(233) MRI metrics in CF before and after elexacaftor / tezacaftor / ivacaftor - the GIFT-CF3 Study

Background: Gastrointestinal (GI) symptoms and lower GI complications in CF impact the quality of life of people with CF (pwCF) and reducing their burden is a priority in the CF community(1). The causes of these symptoms are not fully understood but are thought to be caused by a partial obstruction of flow at the ileocaecal valve (2). Previous work has shown that the orocaecal transit time (OCTT) is prolonged in pwCF(2). There is limited evidence for the effect of CFTR modulators on the GI tract. We aimed to evaluate what effects elexacaftor/tezacaftor/ivacaftor (ETI) has on OCTT, and other magnetic resonance imaging (MRI) metrics in pwCF.

Methods: We conducted a prospective cohort study over 24 weeks in pwCF taking ETI (NCT04618185). Eligible participants were pwCF, aged 12-60 years, with at least one copy of the F508del mutation. All participants underwent a fasted MRI scan followed by serial postprandial MRI scans over 6 hours (2). MRI was performed at baseline, 12 and 24 weeks of ETI. MRI data were collected to measure OCTT our primary outcome, small bowel water content (SBWC) and total colonic volume. We also measured the postprandial fall in SBWC following a second meal between 240 minutes and 300 minutes which reflects the gastro-ileal reflex. We termed this “delta TI”. Image analysis is ongoing. MR images were acquired using T₁-weighted dual echo sequence for OCTT and a heavily T₂-weighted turbo spin RARE sequence for SBWC. To measure OCTT, serial scans were independently reviewed by two researchers and the timepoint that the meal passed from small bowel to caecum identified (2).

Results: We enrolled 24 pwCF, aged 12-41 years (14 F508del homozygous) of whom 21 completed the study. For our primary outcome, we found OCTT was similar for all 3 visits with median times of 300 minutes (IQR 240-300 visit X) 300 minutes (IQR 300-300 visit Y) and 240 minutes (IQR 240-360, visit Z). At each visit ≤50% of participants had completed orocaecal transit by the end of the scanning period (6 hours).

For SBWC and deltaTI we calculated the mean (95% confidence interval) at each time point and adjusted for body surface area. The mean change in adjusted SBWC area under the curve (L·min/m²) between baseline and 24 weeks was not statistically significant 11 (-0.6,22,2) p=0.064. The mean change in adjusted delta TI (mL/m2) between baseline and 24 weeks was statistically significant 54 (24.1,83.7) P< 0.001.

Conclusions: We have demonstrated that ETI increases deltaTI after 24 weeks of use, suggesting the postprandial fall in SBWC is enhanced by ETI and that these values were similar to those we have previously measured in non-CF controls (healthy volunteer median fall 102ml/m2 [IQR 67, 108], p = 0.002, Wilcoxon) (2). We also found that overall SBWC increases after 24 weeks of ETI. OCTT remained mostly unchanged after 24 weeks of ETI, with our cohort continuing to have a prolonged OCTT compared to healthy volunteers (healthy volunteer OCTT 210 mins [IQR 173, 315], p = 0.04) (2).

Acknowledgements: Funded by Vertex Pharmaceuticals (ISS-2020-109445)

References: 1. Rowbotham NJ, Smith S, Leighton PA, Rayner OC, Gathercole K, Elliott ZC, et al. The top 10 research priorities in cystic fibrosis developed by a partnership between people with CF and healthcare providers. Thorax. 2018;73(4):388-90.

2. Ng C, Dellschaft NS, Hoad CL, Marciani L, Ban L, Prayle AP, et al. Postprandial changes in gastrointestinal function and transit in cystic fibrosis assessed by Magnetic Resonance Imaging. Journal of Cystic Fibrosis. 2021;20(4):591-7.