The study was designed as a controlled, randomized preclinical trial with several stages. Young, healthy mice were assessed first, followed by animal models with comorbidities found in many human patients who have had a stroke (specifically, aged mice, mice fed with a high-fat diet to induce obesity, and spontaneously hypertensive rats). Finally, young healthy rats were tested. The trial followed rigorous documentation with a predetermined sample size for each stage, centralized randomization, and an equal distribution of animals across participating groups and testing stages. Protocol compliance was monitored closely based on pre-specified metrics and was high across the network, enabling the authors to include data from all laboratories to evaluate drug efficacy.
As a primary outcome measure, the authors selected a behavioral metric (the corner test for asymmetric turning), which enabled a functional assessment of neurological function after treatment, as opposed to a solely morphometric measure that is commonly used in preclinical trials. After each trial stage, the efficacy of the interventions was assessed and only treatments that exceeded the futility boundary were taken forward to the next stage. Surprisingly, only one treatment — uric acid —exceeded the efficacy boundary after the last stage, thus supporting further clinical evaluation of uric acid supplementation in ischemic stroke treatment but cautioning against clinical assessment of the remaining interventions.
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