Embracing Heterogeneity in The Multicenter Stroke Preclinical Assessment Network (SPAN) Trial.

Area of Science:

• Neuroscience
• Translational Medicine
• Preclinical Research

Background:

• Experimental stroke research faces translational failure.
• The Stroke Preclinical Assessment Network (SPAN) is a multicenter platform using rodent models of transient focal cerebral ischemia.
• SPAN aimed to introduce heterogeneity to better mimic clinical trial conditions.

Purpose of the Study:

• To report the heterogeneity introduced by allowing 6 SPAN laboratories to vary biological and experimental model variables.
• To assess the impact of this heterogeneity on middle cerebral artery occlusion (MCAo) performance.
• To identify predictors of MCAo performance metrics.

Main Methods:

• Analysis of the control mouse cohort (n=421) from the first SPAN trial.
• Examination of biological and procedural independent variables and their covariance.
• Multivariable analyses to determine the impact on cerebral blood flow drop, time to MCAo, and anesthesia duration.

Main Results:

• Heterogeneity in biological and procedural variables, primarily site-driven, was observed.
• All dependent variables (blood flow, time to MCAo, anesthesia duration) showed significant site-specific heterogeneity.
• Filament choice predicted cerebral blood flow drop; comorbidity, sex, monitoring methods, trial day, and anesthesia maintenance predicted time to MCAo.

Conclusions:

• Embracing heterogeneity in multicenter preclinical trials better approximates clinical trial complexity.
• Understanding the sources and impact of heterogeneity is crucial for improving future study designs and statistical modeling.
• This detailed analysis of SPAN's first trial provides granular insights into managing variability in rodent MCAo models.