Developing patient-relevant outcome measures for clinical trials of sight-restoring interventions in very low and ultra-low vision

遗传性视网膜营养不良(IRD)恢复视力的新技术和治疗方法正在迅速发展，包括基因治疗、干细胞和视网膜视觉假体。然而，测试这些创新的有效性是具有挑战性的，因为常规使用的临床终点，如字母表视力或视野测试，不足以获得这些干预措施预期的非常小的功能益处。然而，现实世界的功能和生活质量(QOL)可以通过这些干预措施预期的视觉功能的微小改善来改善，因此应该在临床试验中被捕捉到。此外，它们还反映了通过这些干预措施为患者带来的实际好处。在此背景下，我们开发了两种测量现实世界功能和生活质量的工具，日常生活工具活动-非常低视力(IADL-VLV)和视力损害-非常低视力的影响(IVI-VLVL)。第一个是对在几个真实世界任务中观察到的表现的标准化测量，而后者是与视觉相关的生活质量的标准化测量。这些都是由于IRDS导致的低视力或超低视力的人患上的。在这个项目中，我们将通过跟踪一组IRDS患者两年来评估测量精度和对功能变化的响应性，进一步验证这两种结果指标作为临床终点的有效性。这将使我们能够建立最小的临床相关变化，这对未来介入试验的设计将是重要的。遵循最佳实践将确保结果衡量标准不仅与患者相关，而且还为监管机构所接受。在这个项目结束时，我们将有两个准备好使用的临床终端，这将允许将新的视力恢复干预措施快速转化为临床研究并最终付诸实践。

Promising new technologies and treatments for restoring vision in inherited retinal dystrophies (IRDs) are rapidly evolving, including gene therapy, stem cells and retinal visual prostheses. However, testing the efficacy of these innovations is challenging as conventionally used clinical endpoints such as letter chart visual acuity or visual field testing are inadequate to capture the very small functional benefits expected with these interventions. Real-world functioning and quality of life (QoL), however, can be improved by even the small improvements in visual function expected with these interventions and thus should be captured in clinical trials. In addition, they reflect the real benefit for patients gained through these interventions. Against this background we developed two measures of real-world functioning and QoL, the Instrumental Activities of Daily Living – Very Low Vision (IADL-VLV) and the Impact of Vision Impairment – Very Low Vision (IVI-VLVL). The first is a standardized measure of observed performance on several real-world tasks and the latter is a standardized measure of vision-related QoL. These were developed with persons with low or ultra-low vision due to IRDs. In this project we will further validate these two outcome measures as clinical endpoints by assessing measurement precision and responsiveness to change in function over time by following a group of patients with IRDs for two years. This will allow us to establish a minimal clinically relevant change which will be important for the design of future interventional trials. Following best practice will guarantee that the outcome measures are not only relevant to patients but also acceptable to regulatory agencies. At the end of this project we will have two ready to use clinical endpoints which will allow for a fast translation of novel sight restoration interventions into clinical research and ultimately practice.