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

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 network for the rigorous assessment of candidate stroke treatments combined with intravascular thrombectomy. Futility boundaries in a Multi-Arm Multi-Stage statistical design aimed to exclude less effective interventions, and efficacy boundaries allowed early declaration of success 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 2,615 animals with full data completion and comprehensive animal tracking. SPAN successfully implemented treatment masking, randomization, pre-randomization 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.

Methods
SPAN consists of six research laboratories to conduct preclinical stroke modeling and a coordinating center to mask drugs, conduct centralized randomization, assess blinded outcomes, collect data, and perform statistics. The aim of SPAN was to determine whether such rigor is feasible and practical on a large scale in a multi-laboratory controlled, randomized preclinical study of six investigator-initiated putative interventions for acute ischemic stroke, selected through a rigorous NIH-peer review. Here we report the primary results of SPAN.