The effect of CFTR modulators on CT outcomes in cystic fibrosis

Background: There is a lack of sensitive clinical trial outcome measures to monitor the effect of novel therapies in children with cystic fibrosis (CF). Aim: To assess the effect of CFTR modulators on structural lung disease using computed tomography (CT) analysis methods suitable for early disease. Methods: CF patients receiving ivacaftor or lumacaftor-ivacaftor, and controls (age, sex, genotype matched) contributed clinical data and chest CT scans performed before and after initiation of CFTR modulator therapy. We assessed CT image biomakers from the Perth Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF), CF-CT and airway-artery dimensions. Analysis of Covariance was used to compare lung disease progression in treatment and control groups. We performed subgroup analyses on data of paediatric subjects. Results: We included 16 treatment and 25 control subjects, with median (range) age at baseline of 12.55 (4.25-36.49) years and 8.34 (3.47-38.29) years, respectively. Treatment subjects improved in PRAGMA-CF airways disease [-2.78(-4.44,-1.13), p=0.002] and bronchiectasis extent [-1.92(-3.01,-0.82), p=0.001] compared to controls. There were no significant differences in CF-CT outcomes or airway-artery dimensions between treatment and control groups. Subgroup analysis of paediatric data showed that PRAGMA-CF bronchiectasis [-0.93(-1.77,-0.09), p=0.032] improved in treatment subjects compared to controls. Conclusion: Quantitative CT image biomarkers provide more sensitive assessments of treatment efficacy on lung structure and have the potential to be used in early interventional studies. However, a larger study population is needed to determine the long-term effects of therapy on structural lung disease.