The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results
Authors: Lyden Patrick D. , Bosetti Francesca , Diniz Márcio A. , Rogatko André , Koenig James I. , Lamb Jessica , Nagarkatti Karisma A. , Cabeen Ryan P. , Hess David C. , Kamat Pradip K. , Khan Mohammad B. , Wood Kristofer , Dhandapani Krishnan , Arbab Ali S. , Leira Enrique C. , Chauhan Anil K. , Dhanesha Nirav , Patel Rakesh B. , Kumskova Mariia , Thedens Daniel , Morais Andreia , Imai Takahiko , Qin Tao , Ayata Cenk , Boisserand Ligia S.B. , Herman Alison L. , Beatty Hannah E. , Velazquez Sofia E. , Diaz-Perez Sebastian , Sanganahalli Basavaraju G. , Mihailovic Jelena M. , Hyder Fahmeed , Sansing Lauren H. , Koehler Raymond C. , Lannon Steven , Shi Yanrong , Karuppagounder Senthilkumar S. , Bibic Adnan , Akhter Kazi , Aronowski Jaroslaw , McCullough Louise D. , Chauhan Anjali , Goh Andrew , Siddiqui Shahneela , Sheth Kevin , Matouk Charles , Cruz Charles Dela , Zhou Jiangbing , Dawson Valina L. , Dawson Ted M. , Liang Jian , van Zijl Peter C.M. , Zeiler Steven R. , Taylor Kimberly W. , Erdogan Taylan , Yu Lili , Mandeville Joseph , Whittier Jonah Patrick Weigand 
Published: March 2022

Cerebral ischemia and reperfusion initiate cellular events in brain that lead to neurological disability. Investigating these cellular events provides ample targets for developing new treatments. Despite considerable work, no such therapy has translated into successful stroke treatment. Among other issues—such as incomplete mechanistic knowledge and faulty clinical trial design—a key contributor to prior translational failures may be insufficient scientific rigor during preclinical assessment: nonblinded outcome assessment; missing randomization; inappropriate sample sizes; and preclinical assessments in young male animals that ignore relevant biological variables, such as age, sex, and relevant comorbid diseases. Promising results are rarely replicated in multiple laboratories. We sought to address some of these issues with rigorous assessment of candidate treatments across 6 independent research laboratories. The Stroke Preclinical Assessment Network (SPAN) implements state-of-the-art experimental design to test the hypothesis that rigorous preclinical assessment can successfully reduce or eliminate common sources of bias in choosing treatments for evaluation in clinical studies. SPAN is a randomized, placebo-controlled, blinded, multilaboratory trial using a multi-arm multi-stage protocol to select one or more putative stroke treatments with an implied high likelihood of success in human clinical stroke trials. The first stage of SPAN implemented procedural standardization and experimental rigor. All participating research laboratories performed middle cerebral artery occlusion surgery adhering to a common protocol and rapidly enrolled 913 mice in the first of 4 planned stages with excellent protocol adherence, remarkable data completion and low rates of subject loss. SPAN stage 1 successfully implemented treatment masking, randomization, prerandomization inclusion/exclusion criteria, and blinded assessment to exclude bias. Our data suggest that a large, multilaboratory, preclinical assessment effort to reduce known sources of bias is feasible and practical. Subsequent SPAN stages will evaluate candidate treatments for potential success in future stroke clinical trials using aged animals and animals with comorbid conditions.