By Ian Popple
Face drooping – Arm weakness – Speech difficulty – Time to call for help! The acronym FAST (Face-Arms-Speech-Time) is both a reminder of the early symptoms of stroke and the urgent action necessary. Acute ischemic stroke (AIS) – the most common form of stroke – occurs when a blood vessel to the brain is blocked, starving part of the brain of oxygen. The longer the brain is cut off from its oxygen supply the greater the risk of permanent damage, which is why acting fast is so important.
“It is critical that people suffering a stroke call 911 immediately or go straight to hospital,” says Dr. Jim Christenson, an emergency care researcher at St. Paul’s Hospital in Vancouver and professor in the Faculty of Medicine at the University of British Columbia. “We have effective treatments, like thrombolytic therapy and mechanical clot removal, but they need to be administered quickly and can only be done in a hospital.”
Unfortunately, many AIS patients are unable to receive these potentially life-saving treatments in time. According to the World Health Organization (WHO) around 15 million people worldwide suffer a stroke every year. Of these, five million die and another five million are left permanently disabled.
A group of drugs, known as neuroprotectants, have long held promise as a way of bridging the gap between the onset of stroke symptoms and definitive care. As their name suggests, neuroprotectants aim to safeguard brain tissue in the absence of oxygen, essentially helping the brain hold its breath until blood flow can be restored.
The search for effective neuroprotectants has been going on for several decades. But the results of over 200 human trials have yet to replicate the promise generated from initial animal studies. That is, until now.
In an innovative study co-funded by Brain Canada known as FRONTIER, Canadian researchers have documented promising patient outcomes for a neuroprotective drug called Nerinetide, the results of which are published in The Lancet.
FRONTIER was built on earlier studies that suggested the biggest benefit for stroke patients in their race against time would occur when they receive the drug immediately after their first symptoms.
“In order to test this, we recognized that paramedics would need to be tasked with delivering the medication soon after the 911 call is received,” explains Dr. Christenson, lead researcher of the FRONTIER trial.
Leveraging emergency medical services (EMS) to deliver trial medication was an innovative idea, but it had never been done before in Canada, and there were significant logistical challenges to overcome. For example, the research team had to install mini fridges in each ambulance to keep the medication cool until a patient required it.
“We also had to track every dose of the drug across all ambulances supplied with the drug, which made FRONTIER far more complicated than a trial in a single setting, such as an emergency department or stroke unit,” recalls Dr. Christenson.
“In addition, as primary care paramedics do not usually give intravenous drugs, especially through a pump, initial training along with practice sessions and continued reinforcement was required,” says Dr. Christenson. “Most paramedics only gave the drug once during the trial, so there was no opportunity for them to get used to the procedure. They did a fantastic job and are the real heroes of this study.”
Logistically complex trials such as FRONTIER require the kind of budget that is rarely available from government grants.
“Brain Canada’s financial support was essential,” says Dr. Michael Tymianski, Senior Scientist at the University Health Network’s Krembil Brain Institute and the scientist who discovered Nerinetide. “But Brain Canada provided far more than just funding. Their rigorous peer review process helped validate our entire project, allowing us to get the buy-in of EMS. I can safely say that this trial would have been impossible without Brain Canada.”
While FRONTIER succeeded in getting Nerinetide to patients when it could be most effective, that process also meant that it was given to patients who would not necessarily benefit from it.
“It’s the catch-22 of developing neuroprotectants,” explains Dr. Tymianski. “You reach the patient early, but the urgency makes it more difficult to select the right patient.”
As a result, patients with non-target conditions were also treated with Nerinetide, such as those with hemorrhagic stroke, transient ischemic attack (TIA) and conditions known to mimic strokes, such as a seizure. The effect of Nerinetide was masked when all these patients were included in the initial analysis. However, when focusing on AIS patients alone, the effect was striking.
“FRONTIER demonstrated that neuroprotection in humans is both possible and beneficial,” says Dr. Tymianski. “It also helped define which type of stroke patients benefit from the drug.”
We’re incredibly proud to have supported such an ambitious project. Stroke is one of the leading causes of death and disability worldwide – one in four adults will have a stroke in their lifetime. These game-changing results will bring hope to millions of people around the world.
Dr. Viviane Poupon, President and Chief Executive Officer of Brain Canada
A new trial with a next-generation version of Nerinetide, informed by the FRONTIER findings, is already underway to confirm these results, with the ultimate goal of getting such agents approved by regulatory agencies so they can be incorporated into clinical practice and make a positive difference to as many stroke patients as possible.
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Dr. Jim Christenson, emergency care researcher at St. Paul’s Hospital and Professor in the Faculty of Medicine at the University of British Columbia, and team members, were awarded an $8.07 million MIRI Team grant in 2014 to support The Frontier Trial – Field Randomization of NA-1 Treatment In Early Responders. The grant was made possible with the financial support of Health Canada (through the Canada Brain Research Fund, an innovative partnership between the Government of Canada (through Health Canada) and Brain Canada), St. Michaels Hospital, Canadian Stroke Network, Genome BC, Djavad Mowafaghian Centre for Brain Health, and the University of British Columbia.
Read More:
https://www.uhn.ca/corporate/news/pages/protecting-the-brain-against-stroke.aspx
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00193-X/abstract