Published June 5, 2017
UB’s Buffalo Neuroimaging Analysis Center (BNAC) played a pivotal role in a phase III clinical trial of the first transcatheter cerebral embolic protection (TCEP) device to obtain marketing clearance by the Food and Drug Administration.
Led by Robert Zivadinov, MD, PhD, BNAC director and professor of neurology, BNAC served as the centralized imaging center for this international FDA regulatory multicenter trial, which assessed the safety of Claret Medical’s Sentinel TCEP device during transcatheter aortic valve replacement (TAVR) and its efficacy in reducing the effects of cerebral embolization.
TAVR is a minimally invasive alternative to open-heart surgery. Approved by the FDA in 2011, it is an important, and increasingly popular, therapy for intermediate- and high-risk patients with severe aortic stenosis.
However, stroke remains a concerning complication, occurring in about 9 percent of patients.
Additionally, clinically “silent” brain infarctions seen on MRI may occur in as many of 80 percent of patients after TAVR — complications that have been associated with changes in neurocognitive function.
“With TAVR, you have this beautiful approach to replacing aortic valves,” explains Michael G. Dwyer III, PhD, assistant professor of neurology and biomedical informatics, and BNAC’s technical imaging director. “However, the transcatheter approach also knocks all kinds of embolic debris around that may go straight to the brain and block blood flow.”
This embolic debris can cause small lesions that may not be immediately obvious clinically and can’t be seen without detailed imaging tests, Dwyer notes.
Although the impact of these lesions is not fully understood, the resulting ischemic damage may result in neurocognitive decline, including memory loss. The deterioration may occur over time, well after postoperative patients continue to be monitored.
“Ischemic damage is not an occasional side effect,” Dwyer emphasizes. “Almost everyone who undergoes this procedure is showing some damage to the brain.”
The Sentinel TCEP device is positioned in two of the arteries leaving the aortic arch, supplying three of the four arteries that travel to the brain.
Researchers found that it effectively and safely filters blood-borne debris, preventing it from reaching the brain. In the study, it captured such debris — including thrombus, calcification, valve tissue, artery wall and foreign material — in 99 percent of the study subjects.
Further, the median total new lesion volume was 42 percent lower in those patients who’d been randomly assigned to undergo the TAVR procedure with the embolic protection device than in patients in the control group, who underwent the procedure without the device.
Although that percentage was higher than the 30 percent primary efficacy endpoint that researchers had established, it did not reach statistical significance due to confounding factors, including transcatheter valve type and baseline MRI lesion volume.
The study was not powered for and did not detect a significant reduction in 30-day stroke rates or other major adverse cardiac or cerebrovascular events, although results showed that the use of Sentinel did reduce clinical stroke within the first three days after the procedure by a statistically significant 63 percent.
In all, the study involved 360 patients with severe symptomatic aortic stenosis who were treated at 19 clinical centers — 17 in the United States and two in Germany.
The Sentinel TCEP device study marks another phase III clinical trial in which BNAC served as centralized imaging center.
BNAC previously served as the centralized core imaging lab for the 2011 GALA study, which prompted a change in the FDA labeling for Copaxone, an injectable drug for relapsing-remitting multiple sclerosis.
For the Sentinel study, Dwyer and Zivadinov worked with all 19 clinical sites to establish a novel imaging protocol that Dwyer had previously developed for a clinical trial of a prototype embolic filter device.
“We preapproved all of the sites for the study and worked hand in hand with them to achieve the best possible images from their individual scanners,” Zivadinov explains. “Then, in real time, they were transferring MRI scans to our center, which we calculated according to the study methodology we developed, evaluating the outcomes in a fully blinded manner.”
BNAC has become increasingly attractive to clinicians and scientists seeking a core imaging lab with specialized, state-of-the-art capabilities, Zivadinov says.
“We are being chosen for these studies because of our imaging expertise, ability and innovations,” he notes.
In contrast to a commercial clinical research organization, which tends to use conventional imaging strategies, an academic center like BNAC “brings cutting-edge imaging techniques and quantification to bear on all kinds of real-world clinical trial questions,” Dwyer adds.
BNAC works with clients from across the United States and North America as well as those in Europe, Australia, South America, Asia and Africa.
In addition to the phase III trials, BNAC has helped carry out numerous phase II and phase IV multicenter trials since it opened in 2000.
Its researchers have published their findings in more than 350 peer-reviewed publications, including numerous high-impact journals.
For example, findings from the randomized trial of the prototype embolic protection device — known as the CLEAN-TAVI study — were published last August in the Journal of the American Medical Association; the results of the Sentinel TCEP device trial were published in January in the Journal of the American College of Cardiology.
Other clinical trials in which BNAC served as centralized imaging core center have been published in prominent neurology and radiology journals including Annals of Neurology; Neurology; Radiology; Brain; Multiple Sclerosis; Journal of Neurology, Neurosurgery and Psychiatry; Journal of Neurology and the European Journal of Neurology, among others.