The National Institutes of Health awarded a $38 million, five-year grant to Brian Hoh, M.D., M.B.A., the University of Florida’s chair of neurosurgery, to test two new prospective treatments for symptomatic intracranial arterial stenosis, a leading cause of ischemic stroke worldwide.
Intracranial arterial stenosis is a severe narrowing of an artery in the brain, and this condition accounts for 8-10% of all strokes in the U.S., about 80,000 per year. More than 20% of patients with this type of stenosis who receive current treatment still experience stroke, intracerebral hemorrhage or vascular death within a year. Ischemic strokes, the most common type of stroke, result when a vessel supplying blood to the brain is blocked by a clot.
“Clearly there is a need for better treatment,” said Hoh, who will lead the large national phase 3 clinical trial with co-principal investigator Marc Chimowitz, MBChB, a professor of neurology at the Medical University of South Carolina.
The double-blinded, randomized clinical trial across 115 U.S. sites will include 1,683 participants, who each will be placed into one of three different medical treatment paths for comparison. One group will receive ticagrelor, also known as Brilinta, plus aspirin; the second group will receive rivaroxaban, also known as Xarelto, plus aspirin; and the third group will receive the current treatment of clopidogrel, also known as Plavix, plus aspirin.
The five-year trial is scheduled to start this summer, with patient enrollment planned to begin in January 2022. Each participant will be followed for one year.
“This important study builds upon years of innovative work by Drs. Hoh and Chimowitz and others across the country who are committed to finding better therapies to prevent and treat stroke,” said Colleen G. Koch, M.D., M.S., M.B.A., dean of the UF College of Medicine. “What we learn from this trial has the potential to save lives and improve quality of life for tens of thousands of people each year who suffer from intracranial arterial stenosis.”
Stephen Sugrue, Ph.D., UF’s senior associate dean for research affairs, said the clinical trial exemplifies how UF has established itself as a leader in neuromedicine research.
“Dr. Hoh has been a longtime leader in neurovascular research,” Sugrue said. “We couldn’t be more proud that one of our clinical leaders is not only leading here as chair of neurosurgery, but nationally.”
The size and scope of the new trial is particularly impressive, Sugrue said.
“In order to achieve the results required to really draw a conclusion, these trials have to be big,” he said. “A large-scale, randomized controlled trial will be the definitive answer of what is the best current therapy to offer our patients with stroke risk.”
The new trial, called Comparison of Anticoagulation and anti-Platelet Therapies for Intracranial Vascular Atherostenosis, or CAPTIVA, builds upon previous work by a research team headed by Chimowitz and including Hoh that led to the current treatment for symptomatic intracranial arterial stenosis of medical management with aspirin and Plavix. Findings from that multicenter randomized 451-participant study, called Stenting vs. Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis, or SAMMPRIS, were published in 2011 in The New England Journal of Medicine. It compared stenting, or placement of a tiny tube inside a narrowed artery to keep it open, with aggressive medical management in patients who had had a stroke or transient ischemic attack, or TIA, from 70% or greater intracranial stenosis.
In the 2011 study, both the stenting group and the medical management group received aspirin and Plavix. The trial showed there was no benefit to stenting. And while intensive medical management alone was found to be a superior treatment, greater than 20% of these patients will still suffer a stroke, intracerebral hemorrhage or vascular death within a year. The team published long-term follow-up results in The Lancet in 2014.
“While the SAMMPRIS trial showed that intensive management of risk factors for stroke, such as hypertension and high cholesterol, and promotion of regular exercise are important for lowering the risk of stroke in patients with a narrowed brain artery, it did not clarify which anticlotting medications are best to use in this situation,” Chimowitz said.
CAPTIVA will evaluate two additional anticlotting treatment options in comparison with aspirin and Plavix. The trial will use NIH StrokeNet, a network of 27 regional centers across the U.S. involving some 500 hospitals that serves as an infrastructure for clinical trials to advance potential treatments for acute stroke, stroke prevention, recovery and rehabilitation.
“This three-armed clinical trial is an efficient and innovative way to try to answer this question using one control arm and two experimental arms,” said Hoh, chair of the Lillian S. Wells Department of Neurosurgery in UF’s College of Medicine.
In addition to medical treatments in the trial, all participants will receive intensive risk factor management, including management of diabetes, cholesterol and hypertension as well as a smoking cessation program and an exercise program.
The trial also will include an exploratory aim: It will investigate whether people who carry a specific genetic mutation will have a different benefit from the three compared treatments, Hoh said. Every participant will have blood sent to UF for genotype analysis.
“There is controversy in the field of cardiology as well as neurology regarding whether people with a mutation of the CYP2C19 gene have different treatment outcomes from clopidogrel,” Hoh said. “Clopidogrel is a pro-drug that requires metabolic activation in the liver, and about 20% to 30% of the general population carries a mutation in the CYP2C19 gene that make them poor metabolizers of clopidogrel. There is a belief clopidogrel may be less effective in those people.”