Journal article
The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results
Stroke (1970), Vol.53(5), pp.1802-1812
03/31/2022
DOI: 10.1161/STROKEAHA.121.038047
PMCID: PMC9038686
PMID: 35354299
Abstract
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.
Details
- Title: Subtitle
- The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results
- Creators
- Patrick D Lyden - Department of Neurology, Keck School of Medicine of USC, Los Angeles, CA. (P.D.L.)Francesca Bosetti - National Institute of Neurological Disorders and StrokeMárcio A Diniz - Cedars-Sinai Medical CenterAndré Rogatko - Cedars-Sinai Medical CenterJames I Koenig - National Institute of Neurological Disorders and StrokeJessica Lamb - Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Los Angeles, CA (P.D.L., J.L., K.A.N.)Karisma A Nagarkatti - Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Los Angeles, CA (P.D.L., J.L., K.A.N.)Ryan P Cabeen - Laboratory of Neuro Imaging, USC Mark and Mary Stevens Imaging and Informatics Institute, Keck School of Medicine of USC, Los Angeles, CA. (R.P.C.)David C Hess - Augusta UniversityPradip K Kamat - Augusta UniversityMohammad B Khan - Augusta UniversityKristofer Wood - Augusta UniversityKrishnan Dhandapani - Augusta UniversityAli S Arbab - Augusta UniversityEnrique C Leira - Carver College of Medicine and Department of Epidemiology, College of Public Health, University of Iowa. (E.C.L.)Anil K Chauhan - Department of Internal Medicine, College of Public Health, University of Iowa. (A.K.C., N.D., R.B.P., M.K.)Nirav Dhanesha - Department of Internal Medicine, College of Public Health, University of Iowa. (A.K.C., N.D., R.B.P., M.K.)Rakesh B Patel - Department of Internal Medicine, College of Public Health, University of Iowa. (A.K.C., N.D., R.B.P., M.K.)Mariia Kumskova - University of IowaDaniel Thedens - University of IowaAndreia Morais - Harvard Medical SchoolTakahiko Imai - Harvard Medical SchoolTao QinCenk Ayata - Harvard Medical SchoolLigia S B Boisserand - Yale UniversityAlison L Herman - Yale UniversityHannah E Beatty - Yale UniversitySofia E Velazquez - Yale UniversitySebastian Diaz-Perez - Yale UniversityBasavaraju G Sanganahalli - Yale UniversityJelena M Mihailovic - Yale UniversityFahmeed Hyder - Yale UniversityLauren H Sansing - Yale UniversityRaymond C Koehler - Johns Hopkins UniversitySteven Lannon - Johns Hopkins UniversityYanrong Shi - Johns Hopkins UniversitySenthilkumar S Karuppagounder - Johns Hopkins UniversityAdnan Bibic - Johns Hopkins UniversityKazi Akhter - Johns Hopkins UniversityJaroslaw Aronowski - Department of Neurology, McGovern Medical School, University of Texas HSC, Houston (J.A., L.D.M., A.C., A.G.)Louise D McCullough - Department of Neurology, McGovern Medical School, University of Texas HSC, Houston (J.A., L.D.M., A.C., A.G.)Anjali Chauhan - Department of Neurology, McGovern Medical School, University of Texas HSC, Houston (J.A., L.D.M., A.C., A.G.)Andrew Goh - Department of Neurology, McGovern Medical School, University of Texas HSC, Houston (J.A., L.D.M., A.C., A.G.)SPAN Investigators
- Resource Type
- Journal article
- Publication Details
- Stroke (1970), Vol.53(5), pp.1802-1812
- DOI
- 10.1161/STROKEAHA.121.038047
- PMID
- 35354299
- PMCID
- PMC9038686
- NLM abbreviation
- Stroke
- eISSN
- 1524-4628
- Language
- English
- Date published
- 03/31/2022
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Neurology; Radiology; Electrical and Computer Engineering; Hematology, Oncology, and Blood & Marrow Transplantation; Epidemiology; Iowa Neuroscience Institute; Neurosurgery; Internal Medicine
- Record Identifier
- 9984230624802771
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