The Calgary Stroke Program, a joint University of Calgary and Alberta Health Services initiative at Foothills Medical Centre, has been involved with three papers published this week in The Lancet and Lancet Neurology—the ESCAPE-NEXT trial, the FRONTIER trial, and an individual patient-level meta-analysis across three trials. The studies, in collaboration with NoNO Inc., are focused on neuroprotection and ischemic stroke. While the primary trials were inconclusive, the meta-analysis reveals that the data provide important clues for future research into stroke treatment.
Dr. Michael Hill, MD, is the lead investigator on the ESCAPE-NEXT trial together with Dr. Mayank Goyal, MD, PhD, and co-investigator on the other analyses, along with other members of the Calgary Stroke Program and teams from around the world. Hill explains more about the impact of strokes and how the findings in these three papers will help guide future research.
What happens after an ischemic stroke?
When an ischemic stroke occurs, affected parts of the brain are starved of blood flow and brain cells start to die immediately. Without blood bringing nutrients (glucose, oxygen), it has been estimated that 1.9 million neurons die per minute.
This is why it is critical to immediately call an ambulance and be transported to a specialized stroke centre. The quicker a patient can get to a stroke team, the quicker an intervention can be introduced to minimize the damage. The effects of stroke can be life-altering on patients and their families, so preventing damage with early diagnosis and treatment is key.
What is neuroprotection and how could it benefit patients?
When you arrive in the emergency department, you may be treated with drugs that help dissolve the clot or, if the clot is in a large blood vessel, you may undergo endovascular therapy—where the clot is mechanically removed. Both treatments aim to restore blood flow (reperfusion) as soon as possible and they can be used individually or together varying by individual patient.
A neuroprotective agent is an additional treatment that, if given early on, might mitigate damage to the brain while other treatments are being applied. Millions of neurons could be saved and patient outcomes after a stroke could be improved. The neuroprotective drug being studied in these trials is called nerinetide.
Has neuroprotection been studied by University of Calgary researchers before?
Neuroprotection is an important part of stroke research and has been studied by University of Calgary stroke researchers for years.
The ESCAPE-NA1 trial in 2020 didn't find a statistically significant benefit of nerinetide but researchers discovered, after reviewing the data, that its effect was impacted by another drug in the trial—alteplase.
"In other words, there was an interaction," says Hill, "a negative interaction between the two drugs. In the 40 per cent of trial patients who did not get alteplase, there appeared to be quite a profound benefit."
So more research was necessary. What did the latest trials find?
In ESCAPE-NEXT, a multicentre, randomised, double-blind and placebo-controlled study, patients who presented within 12 hours of stroke onset were given nerinetide before endovascular therapy. Primary outcomes were measured after 90 days and there was not a significant benefit to patients—sometimes called a "neutral" trial.
"But once again, in the subset (of patients treated within) three hours," says Hill, "there was a benefit. So if you treat early, treat fast, open the arteries, give the drug nerinetide, you seem to get a benefit."
In the FRONTIER trial, paramedics administered the neuroprotective agent, nerinetide, to patients with suspected ischemic stroke within three hours of symptom onset. The medication was given during transport and before arriving at the hospital where imaging could be done. Patients were treated quickly but there were many stroke "mimics" (conditions with stroke-like symptoms, but without an actual cerebrovascular event) included in the study —affecting the outcome and resulting in another neutral trial.
Is there still hope for neuroprotection?
The scientists dug into the data from three studies, ESCAPE-NA1, ESCAPE-NEXT and FRONTIER trials, and re-examined the results in a meta-analysis paper published this week in The Lancet Neurology.
These trials included patients from 135 stroke centres in 13 countries (Canada, Australia, Germany, Ireland, Italy, the Netherlands, Norway, Singapore, South Korea, Sweden, Switzerland, the United Kingdom, and the United States) who were treated within three hours of symptom onset. They also narrowed the patients included to those who were selected for reperfusion, either by thrombolysis (a clot-busting drug) or endovascular therapy.
The analysis demonstrated that nerinetide had a clinically significant benefit to patients and showed that future trials with these new parameters were necessary.
In fact, the ACT-42 trial is already underway—administering a neuroprotective agent within three hours of stroke onset to enrolled patients. And this trial will include the next generation of nerinetide.
