the curve from 0 to 15 minutes (FEV₁ AUC_{0-15 minutes}) post-dose and was assessed using a linear mixed-effect model. Secondary endpoints included cumulative incidence of bronchospasm events (reduction in FEV₁ of >15% from baseline at 5 or 15 minutes post-dose with associated wheezing, shortness of breath, or cough). Safety and tolerability were also assessed. Results: Among 52 participants randomized to treatment, noninferiority of HFO-1234ze pMDI versus HFA-134a was established for change from baseline in FEV₁ AUC_{0-15 minutes} post-dose between treatments (least squares mean [LSM]; 95% confidence intervals [CI] change: HFO-1234ze pMDI, -0.014 [-0.033, 0.006] L; HFA-134a, -0.004 [-0.024, 0.015] L; LSM [95% CI] difference: -0.009 [-0.037, 0.018; p = 0.492]). No bronchospasm events were reported. Two patients (3.8%) in each group experienced ≥1 adverse event (AE). No serious AEs, AEs of special interest, or AEs leading to discontinuation were reported. Conclusions: HFO-1234ze pMDI was well tolerated in participants with well or partially controlled asthma. As with HFA-134a pMDI, no significant effects on lung function or bronchospasm events were observed. As HFO-1234ze pMDI has a near-zero GWP, it represents a compelling, environmentally conscious alternative propellant for use in pMDI devices for treatment of chronic respiratory disease. Trial Registration: NCT05850494.