The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results

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.

Reaching a Tipping Point for Neurorehabilitation Research: Obstacles and Opportunities in Trial Design, Description, and Pooled Analysis

“…There is a lack of consensus among researchers, fueled in large part by a murky literature strewn with underpowered preclinical and pilot studies. 8,27,28 Whereas numerous frameworks for identifying promising preclinical candidates have been put forth [28][29][30] and calls have been made to ground rehabilitation trials on better preclinical and early-stage studies, 31 strategies for identifying the best candidates for MCTs in neurorehabilitation remain under-implemented.…”

“…Preclinical and clinical research groups in all aspects of neurorehabilitation should look to the Stroke Preclinical Assessment Network as a sterling example of collaboration between laboratories to increase statistical power and methodological reliability on the pathway toward selecting treatments for RCTs. 28 By de-emphasizing first- and senior-author publications, academic institutions and funding agencies can better incentivize these essential forms of collaboration, enhancing the likelihood of reliable data aggregation and meaningful trial findings.…”

Image-based Stroke Assessment for Multi-site Preclinical Evaluation of Cerebroprotectants

“…This paper describes the development of a fully automated image analysis pipeline for the Stroke Preclinical Assessment Network (SPAN) [20], which is an effort to meet these emerging preclinical study needs. SPAN is funded by the National Institutes of Neurological Disorders and Stroke (NINDS) and was created to address critical issues of rigor, transparency, and reproducibility.…”

Evaluating U-net Brain Extraction for Multi-site and Longitudinal Preclinical Stroke Imaging

“…We investigate these questions in the present paper, with the larger goal of developing a brain extraction tool for an image analysis pipeline for the Stroke Preclinical Assessment Network (SPAN) [19]. SPAN is a multi-center study funded by the National Institutes of Neurological Disorders and Stroke (NINDS) to investigate putative stroke treatments and to address critical issues of rigor, transparency, and reproducibility in preclinical stroke research.…”