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

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 network for the rigorous assessment
of candidate stroke treatments combined with intravascular thrombectomy.
Futility boundaries in a Multi-Arm Multi-Stage statistical design aimed to
exclude less effective interventions, and efficacy boundaries allowed
early declaration of success 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 2,615 animals with full data
completion and comprehensive animal tracking. SPAN successfully
implemented treatment masking, randomization, pre-randomization 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.