Outcome measures for cystic fibrosis gene therapy clinical trials

Background: Cystic fibrosis (CF) is a life-shortening, chronic respiratory disease caused by mutations in the CFTR gene. Novel therapeutic agents such as gene therapy aim to correct CFTR and to demonstrate evidence of molecular, functional and (ultimately) clinical efficacy. It was hypothesised that currently used methods to detect these changes may be optimised to enhance sensitivity and allow quantification, and facilitate an understanding of geographical effects within the airway. Methods: Outcome measures were investigated within two UK CF Gene Therapy Consortium studies; a longitudinal observational study (‘Run-In’), and a single dose gene therapy study (‘Pilot’) which investigated safety and functional efficacy. Measurement of airway function with spirometry and lung clearance index in the Run-In study allowed investigation of variability and change over time and comparison with other outcomes. Development of methodology and data analysis from measurements of potential difference (PD) in the nose and lung in the Pilot study allowed investigation of these as measures of functional efficacy. Results: In the Run-In study, the choice of external reference source was crucial for interpretation of spirometry outcomes. Airway physiology outcomes correlated with structural changes on chest CT however were limited in their ability to detect site of airway abnormality. There was some evidence that disease severity was associated with intra-subject variability and affected rate of change over time. In the Pilot study, airway PD was shown to change post gene therapy within individuals but the responses were not universal and depended on the definitions used. A novel method of nasal PD quantification did not improve an ability to quantify change. Conclusions: There is no single universal outcome measure in CF, but it is important to take account of the patient population in terms of disease severity. Whilst it would be inappropriate to relate PD outcomes with clinical outcomes in the Pilot study; this will be an important relationship to understand in the future in order to allow rational design of CF gene therapy clinical trials.Imperial Users Onl