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- Title
A multi-laboratory preclinical trial in rodents to assess treatment candidates for acute ischemic stroke.
- Authors
Lyden, Patrick D.; Diniz, Márcio A.; Bosetti, Francesca; Lamb, Jessica; Nagarkatti, Karisma A.; Rogatko, André; Kim, Sungjin; Cabeen, Ryan P.; Koenig, James I.; Akhter, Kazi; Arbab, Ali S.; Avery, Brooklyn D.; Beatty, Hannah E.; Bibic, Adnan; Cao, Suyi; Simoes Braga Boisserand, Ligia; Chamorro, Angel; Chauhan, Anjali; Diaz-Perez, Sebastian; Dhandapani, Krishnan
- Abstract
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. Editor's summary: Preclinical science faces a reproducibility crisis. This hampers clinical translation and has led to the call for more rigorous and unbiased preclinical trials. Here Lyden and colleagues present the outcome of a randomized and blinded preclinical trial to assess stroke interventions, conducted by the Stroke Preclinical Assessment Network. Two thousand six hundred fifteen mice and rats were enrolled across six research laboratories that adhered to standardized protocols. Using a multi-arm multi-stage design, the authors tested six treatment candidates in four stages comprising different rodent models of ischemic stroke. Interventions that did not meet statistical criteria were eliminated after each stage. Only one intervention, uric acid, exceeded the efficacy threshold at the last stage of the trial. These results show that standardized preclinical trials across multiple laboratories are feasible. —Daniela Neuhofer
- Subjects
ISCHEMIC stroke; MEDICAL sciences; RODENTS; ANIMAL tracks; URIC acid
- Publication
Science Translational Medicine, 2023, Vol 15, Issue 714, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.adg8656