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A multi-laboratory preclinical trial in rodents to assess treatment candidates for acute ischemic stroke

2023; American Association for the Advancement of Science; Volume: 15; Issue: 714 Linguagem: Inglês

10.1126/scitranslmed.adg8656

1946-6242

Patrick D. Lyden, Márcio A. Diniz, Francesca Bosetti, Jessica Lamb, Karisma Nagarkatti, André Rogatko, Sungjin Kim, Ryan P. Cabeen, James I. Koenig, Kazi Akhter, Ali S. Arbab, Brooklyn Avery, Hannah E. Beatty, Adnan Bibic, Suyi Cao, Lígia Simões Braga Boisserand, Ángel Chamorro, Anjali Chauhan, Sebastián Díaz-Pérez, Krishnan M. Dhandapani, Nirav Dhanesha, Andrew Goh, Alison L. Herman, Fahmeed Hyder, Takahiko Imai, Conor W. Johnson, Mohammad Badruzzaman Khan, Pradip K. Kamat, Senthilkumar S. Karuppagounder, Mariia Kumskova, Jelena Mihailovic, Joseph B. Mandeville, Andreia Morais, Rakesh B. Patel, Basavaraju G. Sanganahalli, Cameron Smith, Yanrong Shi, Brijesh Sutariya, Daniel R. Thedens, Tao Qin, Sofia Velazquez, Jaroslaw Aronowski, Cenk Ayata, Anil K. Chauhan, Enrique C. Leira, David C. Hess, Raymond C. Koehler, Louise D. McCullough, Lauren Sansing,

Neuroinflammation and Neurodegeneration Mechanisms

Human diseases may be modeled in animals to allow preclinical assessment of putative new clinical interventions. Recent, highly publicized failures of large clinical trials called into question the rigor, design, and value of preclinical assessment. We established the Stroke Preclinical Assessment Network (SPAN) to design and implement a randomized, controlled, blinded, multi-laboratory trial for the rigorous assessment of candidate stroke treatments combined with intravascular thrombectomy. Efficacy and futility boundaries in a multi-arm multi-stage statistical design aimed to exclude from further study highly effective or futile interventions after each of four sequential stages. Six independent research laboratories performed a standard focal cerebral ischemic insult in five animal models that included equal numbers of males and females: young mice, young rats, aging mice, mice with diet-induced obesity, and spontaneously hypertensive rats. The laboratories adhered to a common protocol and efficiently enrolled 2615 animals with full data completion and comprehensive animal tracking. SPAN successfully implemented treatment masking, randomization, prerandomization inclusion and exclusion criteria, and blinded assessment of outcomes. The SPAN design and infrastructure provide an effective approach that could be used in similar preclinical, multi-laboratory studies in other disease areas and should help improve reproducibility in translational science.