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（IRDs）患者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，因为传统使用的临床终点，如字母图视力或视野测试不足以捕捉到这些干预措施所期望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所期望的视觉功能的微小改善而得到改善，因此应该在临床试验中加以捕捉。此外，它们反映了通过这些干预措施为患者获得的真正益处。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方法，即日常生活工具活动-极低视力（IADL-VLV）和视力障碍的影响-极低视力（IVI-VLVL）。前者是对几个现实世界任务中观察到的性能的标准化度量，后者是对视觉相关生活质量的标准化度量。这些是由于IRDs导致的低视力或超低视力的人发展起来的。在这个项目中，我们将进一步验证这两个结果测量作为临床终点，通过跟踪一组ird患者两年，评估测量精度和对功能变化的反应性。这将使我们能够建立最小的临床相关变化，这对未来介入性试验的设计非常重要。遵循最佳实践将保证结果测量不仅与患者相关，而且为监管机构所接受。在这个项目结束时，我们将有两个准备使用的临床终点，这将允许将新的视力恢复干预措施快速转化为临床研究和最终实践。

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.