University Hospital of Leuven, Leuven, Belgium.
Eur Respir J. 2013 Jan;41(1):203-16. doi: 10.1183/09031936.00057512. Epub 2012 Aug 9.
In patients with cystic fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers, such as sweat chloride concentration and/or nasal potential difference, are used as end-points 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 four key questions were discussed and agreed by the team of experts. The 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, but further information is required on reliability and responsiveness. For all three end-points, 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 end-points and to guide further research in the area.
在囊性纤维化患者中，囊性纤维化跨膜电导调节因子 (CFTR) 生物标志物，如汗液氯化物浓度和/或鼻电位差，被用作疾病修正药物 ivacaftor (VX-770)、VX809 和 ataluren 的 III 期临床试验的疗效终点。本项目的目的是回顾囊性纤维化患者鼻电位差、汗液氯化物和肠道电流测量的可靠性、有效性和反应性的文献。为每个生物标志物收集了临床计量学特性的数据，并由一个国际专家小组进行了审查。对可靠性、有效性和反应性的数据进行了制表。此外，还对专家组讨论并达成一致的四个关键问题的叙述性答案进行了讨论。收集的数据表明鼻电位差具有可靠性、有效性和反应性。关于汗液氯化物浓度的可靠性数据较少，但也证明了其有效性和反应性。肠道电流测量的有效性得到了证明，但需要进一步了解其可靠性和反应性。对于所有三个终点，都收集了正常值，并提出了进一步的研究要求。这项工作提供了有用的信息，支持将 CFTR 生物标志物推广为替代终点，并指导该领域的进一步研究。
