Cftr biomarkers: time for promotion to surrogate endpoint?

De Boeck, Christiane; Kent, L; Davies, J; Derichs, N; Amaral, M; Rowe, Sm; Middleton, P; de Jonge, H; Bronsveld, I; Wilschanski, M; Melotti, P; Danner-Boucher, I; Boerner, S; Fajac, I; Southern, K; de Nooijer, Ra; Bot, A; de Rijke, Y; De Wachter, Eva; Leal, T; Vermeulen, François; J Hug, M; Rault, G; Nguyen-Khoa, T; Barreto, C; Proesmans, Marijke; Sermet-Gaudelus, I; On behalf of the European Cystic Fibrosis Society Clinical Trial Network Standardisation Committee,

doi:10.1183/09031936.00057512

Cftr biomarkers: time for promotion to surrogate endpoint?

Author:

De Boeck, Christiane

Kent, L ; Davies, J ; Derichs, N ; Amaral, M ; Rowe, Sm ; Middleton, P ; de Jonge, H ; Bronsveld, I ; Wilschanski, M ; Melotti, P ; Danner-Boucher, I ; Boerner, S ; Fajac, I ; Southern, K ; de Nooijer, Ra ; Bot, A ; de Rijke, Y ; De Wachter, Eva ; Leal, T ; Vermeulen, François ; J Hug, M ; Rault, G ; Nguyen-Khoa, T ; Barreto, C ; Proesmans, Marijke ; Sermet-Gaudelus, I ; On behalf of the European Cystic Fibrosis Society Clinical Trial Network Standardisation Committee,

Keywords:

Science & Technology, Life Sciences & Biomedicine, Respiratory System, Clinical trials, cystic fibrosis transmembrane conductance regulator, intestinal current measurement, nasal potential difference, surrogate end-point, sweat test, NASAL POTENTIAL-DIFFERENCE, CYSTIC-FIBROSIS PATIENTS, TRANSMEMBRANE CONDUCTANCE REGULATOR, INCREASED NA+ CONDUCTANCE, HUMAN AIRWAY EPITHELIUM, BORDERLINE SWEAT TEST, CL-CHANNEL FUNCTION, GENE-TRANSFER, STOP MUTATIONS, IN-VIVO, Biomarkers, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Humans, Reproducibility of Results, European Cystic Fibrosis Society Clinical Trial Network Standardisation Committee, 11 Medical and Health Sciences, 3201 Cardiovascular medicine and haematology

Abstract:

In patients with cystic fibrosis, CFTR biomarkers such as sweat chloride concentration and/or nasal potential difference are used as endpoints of efficacy in phase III clinical trials with the disease modifying drugs ivacaftor (VX-770), VX809 and ataluren. The aim of this project was to review the literature on reliability, validity and responsiveness of nasal potential difference, sweat chloride, and intestinal current measurement in patients with cystic fibrosis.Data on clinimetric properties were collected for each biomarker and reviewed by an international team of experts. Data on reliability, validity and responsiveness were tabulated. In addition, narrative answers to 4 key questions were discussed and agreed by the team of experts.Data collected demonstrated the reliability, validity and responsiveness of nasal potential difference. Fewer data were found on reliability of sweat chloride concentration, however validity and responsiveness were demonstrated. Validity was demonstrated for intestinal current measurement, however further information is required on reliability and responsiveness. For all three endpoints, normal values were collected and further research requirements were proposed.This body of work adds useful information to support the promotion of CFTR biomarkers to surrogate endpoints and to guide further research in the area.