C108-08 Quantification Method Matters: 129Xe MRI Ventilation Defect Percent as a Clinical Trial Endpoint

Abstract Introduction Ventilation defect percent (VDP) measured by 129Xe MRI is an emerging outcome measure for clinical trials. However, there is disaccord as to how VDP is quantified, and the effect of quantification method on treatment response has not been evaluated. The objective of this study was to investigate the impact of 129Xe MRI VDP quantification method on treatment response and how this might relate to the design of a clinical trial. This is examined in the context of the response of patients with asthma to dupliumab and the response of patients with cystic fibrosis (CF) to triple combination CFTR modulator therapy. Methods Twenty-eight patients with severe asthma (14F/14M, age=55±13 years) were treated for 16-weeks with dupilumab (n = 15) or continued their current treatment without dupilumab (n = 13), and 40 patients with CF (12F/28M, age=25±17 years) were treated with elexacaftor/tezacaftor/ivacaftor (ETI) for 3-18weeks. All patients underwent 129Xe MRI at baseline and end-of-study. Using XIPline, an open-source MATLAB application, VDP was quantified using k-means, adaptive k-means (AKmeans), 60% thresholding of the mean signal (60%TH), linear-binning normalized by mean signal (LBm), and generalized linear-binning normalize by mean (GLBm) and the 99th-percentile (GLB99p). Within-group and between-group treatment change in VDP were evaluated by paired and unpaired t-tests, respectively. The effect of quantification method on change in VDP was evaluated using Friedman’s test. The treatment effect sizes were evaluated using Cohen’s d. Results Figure 1A shows the effect of dupilumab in comparison to control on VDP quantified by each method. Following dupilumab, a significant decrease in VDP was measured using every quantification method except for LBm (k-means: -2.8%, AKmeans: -3.9%, 60%TH: -4.9% LBm: -2.9%, GLBm: -5.2%, GLB99p: -7.3%; LBm p = 0.060, all other p 0.05). Compared to control, the treatment effect of dupilumab was significant when quantified by all methods (all p 0.05). Figure 1B shows that ETI therapy reduced VDP when quantified by any method (k-means: -2.6%, AKmeans: -4.8%, 60%TH: -5.3%, LBm: -3.3%, GLBm: -5.7%, GLB99p: -5.9%, all p 0.05). Importantly, in both cohorts, the choice of quantification method had a significant effect on change in VDP (dupilumab and ETI p 0.0001). Treatment effect size was greatly varied between the methods. Conclusions 129Xe MRI VDP quantification methods have an impact on measured treatment effect in asthma and CF interventional studies, with the 60%TH and GLB techniques seen to be most sensitive to treatment effect. To minimize required clinical trial sample sizes, it behoves researchers to consider the choice of VDP quantification method. This abstract is funded by: CF Foundation