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Life sciences · Journal article
Circulation Research · September 23, 2026
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BACKGROUND: Negative clinical trials foster therapeutic nihilism and public skepticism, especially if they follow optimistic preclinical results. One way to increase the likelihood of successful clinical trials is to enhance the preclinical testing of new treatments. Recently, multicenter preclinical testing networks have gained attention as one tool to enhance rigor and reduce the likelihood of erroneously recommending a new candidate treatment for advancement to clinical trial testing. METHODS: The SPAN (Stroke Preclinical Assessment Network) consists of 6 research laboratories performing the experiments and 1 coordinating center at which treatments are prepared in a blinded manner, subjects are randomized, and statistical analysis is performed. We conducted a rigorous trial that included both sexes, multiple comorbidities, randomization, concealment of treatment status, blinded outcome assessments, prespecified sample sizes, and comprehensive data tracking. Five promising treatments were evaluated: BPN-27332, a lipoxygenase inhibitor; uric acid, a potent natural scavenger of free radicals; tatCN19o, a peptide inhibitor of activated CaMKII (Ca 2+ /CaM–dependent protein kinase II); GSK2256294, an inhibitor of sEH (soluble epoxide hydrolase); and NVX-058, an oxygen-carrying compound. A behavioral battery was selected as the end point for the primary analysis. The primary analysis used the modified intention-to-treat population. RESULTS: In total, 1768 rodents (882 females and 886 males) were enrolled: 441 young healthy mice, 444 aging mice, 450 mice with obesity-induced hyperglycemia and metabolic syndrome, and 433 spontaneously hypertensive rats. Data missing due to death before 30 days of follow-up were imputed from the same treatment group, animal model, sex, and stage. Although none of the candidates met the prespecified efficacy boundary, GSK2256294 showed an odds ratio for benefit of 1.28 (95% CI, 0.99–1.65), which was significant at P <0.05. CONCLUSIONS: The second SPAN study reaffirms the importance and feasibility of rigorous, multilaboratory preclinical testing networks to potentially reduce false positives in the development pipeline.