Background: Elexacaftor in combination with Tezacaftor and Ivacaftor (ETI) became licensed in the United Kingdom in early 2022 for children aged 6-11 years with cystic fibrosis (CF) and an eligible mutation. Many in this age group have excellent prior lung health making quantitative measurement of benefit challenging. Clinical trials purport that lung clearance index (LCI 2.5 ) measurement is most suitable for this purpose., Objectives: This study aimed to understand the clinical utility of LCI 2.5 in detecting change after commencing ETI in the real world., Patient Selection/methods: Baseline anthropometric data were collected along with spirometry (forced expiratory volume in 1 s [FEV 1 ], forced vital capacityFV and LCI 2.5 measures in children aged 6-11 years with CF before starting ETI. Measures were repeated after a mean (range) of 8.2 (7-14) months of ETI treatment. The primary endpoint was a change in LCI 2.5 , with secondary endpoints including change in FEV 1 and change in body mass index (BMI) also reported., Results: Twelve children were studied (seven male, mean age 9.5 years at baseline). Our study population had a mean (SD) LCI 2.5 of 7.01 (1.14) and FEV 1 of 96 (13) %predicted at baseline. Mean (95% confidence interval) changes in LCI 2.5 [-0.7 (-1.4, 0), p = .06] and BMI [+0.7 (+0.1, +1.3), p = .03] were observed, along with changes in FEV 1 of +3.1 (-1.9, +8.1) %predicted., Conclusions: Real-world changes in LCI 2.5 (-0.7) are different to those reported in clinical trials (-2.29). Lower baseline LCI 2.5 as a result of prior modulator exposure, high baseline lung health, and new LCI 2.5 software analyses all contribute to lower LCI 2.5 values being recorded in the real world of children with CF., (© 2024 Wiley Periodicals LLC.)