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

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.

A randomized, controlled, two-center preclinical trial assessing the efficacy of a new benzodiazepine–dihydropyridine hybrid molecule (JM-20) in rodent models of ischemic stroke

“…To the best of our knowledge, the only study in experimental research that discusses this important issue and tries to limit its impact is the Stroke Preclinical Assessment Network (SPAN) study [28]. Clinical trials often try to minimize attrition bias by imputation of missing values.…”

Intravenous Thrombolysis to Dissolve Acute Stroke Thrombi: Reflections on the Past Decade

“…27 Strategies to protect brain tissue before, during, and after recanalization such as nerinetide have not, thus far, been successful, 28 but earlier treatment and novel drug targets offer continued hope. 29…”

Immunothrombosis in neurovascular disease

“…In light of the successful thrombectomy trials, interest has reemerged in neuroprotective and/or anti-inflammatory drugs to further improve outcomes in patients who experience stroke and achieve reperfusion [ 85 ]. Trials in this patient population will be the first to really evaluate the translational potential of preclinical stroke research and will be the critical first step in the evaluation of a new generation of anti-inflammatory drugs for the broader stroke patient population.…”