Accelerating Osteoarthritis Clinical Trials Through Responsive Low-Dose Standing CT Imaging

项目总结/摘要 这项研究的长期目标是使更多的负担得起的和更短的持续时间的临床试验， 从而促进了对膝骨关节炎（OA）的有效疾病改善疗法的引入。 OA影响超过2700万美国人，使他们遭受疼痛，严重的移动限制和大面积的疼痛。 医疗保健支出。我们预测和检测疾病进展的能力存在差距， 预防这种流行病的潜力。决定预后的关键障碍， 纵向监测膝关节OA是X线片的敏感性和反应性差， 评价膝关节OA的常用方法。有时，这些局限性使小说的进步 治疗费用昂贵，需要大样本量和长时间的随访 用于临床研究。我们的初步研究确立了检测膝关节OA关键特征的可行性 准确和可靠的站立CT（SCT）成像。在建议的计划中，我们会设立 比放射学检查更有用的OA生物标志物的性能。我们建议解决 开始对这些基于SCT的OA生物标志物进行鉴定所需的其余步骤。目标1： 确定SCT生物标志物用于检测膝关节OA进展的反应性，并建立 通过与MRI上软骨恶化比较的同时有效性。目标2是量化 更灵敏的胰腺挤压检测对预测快速胰腺炎的预后价值增加 软骨损伤和膝关节疼痛恶化。实现这些目标将是变革性的;引入 用于评估OA的更敏感和响应性更高的生物标志物，而不会显著增加成本， 时间或辐射暴露。早期检测骨和骨组织结构变化的能力， 疾病的过程可以加速科学进步和临床护理。增强的性能可以 确定患者最有可能对干预措施作出反应的阶段。预期的产品将是 立即递送用于检测和纵向评估OA的显著改进的生物标志物， 可以在临床试验中部署，使用具有相同相对辐射水平的紧凑型扫描仪， X光片增强的预测和测量OA进展的能力将解决 通过更有效地评估治疗效果，促进OA研究和患者护理的进展。 将OA指定为严重疾病为OA治疗的批准开辟了快速途径， 这项研究及时。该项目的长期影响将是临床试验和护理的潜在转变- 替代X线片监测膝关节OA。这项研究将促进预测能力， 监测膝关节OA恶化，通过减少所需的治疗， 临床试验的样本量、持续时间和成本，从而有力地影响预防和治疗。

Project Summary/Abstract The long-term objective of this research is to enable more affordable and shorter duration clinical trials, thereby facilitating the introduction of effective disease modifying therapies for knee osteoarthritis (OA). OA affects over 27 million Americans, afflicting them with pain, substantial mobility limitations, and large health care expenditures. There are gaps in our ability to predict and detect progression, limiting the potential to forestall this prevalent disease. The critical barriers to determining prognosis and longitudinally monitoring knee OA are the poor sensitivity and responsiveness of radiographs, the most common means of evaluating knee OA. At times, these limitations have made advancement of novel treatments prohibitively expensive, through necessitating large sample sizes and long durations of follow-up for clinical studies. Our preliminary studies established the feasibility of detecting key knee OA features accurately and reliably with standing CT (SCT) imaging. In the proposed project, we will establish the performance of more useful biomarkers for OA than are available with radiographs. We propose to address the remaining steps necessary to begin qualification of these SCT-based OA biomarkers. Aim 1 is to determine the responsiveness of SCT biomarkers for detecting knee OA progression, and to establish concurrent validity through comparison with worsening of cartilage on MRI. Aim 2 is to quantify the added prognostic value of more sensitive detection of meniscal extrusion for prediction of rapid worsening of cartilage lesions and knee pain. Achieving these aims will be transformative; introducing more sensitive and responsive biomarkers for assessing OA, without significantly increasing the cost, time or radiation exposure. The ability to detect structural changes in bone and menisci earlier in the disease process could accelerate scientific progress and clinical care. The enhanced performance could identify stages when patients are most likely to respond to interventions. The expected product will be immediate delivery of substantially improved biomarkers for detection and longitudinal evaluation of OA, that could be deployed in clinical trials, using a compact scanner with the same Relative Radiation Level as radiographs. The enhanced ability to predict and measure OA progression will address critical barriers to progress in OA research and patient care by enabling more efficient assessment of therapeutic efficacy. Designation of OA as a serious disease is opening expedited pathways to approval of OA therapies, making this research timely. The long-term impact of this project will be a potential shift in clinical trials and care— replacement of radiographs for monitoring of knee OA. This research will catalyze the ability to predict and monitor knee OA worsening, enabling more rapid development of therapies by reducing the required sample sizes, duration and costs of clinical trials, thereby powerfully influencing prevention and treatment.