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

用于恢复遗传性视网膜营养不良（IRD）视力的有前途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，如字母表视力或视野测试不足以捕捉这些干预措施预期的非常小的功能性益处。然而，即使是这些干预措施预期的视觉功能的微小改善，也可以改善现实世界的功能和生活质量（QoL），因此应在临床试验中获得。此外，它们反映了通过这些干预措施为患者带来的真实的益处。在此背景下，我们开发了两种真实世界功能和生活质量的测量方法，即工具性日常生活活动-极低视力（IADL-VLV）和视力损害的影响-极低视力（IVI-VLVL）。第一个是在几个现实世界的任务上观察到的性能的标准化测量，后者是视觉相关的QoL的标准化测量。这些是针对因IRD导致的低视力或超低视力的人开发的。在本项目中，我们将通过对一组IRD患者进行为期两年的随访，评估测量精度和对功能随时间变化的反应性，进一步验证这两种结局指标作为临床终点。这将使我们能够确定最小的临床相关变化，这对未来干预性试验的设计非常重要。遵循最佳实践将保证结局指标不仅与患者相关，而且也能为监管机构所接受。在这个项目结束时，我们将有两个准备使用的临床终点，这将允许快速翻译的新的视力恢复干预到临床研究和最终的实践。

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.