Mucociliary Clearance Following a Next-Generation Propellant Versus Hydrofluoroalkane-134a via Pressurized Metered-Dose Inhaler: A Randomized,Double-Blind,Two-Way Crossover Study in Healthy Adults

Abstract

Background:

Pressurized metered-dose inhalers (pMDIs) are commonly used for respiratory disease treatment but contain propellants, such as hydrofluoroalkane-134a (HFA-134a), with global warming potential (GWP) that contribute to the climate emergency. To safeguard essential medicine access, it is crucial to transition to lower-GWP propellants, such as hydrofluoroolefin-1234ze (HFO-1234ze), which has 99% lower GWP than HFA-134a. In accordance with global regulatory requirements, this study was conducted to support the registration of pMDIs with HFO-1234ze.

Methods:

This randomized, double-blind, multicenter, two-way crossover study assessed the effects of HFO-1234ze versus HFA-134a on mucociliary clearance (MCC) in healthy participants aged 18–60 years. Participants received six inhalations twice daily of HFO-1234ze and HFA-134a in two 7-day (+3) intervention periods separated by a 7- to 14-day washout. The primary and secondary endpoints were change from period-specific baseline in average whole lung MCC (%) through 60 minutes (MCC60) and at 3 hours (MCC3h), respectively, measured via inhalation of ^99mTc-labeled colloid and gamma camera imaging. Given significant baseline variability, a post hoc analysis of the primary endpoint assessed change from average baseline instead of period-specific baseline MCC60. Additional safety and tolerability measures were assessed.

Results:

Forty-five participants were screened; the Primary Analysis Set included 34 participants who completed both intervention periods. For the primary endpoint, change from period-specific baseline in MCC60 was negligible, with an estimated change (95% confidence interval [CI]) of −0.6% (−3.2%, 1.9%) for HFO-1234ze and 0.8% (−1.7%, 3.3%) for HFA-134a. The estimated least-squares mean difference (95% CI) between HFO-1234ze and HFA-134a was −1.4% (−5.8%, 2.9%). For the secondary endpoint, the estimated least-squares mean difference for change from period-specific baseline in MCC3h between HFO-1234ze and HFA-134a was −5.7% (−10.9%, −0.5%). There were no unexpected safety findings.

Conclusion:

There was no clinically relevant impact of HFO-1234ze versus HFA-134a on MCC in healthy participants.

Clinical trial registration number:

NCT05755932.

Keywords

HFA-134a HFO-1234ze metered-dose inhaler mucociliary clearance next-generation propellant

Introduction

Pressurized metered-dose inhalers (pMDIs) are commonly used to treat respiratory diseases.¹ People with moderate-to-severe disease are often unable to generate sufficient inspiratory flow to use dry powder inhalers and may benefit from pMDIs,^2,3 which use propellants to facilitate drug delivery.¹ However, many current pMDI propellants, such as hydrofluoroalkane-134a (HFA-134a), have a high global warming potential (GWP)⁴ and contribute to the impact of health care on the climate emergency.

Due to the environmental impact of currently marketed pMDI propellants, a reduction in their use is included in the Kigali Amendment of the Montreal Protocol.⁵ Therefore, to reduce the carbon footprint of health care while safeguarding access to essential medicines, a transition to low-GWP propellants is needed. Hydrofluoroolefin-1234ze (HFO-1234ze) is a propellant with a near-zero GWP (99% lower than HFA-134a) that is being investigated as a replacement for HFA-134a in pMDIs.⁶

Mucociliary clearance (MCC) is a key innate lung defense against inhaled or aspirated bacteria and irritants and is impaired in a number of inherited and acquired airway diseases, including cystic fibrosis, chronic obstructive pulmonary disease (COPD), and asthma.^7–9 When transitioning to a propellant not previously used in humans, such as HFO-1234ze, it is important to understand the potential for deleterious effects on the respiratory system, and regulatory agencies may request evaluation of such effects as part of a safety assessment,^10,11 for example, by assessing bronchospasm following exposure.¹² In addition, the European Medical Agency (EMA) has suggested that effects on MCC should be assessed for new propellants (or excipients) and data on ciliary function for a new propellant should be obtained from a study in healthy, nonsmoking volunteers.^11,13 MCC measurements have been used to assess the potential benefit of interventions in patients with chronic respiratory disease^14–16; however, few studies have used MCC to screen for safety concerns in healthy populations.

Here, as part of the clinical development program for HFO-1234ze as a pMDI propellant, and per regulatory guidance,¹¹ we evaluated the safety of HFO-1234ze and HFA-134a by assessing their impact on MCC, using gamma scintigraphy, in healthy participants. Additional safety and tolerability measures were also assessed.

Methods

Study design

This randomized, double-blind, multicenter, two-way crossover study (ClinicalTrials.gov registry: NCT05755932) investigated the effects of HFO-1234ze MDI versus HFA-134a MDI on MCC and other safety measures in healthy adult participants. In particular, the study aimed to determine if HFO-1234ze is non-inferior to HFA-134a with respect to changes in MCC. The study initially included four sites from the United States; however, an additional site from the United Kingdom was included to aid recruitment.

Following a 7- to 14-day screening period, participants were randomized 1:1 to receive intervention in one of two sequences (AB or BA; Fig. 1). Study personnel and participants were blinded to the treatment sequence. Each participant received six inhalations twice daily of HFO-1234ze (intervention A; test formulation) and HFA-134a (intervention B; reference formulation) in two separate 7-day (up to +3 days) intervention periods separated by a 7- to 14-day washout period (Fig. 1). Dosing occurred in the morning and evening, ∼12 hours apart. A single dose was three times the dosing regimen used in fixed-dose MDIs (i.e., six inhalations vs. two inhalations) to simulate settings where greater doses are taken by patients. Participants were trained and required to demonstrate correct inhalation technique at screening.

The study was performed in accordance with the Declaration of Helsinki and International Council for Harmonization Good Clinical Practice Guidelines, applicable regulatory requirements, and the AstraZeneca policy on Bioethics. Participants were required to sign informed consent documents. The study protocol, informed consent documents, and other relevant documents were reviewed by the University of North Carolina Office of Human Research Ethics.

Participants

Healthy nonsmokers aged 18–60 years with no respiratory comorbidities; a forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) ratio of >0.70; FEV₁ ≥80% of the predicted normal value for age, height, and ethnicity at screening; and ability to demonstrate correct inhalation technique were enrolled. Female participants were required to use highly effective birth control or not be of childbearing potential and to have a negative serum pregnancy test at Visit 1.

Key exclusion criteria included current smoking or smoking history with >10 pack-years or use of nicotine products (including electronic cigarettes), marijuana, or vaping within 6 months prior to screening, any acute or chronic upper or lower respiratory pathology, use of respiratory medication or medication that may impact ciliary clearance for any indication within 30 days of screening, and a history of >2 chest computed tomography scans or equivalent (>10 mSv) within the past year.

Endpoints and assessments

The primary and secondary endpoints were change from period-specific baseline in average whole lung MCC (%) through 60 minutes (MCC60) and at 3 hours (MCC3h), respectively. To assess MCC, ^99mTc-labeled colloid (U.S. participants: sulfur, UK participants: albumin) was administered prior to the first dose on Day 1 and 2 hours after the morning dose on Day 7 (up to +3 days) of each intervention period and was imaged with gamma scintigraphy.

Lung boundaries were defined via ⁵⁷Co transmission scanning, and background radioactivity was measured for each participant. Following a review of correct inhalation technique, participants inhaled nebulized ^99mTc-labeled colloid with a slow, controlled inhalation (50 mL/s for 6 seconds). After ∼40 µCi (∼1.48 MBq) lung deposition, serial acquisition of 2-minute gamma scintigraphy images began with the participant seated. Radioactive counts obtained from sequential 2-minute images were averaged to reduce noise; MCC60 was then calculated using values obtained at 10-minute intervals through 64 minutes after imaging initiation. An additional 15-minute static gamma scintigraphy image was acquired at 3 hours after imaging initiation for the MCC3h endpoint. Except the different colloids used between the U.S. and UK sites, all sites used the same methodology, and all images were read centrally to reduce variability.

Additional safety and tolerability endpoints included adverse event (AE) monitoring, vital signs, physical examinations, clinical laboratory assessments, and electrocardiograms. AEs were recorded at screening, Days 1 and 7 of both intervention periods, and the final safety follow-up visit and were reported by Preferred Terms and System Organ Class using Medical Dictionary for Regulatory Activities version 27.0. Vital signs (systolic blood pressure, diastolic blood pressure, heart rate, body temperature, and respiratory rate) and a 10-second 12-lead electrocardiogram were recorded at screening and Day 7 of the second intervention period.

Statistical analysis

The study included four populations: the Enrolled Set comprised all participants who signed the informed consent form and was used to summarize participant disposition, the Randomized Set comprised all participants who were randomized to treatment and was used to summarize baseline characteristics, and the Safety Set included all participants who were randomized to treatment and received at least one dose of any interventional product. The Primary Analysis Set included all participants who were randomized to one of the study intervention sequences with ≥80% dose compliance in both intervention periods. Participants were excluded from the Primary Analysis Set if they had any important protocol deviation that could affect MCC. Period-level data were analyzed according to the actual intervention received. The study sample size (N = 28) was based on an assumed true difference of −0.5% between the mean change from baseline in MCC60 following inhalation of radiolabeled colloid for HFO-1234ze MDI versus HFA-134a MDI, a standard deviation (SD) of 7%, 90% power, a non-inferiority margin of −5%, and a one-sided significance level of 0.025. The SD assumption was informed by a prior study evaluating the impact of hypertonic saline on MCC in healthy volunteers,¹⁷ and the non-inferiority margin was based on a prior study assessing the effect of hypertonic saline on MCC in patients with cystic fibrosis.¹⁴

For primary endpoint, a linear mixed model with participant within sequence as a random effect was applied with a dependent variable of change from baseline in MCC60 and independent fixed effect variables of actual sequence, intervention period, average baseline MCC (period-specific baseline MCC averaged over each of the intervention periods), and intervention received. Non-inferiority was assessed using a two-sided 95% confidence interval (CI) and was declared if the lower limit of the two-sided 95% CI for the difference between HFO-1234ze MDI and HFA-134a MDI for the primary endpoint was greater than −5%. The same model was used for the secondary endpoint, but with a dependent variable of change in MCC3h and adjusting for average baseline MCC at 3 hours. It was expected that any carryover effect was unlikely based on the known rapid elimination of the propellant, but if present, it would be eliminated through a washout period and was not included in the models.

Based on observed variability in baseline MCC data at study readout, a post hoc analysis of the primary endpoint was performed using an alternative definition of change from average baseline MCC60 instead of change from period-specific baseline MCC60.

All analyses were performed using SAS^® version 9.4.

Results

Participant demographics and clinical characteristics

In total, 45 participants were screened and 35 were randomized to treatment sequence AB (n = 18) or BA (n = 17), of whom all received treatment and were included in the Safety Set (Fig. 2). Of these, 34 participants completed both intervention periods (AB, n = 17; BA, n = 17) and were included in the Primary Analysis Set. One participant in intervention sequence AB was excluded from the Primary Analysis Set due to an important protocol deviation with the potential to affect MCC, whereby intervention was not dispensed, and MCC scans were not conducted due to a technical issue.

Baseline characteristics for the Randomized Set are summarized in Table 1. Mean age (SD) was 30.6 (8.3) years, and the majority of participants were male (57.1%) and White (91.4%). Except for a high mean (SD) body mass index of 26.5 (3.9) kg/m², baseline characteristics were consistent with those of healthy, nonsmoking volunteers, with a mean (SD) FEV₁% and FEV₁/FVC ratio of 99.1% (10.2%) and 82.9% (6.5%), respectively.

Table 1.

Baseline Demographics and Clinical Characteristics (Randomized Set)

	All participantsN = 35
Age (years), mean (SD)	30.6 (8.3)
Female, n (%)	15 (42.9)
Race, n (%)
White	32 (91.4)
Black or African American	1 (2.9)
American Indian or Alaskan Native	1 (2.9)
Other	1 (2.9)
Ethnicity, n (%)
Hispanic or Latino	4 (11.4)
Not Hispanic or Latino	30 (85.7)
Not reported	1 (2.9)
BMI (kg/m²), mean (SD)	26.5 (3.9)
FEV₁ (L), mean (SD)	3.9 (0.8)
FEV₁%, mean (SD)	99.1 (10.2)
FVC (L), mean (SD)	4.7 (1.0)
FEV₁/FVC (%), mean (SD)	82.9 (6.5)

BMI, body mass index; FEV₁, forced expiratory volume in 1 second; FEV₁%, FEV₁ percent predicted normal; FVC, forced vital capacity; SD, standard deviation.

Mucociliary clearance

For the primary endpoint, change from period-specific baseline in MCC60 was negligible in both arms (Fig. 3). For HFO-1234ze, mean (SD) baseline MCC60 was 9.9% (7.1%) in intervention period 1 and 6.5% (7.4%) in intervention period 2, and the estimated mean change (95% CI) from period-specific baseline in MCC60 was −0.6% (−3.2%, 1.9%). For HFA-134a, mean (SD) baseline MCC60 was 7.6% (6.8%) in intervention period 1 and 7.6% (6.7%) in intervention period 2, and the estimated mean change (95% CI) from period-specific baseline in MCC60 was 0.8% (−1.7%, 3.3%). The estimated least-squares mean difference (95% CI) between HFO-1234ze and HFA-134a was −1.4% (−5.8%, 2.9%). As the lower bound of the two-sided 95% CI was below the prespecified non-inferiority threshold of −5%, non-inferiority was not demonstrated. For both HFO-1234ze and HFA-134a, interparticipant variability in MCC60 was observed, as demonstrated by the spread of MCC60 values for individual participants from baseline to Day 7 (Supplementary Fig. S1). Indeed, some participants appeared to be outliers, demonstrating higher variability from baseline to Day 7, including with the reference formulation, HFA-134a.

Given the degree of observed variability in MCC60, a post hoc analysis of the primary endpoint using average baseline (period-specific baseline MCC averaged over each of the intervention periods) was conducted (Fig. 4). Here, mean (SD) baseline MCC60 was 8.2% (7.3%) for HFO-1234ze and 7.6% (6.6%) for HFA-134a. Estimated mean change (95% CI) from average baseline MCC60 was −0.3% (−2.2%, 1.6%) and 0.5% (−1.4%, 2.4%) for HFO-1234ze and HFA-134a, respectively. The estimated least-squares mean difference (95% CI) between HFO-1234ze and HFA-134a was −0.8% (−3.5%, 1.9%), with a lower bound of the two-sided 95% CI above the prespecified non-inferiority threshold of −5%.

For the secondary endpoint, for HFO-1234ze, mean (SD) baseline MCC3h was 26.6% (11.5%) in intervention period 1 and 27.8% (9.0%) in intervention period 2, and the estimated mean change (95% CI) from period-specific baseline in MCC3h was −2.4% (−5.6%, 0.9%) (Fig. 5). For HFA-134a, mean (SD) baseline MCC3h was 24.6% (10.2%) in intervention period 1 and 23.5% (9.7%) in intervention period 2, and the estimated mean change (95% CI) from period-specific baseline in MCC3h was 3.3% (0.1%, 6.5%). The estimated least-squares mean difference between HFO-1234ze and HFA-134a was −5.7% (−10.9%, −0.5%).

Safety and tolerability

AE occurrence is summarized in Table 2. The number of participants who experienced any AE was the same for HFO-1234ze and HFA-134a. All AEs were of mild or moderate intensity, and there were no serious AEs, AEs leading to treatment discontinuation, or deaths during the study. There were no trends in the occurrence of AEs in any System Organ Class or Preferred Term.

Table 2.

Summary of Adverse Events (Safety Set)^a

AE category, n (%)	HFO-1234zeN = 35	HFA-134aN = 34
Any AE	5 (14.3)	5 (14.7)
Any SAE	0 (0.0)	0 (0.0)
AE leading to discontinuation of the study intervention	0 (0.0)	0 (0.0)
Possibly treatment-related AE	3 (8.6)	2 (5.9)
Specific AEs by System Organ Class and Preferred Term (MedDRA version 27.0)
Nervous system disorders
Headache	2 (5.7)	0
Respiratory, thoracic, and mediastinal disorders	2 (5.7)	2 (5.9)
Dry throat	1 (2.9)	2 (5.9)
Oropharyngeal pain	1 (2.9)	0
Productive cough	1 (2.9)	0
Throat irritation	0	1 (2.9)
Skin and subcutaneous tissue disorders	0	1 (2.9)
Eczema	0	1 (2.9)
Injury, poisoning, and procedural complications	0	1 (2.9)
Sunburn	0	1 (2.9)

Includes AEs with start date on or after the first dose date during intervention period 1 up to and including 7 days after the last dose date. Participants with multiple occurrences are counted once per System Organ Class and Preferred Term regardless of the number of occurrences.

AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities; SAE, serious adverse event.

Discussion

This study compared the effect of HFO-1234ze versus HFA-134a on MCC in healthy participants. Additional safety measures were also assessed. The impact on MCC60 was similar with both HFO-1234ze and HFA-134a, with negligible changes from baseline. However, given observed variability in MCC for the primary endpoint (change from period-specific baseline in MCC60), non-inferiority was not demonstrated for HFO-1234ze versus HFA-134a, as the lower CI was not greater than the −5% non-inferiority boundary. This result is not clinically relevant, as the mean change from baseline for HFO-1234ze was very small, supporting the lack of effect of HFO-1234ze on MCC, and is likely to be explained by the variability of MCC in healthy participants, who have higher MCC than those with airway disease (in whom MCC testing is considered more relevant).^7–9,18 Indeed, a post hoc analysis assessing change from average baseline in MCC (instead of change from period-specific baseline) demonstrated reduced variability between HFO-1234ze and HFA-134a; here, the lower limit of the 95% CI for the treatment difference was greater than the prespecified non-inferiority threshold of –5%.

For the secondary endpoint, change from period-specific baseline in MCC3h, greater variability was observed between HFO-1234ze and HFA-134a compared with the primary endpoint (MCC60). This observed variability may be explained by multiple factors, including subtle differences in alveolar radiotracer deposition that increasingly impact clearance assessments at later time points, and differences in data collection.¹⁸ MCC60 was derived as an average from multiple time point measurements through 60 minutes, whereas MCC3h was based on a single measurement taken 3 hours post-dose; thus, MCC3h may be more sensitive to individual variability and external influences. Additionally, participant activity between hours 1–3 following inhalation was not monitored or controlled for, which may have contributed to variability in the MCC3h analysis. Finally, it should be noted that there is currently no consensus on the threshold for a clinically meaningful difference in MCC3h, limiting the value of this measure.

Notably, previous work did not show acute bronchospasm events (defined by a decline in FEV₁ and symptoms) following four inhalations of the HFO-1234ze propellant alone, and no difference in respiratory AEs was observed over 52 weeks of treatment when HFO-1234ze was used in a fixed-dose combination inhaler (budesonide/glycopyrrolate/formoterol fumarate), compared with the same formulation delivered using HFA-134a.^12,19

The lack of demonstrated non-inferiority between HFO-1234ze and HFA-134a for MCC is not clinically relevant for several reasons. First, minimal changes in MCC were observed for either propellant, despite dosing levels substantially exceeding those used in clinical practice, with a <1% difference from baseline in MCC60 with either HFO-1234ze or HFA-134a. Second, there are major methodological limitations to assessing the impact of interventions on MCC, including a lack of a current gold standard for measurement of ciliary function, as recently acknowledged by the EMA.¹³ Notably, there are limited studies that establish significant changes in MCC in healthy participants, no widely agreed-upon methods for MCC assessment, no validated minimal clinically important difference from gamma scintigraphy testing, and no established consensus or guideline-based equivalence or non-inferiority margin for MCC in healthy participants or those with respiratory disease. In addition, changes in MCC alone cannot be directly equated to toxicity; instead, MCC was selected for ciliary function assessment as a component of local safety and tolerability assessment. Due to the lack of studies examining MCC using gamma scintigraphy in healthy participants, the non-inferiority boundary of 5% used in this study was informed by a study by Donaldson et al. in participants with cystic fibrosis.¹⁴ Selection of this value as the non-inferiority boundary is limited by different methodologies and populations (i.e., healthy participants vs. patients with cystic fibrosis) between studies. It is well established that patients with cystic fibrosis have abnormal mucus rheology compared with healthy individuals,²⁰ with abnormal deposition and clearance.²¹ Therefore, indirect measures of MCC, such as those generated using gamma scintigraphy, are not directly translatable between healthy and cystic fibrosis populations. As such, a −5% non-inferiority boundary seems to be less relevant in this population of healthy participants than in those with cystic fibrosis. While a larger sample size may have increased the likelihood of achieving non-inferiority, operational difficulties resulted in the addition of an extra trial site to meet the a priorisample size, which likely increased variability in MCC.

For the primary and secondary endpoints, this study used period-specific baseline MCC measurements, with post hoc analyses assessing change from the average baseline in MCC. While both methods are statistically valid, the period-specific approach is sensitive to baseline variability, which was clearly observed in this study. Indeed, some participants who had a greater level of variability in MCC60 from baseline to Day 7 were identified as outliers who may have potentially skewed the findings and, crucially, demonstrate the limitations of using the current experimental methodology to strictly define the impact of a change in propellant on ciliary function. Utilizing the average baseline rather than the period-specific baseline approach resulted in a lower estimated mean difference and variability in MCC between HFO-1234ze and HFA-134a. In retrospect, the present study should have aligned with the approach utilized by Bennett et al.,¹⁷ which served as the basis for treatment effect, variability, and sample size in this study.

Conclusions

Based on a full review of the methodology, available literature, and findings of this study, the data suggest that neither HFO-1234ze nor HFA-134a had a clinically meaningful impact on MCC in healthy participants. No new or unexpected safety signals of concern were observed. While the pre-specified non-inferiority margin of −5% for the primary endpoint was not met—primarily due to baseline variability—the totality of evidence indicates no harmful effect of HFO-1234ze on MCC. In light of the findings of previous studies demonstrating similar safety profiles for HFO-1234ze and HFA-134a in participants with asthma or COPD,^12,19 the findings of this study support the use of HFO-1234ze as an environmentally conscious pMDI propellant. This study aids future investigation into establishing/approximating non-inferiority margins and assessment of mucociliary function for future drug development.

Authors’ Contributions

S.D.: Conceptualization, data curation, formal analysis, investigation, methodology, project administration, supervision, and writing—review and editing. K.L.Z.: Data curation, formal analysis, methodology, and writing—review and editing. A.B.: Project administration and writing—review and editing. M.J.: Formal analysis, investigation, methodology, project administration, validation, and writing—review and editing. H.P.: Formal analysis, supervision, validation, visualization, and writing—review and editing. J.L.B.: Formal analysis, methodology, supervision, validation, and writing—review and editing. M.P.: Formal analysis, methodology, and writing—review and editing. M.A.: Formal analysis, methodology, investigation, and writing—review and editing. M.P.: Formal analysis, investigation, and writing—review and editing. W.B.: Conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, resources, validation, and writing—review and editing. All authors had access to the study data and made a significant contribution to the data reported.

Supplemental Material

sj-docx-1-pdd-10.1177_19412711261470884 — Supplemental material for Mucociliary Clearance Following a Next-Generation Propellant Versus Hydrofluoroalkane-134a via Pressurized Metered-Dose Inhaler: A Randomized, Double-Blind, Two-Way Crossover Study in Healthy Adults

Supplemental material, sj-docx-1-pdd-10.1177_19412711261470884 for Mucociliary Clearance Following a Next-Generation Propellant Versus Hydrofluoroalkane-134a via Pressurized Metered-Dose Inhaler: A Randomized, Double-Blind, Two-Way Crossover Study in Healthy Adults by Scott H. Donaldson, Kirby L. Zeman, Alan Bell, Mandeep Jassal, Hitesh Pandya, Jennifer L. Bell, Margareta Puu, Magnus Aurivillius, Mehul Patel, and William Bennett

Footnotes

Data Sharing Statement

Data underlying the findings described in this article may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Data for studies directly listed on Vivli can be requested through Vivli at www.vivli.org. Data for studies not listed on Vivli could be requested through Vivli at https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform. The AstraZeneca Vivli member page is also available, outlining further details at .

Acknowledgments

The authors thank the study participants. They also thank the investigators and staff from each of the study sites: BDD Pharma (Bio-imaging Unit, Glasgow Royal Infirmary, Glasgow, UK; principal investigator: Lyn Corry), University of North Carolina School of Medicine (Center for Environmental Medicine, Asthma and Lung Biology, University of North Carolina, NC, USA; principal investigator: W.B.), University of Kansas Medical Center (Kansas City, KS, USA; principal investigator: Andreas Schmid), University of Pittsburgh Medical Center (Montefiore University Hospital, Pittsburgh, PA, USA; principal investigator: Timothy E. Corcoran), and The Johns Hopkins Hospital (Baltimore, MD, USA; principal investigator: Daniel Sullivan). The authors also thank Meng Li for programming support in this study. Medical writing support, under the guidance of the authors, was provided by Daniel Spindlow, MSc, CMC Connect, a division of IPG Health Medical Communications, funded by AstraZeneca, in accordance with Good Publication Practice (GPP 2022) guidelines.²²

Author Disclosure Statement

S.H.D. reports grants and contracts to his institution from the Cystic Fibrosis Foundation, Chiesi USA, Enterprise Therapeutics, the National Institutes of Health, Vertex Pharmaceuticals, and 4D Molecular Therapeutics; consulting fees from Boehringer Ingelheim; and participation on a data and safety monitoring board for AbbVie Inc. K.L.Z. reports a consulting contract with AstraZeneca for assisting in multisite coordination. A.B., M.J., H.P., M.P., M.A., and M.P. are employees of AstraZeneca and hold stock and/or stock options in the company. J.B. is contracted by AstraZeneca. W.B. reports no conflicts of interest.

Funding Information

The study was supported by AstraZeneca.

Abbreviations Used

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