The NIH SPAN Coordinating Center

摘要 我们提出了一种新颖的，自适应的，安全的系统，用于并行测试有前途的干预措施，旨在提高 与单独再灌注联合溶栓、血栓切除术或两者相比的结局。申请人PI和合作者 一起拥有数十年的临床前动物中风模型使用经验。此外，也许是唯一的，申请人 PI和合作者领导了大型和小型多中心和单中心I期临床试验协调中心， 2，和3临床试验代表联邦政府和各种行业合作伙伴。因此，通过结合几十年来 在动物建模和临床试验管理方面的经验和专业知识，该应用程序为NINDS提供了 机会，以显着提高的可能性，SPAN将指导选择最佳代理人过渡到 未来的临床试验可能会通过中风网络进行。申请人PI和合作者知道，并且 参与了许多综述和研讨会，详细介绍了以前临床前卒中发展的重大失败。 基于有利的临床前评估，大量假定的神经保护剂进入临床试验，但都失败了 在随后的人类中风患者的临床试验中。过多的临床失败让工业和政府付出了代价 数亿美元，浪费了数百名调查人员和协调员的时间、人才和努力。 最近血栓切除术治疗急性缺血性卒中的成功发展， 重新测试化合物与血栓切除术的组合。因此，SPAN的目的是筛选和选择高度有前途的 在StrokeNet中进行可能研究的候选治疗方法。跨太平洋战略伙伴关系的成功将大大推动 为成功的临床部署的新的，有前途的神经保护剂的努力。在过去的五年里，两个重要的 发展为神经保护带来了新的希望：具有多种作用机制的化合物的出现， 以及颁布严格的中风治疗候选药物临床前开发的新标准。的 SPAN的努力提供了一个非常重要的机会，找到一个有前途的候选治疗，测试它在中风网络， 然后反向验证预测临床试验成功的理想临床前测试范例。这个礼物 如果获得资助，申请将通过以下方式实现临床前开发的显著改善和进步： 实施关键技术创新。我们的合作伙伴提供的最先进的技术解决方案， 神经影像实验室（LONI）是安全，强大，可靠，并准备立即实施，因为博士 和Toga在RHAPSODY期间合作，为网站提供上传图像的交钥匙解决方案（www.LONI.usc.edu）。 我们还提出了高度新颖的使用分布式，掩蔽评价。这种新颖的方法允许一种安全的， 设盲、经济高效、内置中央质量控制。

Abstract We propose a novel, adaptive, secured system for parallel testing of promising interventions designed to improve outcome compared to reperfusion alone with thrombolysis, thrombectomy or both. The applicant PI and collaborators together have decades of experience using preclinical animal stroke models. Also, and perhaps uniquely, the applicant PI and collaborators have led clinical trial coordinating centers for large and small multi‐center and single center Phase 1, 2, and 3 clinical trials on behalf of the Federal Government and various industry partners. Thus, by combining decades of experience and expertise in animal modeling with clinical trial management this application affords NINDS an opportunity to significantly enhance the likelihood that SPAN will guide the selection of the best agent(s) to transition to future clinical trials likely to be conducted through StrokeNet. The applicant PI and collaborators are aware of, and have participated in, many reviews and symposia detailing the significant failures of previous preclinical stroke development. A plethora of putative neuroprotectants proceeded to clinical trial based on favorable preclinical assessment, only to fail in subsequent clinical trials of human stroke patients. The plethora of clinical failures has cost industry and governments hundreds of millions of dollars and wasted the time, talent, and effort of hundreds of investigators and coordinators. The recent successful development of thrombectomy for acute ischemic stroke generated considerable enthusiasm for re‐testing compounds in combination with thrombectomy. Thus, SPAN is intended to screen and select highly promising candidate treatments for possible study in StrokeNet. A success in SPAN will provide a significant impetus to renew efforts toward successful clinical deployment of novel, promising neuroprotectants. In the past 5 years, two significant developments raise new hope for neuroprotection: the appearance of compounds with multiple mechanisms of action, and the promulgation of new standards for the rigorous preclinical development of stroke treatment candidates. The SPAN effort affords the highly significant opportunity to find a promising candidate treatment, test it in StrokeNet, and then back‐validate the ideal preclinical testing paradigm that predicts success in clinical trials. This present application, if funded, will achieve significant improvement and advancement of preclinical development by implementing critical technical innovations. The state‐of‐the‐art technical solution offered by our collaborator, the Laboratory of Neuroimaging (LONI) is secure, robust, reliable, and ready to implement immediately because Drs. Lyden and Toga collaborated during RHAPSODY to provide sites a turn‐key solution for uploading images (www.LONI.usc.edu). We also propose the highly novel use of distributed, masked evaluation. This novel approach allows for a secure, blinded, cost efficient, with built in central quality‐control.