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Updated: Jul 16, 2025
A Preclinical Model to Assess Brain Recovery After Acute Stroke in Rats
Published on: November 6, 2019
A multi-laboratory preclinical trial in rodents to assess treatment candidates for acute ischemic stroke
Patrick D Lyden1,2, Márcio A Diniz3, Francesca Bosetti4
1Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine of USC, Los Angeles, CA 90033, USA.
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.
Insights
The Stroke Preclinical Assessment Network (SPAN) established a rigorous, multi-laboratory trial to evaluate stroke treatments. This innovative design improved preclinical research reproducibility and assessed interventions effectively.
Area of Science:
- Neuroscience
- Translational Science
- Pharmacology
Background:
- Recent clinical trial failures have raised concerns about the reliability of preclinical research.
- There is a critical need for robust preclinical models to assess novel therapeutic interventions.
Purpose of the Study:
- To design and implement a rigorous, multi-laboratory randomized controlled trial for assessing candidate stroke treatments.
- To evaluate the efficacy and futility of interventions using a multi-arm multi-stage statistical design.
Main Methods:
- The Stroke Preclinical Assessment Network (SPAN) involved six laboratories using five distinct animal models of focal cerebral ischemia.
- A standardized protocol ensured consistency across laboratories, enrolling 2615 animals with comprehensive tracking.
- Key methodological elements included randomization, treatment masking, and blinded outcome assessment.
Main Results:
- SPAN successfully implemented a complex preclinical trial design across multiple sites and animal models.
- The study demonstrated the feasibility of enrolling a large number of animals with complete data and adherence to protocol.
- The implemented design effectively managed treatment masking, randomization, and blinded assessments.
Conclusions:
- The SPAN infrastructure and trial design offer a robust model for future preclinical, multi-laboratory studies in various disease areas.
- This approach has the potential to significantly enhance the reproducibility and translational value of preclinical research.
- The study provides a framework for more reliable assessment of therapeutic interventions before clinical trials.
