The NIH SPAN Coordinating Center

我们提出了一种新的、适应性的、安全的系统，用于平行测试有希望的干预措施，旨在改善再灌注与溶栓、取栓或两者相比较的结果。申请人PI和合作者共同拥有数十年使用临床前动物中风模型的经验。此外，也许是独一无二的，申请人PI和合作者代表联邦政府和各种行业合作伙伴领导了大型和小型多中心和单中心1、2和3期临床试验的临床试验协调中心。因此，通过将动物建模和临床试验管理方面数十年的经验和专业知识相结合，该应用程序为NINDS提供了一个机会，可以显著提高SPAN指导选择最佳药物的可能性，以过渡到可能通过StrokeNet进行的未来临床试验。申请人PI和合作者了解并参与了许多综述和专题讨论会，详细介绍了以前临床前卒中发展的重大失败。基于良好的临床前评估，大量假定的神经保护剂进入临床试验，但在随后的人类中风患者临床试验中失败。过多的临床失败已经使行业和政府损失了数亿美元，浪费了数百名研究人员和协调人员的时间、才能和努力。近年来，急性缺血性卒中的血栓切除术的成功发展，引起了对联合血栓切除术的化合物再测试的极大热情。因此，SPAN旨在筛选和选择非常有前途的候选治疗方法，用于可能的StrokeNet研究。SPAN的成功将为新的、有前途的神经保护剂的成功临床应用提供重要的推动力。在过去的5年中，两项重大进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，以及中风治疗候选药物临床前开发的严格新标准的颁布。SPAN的努力提供了一个非常重要的机会，可以找到一个有前途的候选治疗方法，在StrokeNet中进行测试，然后反向验证理想的临床前测试范式，预测临床试验的成功。目前的应用，如果得到资助，将通过实施关键的技术创新，实现显著的改善和临床前开发的进步。我们的合作伙伴神经成像实验室（LONI）提供的最先进的技术解决方案是安全、稳健、可靠的，并且可以立即实施。Lyden和Toga在RHAPSODY期间合作，为网站提供了上传图像的交钥匙解决方案（www.LONI.usc.edu）。我们还提出了一种高度新颖的分布式、掩码评估方法。这种新颖的方法可以实现安全，盲法，成本效益高，内置中央质量控制。

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.