The NIH SPAN Coordinating Center

我们提出了一种新颖的、适应性的、安全的系统，用于并行测试有希望的干预措施，与单独再灌注和溶栓、血栓切除术或两者相比，旨在改善结果。申请人的 PI 和合作者拥有数十年使用临床前动物中风模型的经验。此外，也许独特的是，申请人的 PI 和合作者代表联邦政府和各个行业合作伙伴领导了大型和小型多中心和单中心 1 期、2 期和 3 期临床试验的临床试验协调中心。因此，通过将数十年的动物建模经验和专业知识与临床试验管理相结合，该应用程序为 NINDS 提供了一个机会，可以显着提高 SPAN 指导选择最佳药物以过渡到可能通过 StrokeNet 进行的未来临床试验的可能性。申请人的 PI 和合作者了解并参与了许多详细介绍先前临床前卒中开发的重大失败的审查和研讨会。基于有利的临床前评估，大量假定的神经保护剂进入了临床试验，但在随后的人类中风患者临床试验中却失败了。大量的临床失败给行业和政府造成了数亿美元的损失，并浪费了数百名研究人员和协调员的时间、人才和精力。最近成功开发的治疗急性缺血性中风的血栓切除术引起了人们对重新测试与血栓切除术相结合的化合物的极大热情。因此，SPAN 旨在筛选和选择高度有前途的候选治疗方法，用于 StrokeNet 中的可能研究。 SPAN 的成功将为重新努力成功临床部署新型有前途的神经保护剂提供重要动力。在过去的五年里，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严格临床前开发的新标准的颁布。 SPAN 的努力提供了一个非常重要的机会，可以找到一种有前途的候选治疗方法，在 StrokeNet 中对其进行测试，然后对预测临床试验成功的理想临床前测试范例进行反向验证。本申请如果获得资助，将通过实施关键技术创新来实现临床前开发的重大改进和进步。我们的合作者神经影像实验室 (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，因为 Drs. Lyden 和 Toga 在 RHAPSODY 期间合作，为网站提供上传图像的统包解决方案 (www.LONI.usc.edu)。我们还提出了分布式、屏蔽评估的高度新颖的使用。这种新颖的方法可以实现安全、盲目、经济高效，并具有内置的中央质量控制。

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.