SPAN Study Finds a Winner for Treating Stroke in Rodents

DALLAS -- Uric acid was shown to be the most successful neuroprotectant among rodents in a study from the Stroke Preclinical Assessment Network (SPAN), a nationwide trial platform that applies clinical research practices to preclinical studies in hopes of better informing human studies.

Of the six interventions studied in the randomized rodent trial, uric acid 16 mg/kg administered intravenously at the time of reperfusion exceeded the efficacy boundaries, reported Lauren H. Sansing, MD, of Yale University in New Haven, Connecticut, and colleagues during the American Stroke Association's International Stroke Conference.

The other interventions included the Rho-associated kinase inhibitor fasudil, the PARP inhibitor veliparib, the immunosuppressive drug tocilizumab (Actemra), the S1P analogue fingolimod (Gilenya), and remote ischemic conditioning, which were analyzed via corner test at 28 days.

Three interventions fell below SPAN's inferiority barriers after just the first stage. Only uric acid remained within the study's efficacy boundaries after four stages, ultimately surpassing their original acceptable outcomes.

The study showed that SPAN is an effective preclinical research tool, noted James C. Grotta, MD, a vascular neurologist at Memorial Hermann-Texas Medical Center in Houston, who was not involved in the study.

"The SPAN project entailed a tremendous amount of careful planning and meticulous work by a large team, and kudos to the network for a successful result. The 'winner,' e.g., uric acid, has withstood rigorous testing and the stroke community is now looking forward to the clinical trial of this approach that may complement existing reperfusion strategies," he told MedPage Today.

During a press conference, Sansing explained that "experimental rigor is something we can control. SPAN embraced all of the rigor of a clinical trial."

The study also aimed to "embrace heterogeneity," allowing for some variation in its subjects in an effort to mimic clinical trials, she and her colleagues noted.

Sansing cited growing public distrust in scientific research, recently exacerbated by the COVID-19 pandemic, as part of the reason behind the development of SPAN. Stroke research is no exception. Several neuroprotectant agents have performed well during the course of preclinical trials, but failed to prove effective when introduced in human trials -- a trend that has been documented for decades.

Sansing also pointed to an opinion piece published in Trends in Neurosciences in 2007 that cited research that showed that as the quality or rigor of a preclinical study on treatments for stroke increased, their efficacy decreased, with the authors noting that animal models for stroke research were "profoundly biased by aspects of study design."

More recent research compiled evidence listing albumin, the potassium channel activator BMS-204352, and the sodium channel blocker lubeluzole as just a few of many therapies that showed promise as neuroprotectors in animal studies, which then fell short in clinical research on humans.

For this National Institute of Neurological Disorders and Stroke (NINDS)-funded study, six independent labs were used to conduct the research, including Yale University, Massachusetts General Hospital, Johns Hopkins University, the University of Texas Health Science Center at Houston, the Medical College of Georgia at Augusta University, and the University of Iowa.

A total of 2,651 rodents were included in the study, including young mice, aging mice, mice experiencing diet-induced obesity or hyperglycemia, young rats, and spontaneously hypertensive rats, with an equal number of male and female rodents.

After receiving more funding from NINDS, SPAN 2.0 will continue to test neuroprotectants, utilizing six more experimental sites.

The positive results for uric acid, the experimental rigor present in the trials, and the renewal of the SPAN program may bring change to years of issues regarding neuroprotectants, commented Gregory Albers, MD, director of the Stanford Stroke Center in Palo Alto, California, during a Q&A session on SPAN's results.

"I think it's really exciting that the winning drug had a lot of clinical data prior to going into SPAN," he said. "We have seen a number of these agents that have gotten into the human trials where the trial was close but didn't quite make it, some subgroups looked great, and then you repeat, focusing on those subgroups, and then again they didn't make it. What I think we now have is a much higher level of enthusiasm for this drug than what we just had from the prior clinical work that was done for that."

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