The NIH SPAN Coordinating Center

我们提出了一种新的、自适应的、安全的系统，用于平行测试有希望的干预措施，这些干预措施旨在改善结果，与单纯再灌注和/或溶栓、血栓切除相比。申请者Pi和合作者一起拥有数十年使用临床前动物中风模型的经验。此外，可能是独一无二的是，申请者PI和合作者代表联邦政府和各种行业合作伙伴领导了大小多中心和单中心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，这一应用为NINDS提供了一个机会，显著提高了SPAN将指导最佳代理人(S)的选择过渡到可能通过StrokeNet进行的未来临床试验的可能性。申请者PI和合作者知道并参与了许多综述和研讨会，详细描述了先前临床前卒中开发的重大失败。基于良好的临床前评估，大量假定的神经保护剂继续进行临床试验，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花费了工业界和政府数亿美元，浪费了数百名研究人员和协调员的时间、人才和努力。最近成功开发了治疗急性缺血性卒中的血栓切除术，这引起了人们对结合血栓切除术重新测试化合物的相当大的热情。因此，SPAN旨在为StrokeNet的可能研究筛选和选择非常有希望的候选治疗方法。SPAN的成功将为成功应用新型、有前景的神经保护剂提供重要的推动力。在过去的5年里，两个重大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，以及中风候选治疗方案的严格临床前开发的新标准的颁布。SPAN的努力提供了非常重要的机会，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。这项目前的应用，如果得到资助，将通过实施关键的技术创新，实现临床前开发的显著改进和进步。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、可靠、可靠的，并且可以立即实施，因为Lyden博士和Toga博士在Rhapsody期间进行了合作，为网站提供了上传图像的交钥匙解决方案(www.LONI.usc.edu)。我们还提出了分布式掩蔽评估的高度新颖的使用。这种新的方法允许安全、盲目、具有成本效益的、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.