Examining Airway Tolerability of a Climate Conscious Inhaler

Pressurized metered dose inhalers (pMDIs) are widely used in asthma management. Current pMDI propellants, including hydrofluoroalkane-134a (HFA-143a), have relatively high global warming potential, but hydrofluoroolefin-1234ze (HFO-1234ze) has been developed as an alternative propellant with near-zero global warming potential. A recent study by Pleasants and colleagues examined post-dose lung function and clinical manifestations of bronchospasm after inhalation of HFO-1234ze delivered by pMDI, using HFA-134a as a reference comparator.

Let’s take a closer look.

Study Design

The investigation was a Phase IIIb, randomized, double-blind, single-dose crossover study conducted at 4 clinical sites in the United States. The study enrolled 52 adults aged 18 to 45 years with well or partially controlled asthma based on mean forced expiratory volume in one second (FEV₁) and asthma control questionnaire (ACQ) scores.

Each participant received two propellant-only pMDIs, one containing HFO-1234ze and one containing HFA-134a, in randomized order. Each treatment consisted of 4 inhalations, with a washout period of 3-12 days between dosing sessions. No active drug was included in either inhaler, allowing the assessment to focus specifically on airway responses and overall tolerability of the propellants themselves. The total duration of study participation was up to 37 days, including screening and follow-up.

The primary endpoint was the change from baseline in FEV₁ area under the curve from 0 to 15 minutes (AUC_{0–15 min}) after dosing. This endpoint was selected to detect acute airway narrowing consistent with transient bronchospasm.

FEV₁ was performed within 30 minutes before dosing and repeated at 5, 15, and 30 minutes after dosing. The prespecified noninferiority margin for the between-treatment difference was −0.200 liters, representing a threshold considered clinically relevant for reversibility in asthma. Statistical analysis used a linear mixed-effects model incorporating treatment sequence, treatment period, mean baseline FEV₁, and participant-level random effects.

Findings on Lung Function Change

Mean changes in FEV₁ AUC_{0–15 min} after dosing were small for both treatments. The least squares mean change from baseline was −0.014 liters for HFO-1234ze and −0.004 liters for HFA-134a. The estimated difference between treatments was −0.009 liters and was not significant (95% confidence interval [CI] −0.037, 0.018). The lower bound of this interval exceeded the prespecified noninferiority margin, meeting the statistical criterion for noninferiority.

Exploratory analyses at individual time points showed no statistically significant differences in FEV₁ change between treatments at 5, 15, or 30 minutes after dosing.

Bronchospasm and Safety Outcomes

Bronchospasm events were defined as a reduction in FEV₁ greater than 15% from baseline accompanied by respiratory symptoms such as wheeze, cough, or shortness of breath. No such events were observed in either treatment group at any time point.

Adverse events were infrequent; 2 participants reported adverse events after HFO-1234ze exposure, and 2 after HFA-134a exposure. Reported events were mild or moderate in intensity, including dysgeusia and pyrexia in the HFO-1234ze group and fatigue, urinary tract infection, nephrolithiasis, and ovarian cyst in the HFA-134a group. No serious adverse events, adverse events of special interest, or treatment discontinuations occurred during the study.

Interpretation Within the Study’s Stated Limits

The findings indicate that, under the conditions studied, inhalation of HFO-1234ze via pMDI did not result in greater short-term reductions in lung function than HFA-134a in adults with stable asthma. The absence of observed bronchospasm events and the similarity in adverse event profiles between treatments support the conclusion that acute airway responses were comparable.

The study was designed to detect short-term tolerability signals and was not intended to assess long-term safety, repeated dosing, pediatric use, or the performance of active drug formulations. The authors noted that additional studies are planned to evaluate HFO-1234ze in combination with active inhaled medications and over longer exposure periods.

By demonstrating comparable airway responses, this study suggests that reducing the contribution of inhaled therapies to global warming may be achievable without sacrificing tolerability.

Reference:

Pleasants RA, Bell AS, Jassal M, et al. 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. J Aerosol Med Pulm Drug Deliv. 2025;38(5):275-283. doi:10.1089/jamp.2024.0061