Treating brain swelling after stroke, one trial at a time

In 2006, Kevin Sheth was a 26-year-old neurology resident in Boston, at both Massachusetts General Hospital and Brigham and Women’s Hospital. In that role, he did rotations within their neurology intensive care units and often saw patients who had very massive, acute strokes. 

“They couldn’t speak, and their right side of the body was completely paralyzed,” said Sheth, who went on to become the founding director of the Yale Center for Brain & Mind Health and is now the vice chair for clinical and translational research for the departments of neurology and neurosurgery at Yale School of Medicine. “They were young, in their fifties, and seemingly healthy. All of a sudden, their lives changed in a moment.” 

At the time, Sheth’s patients not only had to deal with those kinds of complications after stroke but also another serious — and potentially fatal — one: brain swelling. 

“I think about stroke like a bruise, like you have a bruise on your hand,” he said. “You swell after the bruise. At some point, the swelling goes down. But you can imagine if you have a huge bruise in your brain and you swell, you don’t have room for that swelling. That swelling now damages other tissue, and it creates a bad cycle.”

At the time, there were few treatments for patients with brain swelling. In fact, the best option was removing part of the skull in order to give the brain room to expand. 

Sheth thought that there had to be a better way — and it turns out he might be right. 

For the past 15 years, he has helped lead a translational program in acute stroke treatment from the laboratory to human studies, specifically a first-of-its-kind treatment for brain swelling after stroke. What started as an observation as a medical resident has now become a cornerstone of his life’s work.  

Brain gain

Kevin Sheth first got interested in the human brain during the early 1990s. 

That decade saw major advances — and investments — in neuroscience thanks, in part, to then-President George H.W. Bush. At the time, Bush had declared the 1990s the “Decade of the Brain” to promote public awareness and support for brain research. As a neuroscience major at Johns Hopkins University, Sheth was one of the college students who wanted to be part of this new “brain gain.”

“Nowadays, every university has a neuroscience major,” he said. “But I remember I was in the first graduating class of it as a new major [at Johns Hopkins].” 

Eventually, Sheth decided to attend medical school at the University of Pennsylvania where he specialized in neurology — the branch of medicine that studies, diagnoses, and treats disorders and diseases of the nervous system, including the brain. He was drawn to neurology for two reasons. One, he felt most inspired by and connected to the neurology faculty, and two, he connected with the patients. 

“To me, these were very common conditions that were confusing to people, whether you have a stroke or Alzheimer’s disease,” Sheth said. “There’s a stigma associated with them, and that makes it even harder to understand in the first place. I saw interacting with those patients as an opportunity to take away some of that stigma and to educate them as part of trying to heal them.”

Plus, Sheth was drawn to the mystery of the brain itself. 

Moving from medical school to residency, Sheth became especially interested in stroke, which, among chronic diseases, remains the second leading cause of death in the world — and the third leading cause of death and disability combined.

“That struck me as something that was of huge public health importance,” he said.

The art of translation

During his residency at Massachusetts General Hospital and Brigham and Women's Hospital (both of which are part of the Mass General Brigham integrated health care system), Kevin Sheth worked with stroke patients, many of whom ended up in the intensive care unit (ICU). He often saw patients with severe strokes who experienced a lot of swelling in their brains.

When he finished his medical training in 2009, he joined a renowned trauma center at the University of Maryland as its first intensive care neurologist on staff. Still interested in brain swelling, Sheth found and teamed up with a neurosurgeon, J. Marc Simard, who was studying ion channels in the brain, or holes in the cell membrane that allow the passage of electrically charged particles called ions. 

After stroke, some ion channels open up. Because water sometimes follows the ions, that’s why the brain often swells after stroke. When Simard looked at one of the ion channels more closely, he noticed that its structure was similar to that of ion channels in the pancreas. In the pancreas, ion channels are important in diabetes and the regulation of insulin and glucose. 

Some drugs used to treat diabetes, like glyburide, specifically target those ion channels, and so Sheth and Simard wondered if you could similarly target ion channels in the brain with glyburide to treat brain swelling after stroke. After spending time in the lab working alongside Simard, including on animal studies, Sheth discovered that the research was at the stage where it could potentially be translated to human patients. 

“It looked like it was ready to translate,” he said. “But there were all these problems that needed to be solved, problems that could not be solved in the lab. Even though I was just starting out, these were things that I was interested in and wanted to learn about.”

Translational research bridges the gap between basic research and clinical research. It’s the process of applying basic scientific findings from the laboratory and testing them in the real world, including in the development of new treatments for diseases. 

After a series of experiments, and with funding from the National Institutes of Health (NIH), the collaboration between Sheth and Simard led to the development of an intravenous form of glyburide that could be tested to see if it reduced brain swelling. 

That was the start of Sheth’s efforts to translate a first-of-its-kind treatment for brain swelling after acute stroke from the lab to human studies — work he’s expanded upon at Yale since joining the faculty in 2013.   

Third time’s the CHARM

Since coming to Yale, Kevin Sheth has built upon his pioneering translational program for brain swelling after stroke. He’s helped lead a series of human studies to test the efficacy of intravenous (IV) glyburide in treating brain swelling, including a pilot with 10 patients in 2013 and a double-blind, randomized, placebo-controlled Phase II clinical trial across 18 stroke centers in 2016.  

“The premise for testing IV glyburide, in terms of the drug’s mechanism of action to improve outcomes for patients who suffer stroke, has been very compelling,” said Pooja Khatri, chair of the Department of Neurology at Yale School of Medicine. “The challenge now is to find the subset of patients who will definitively benefit from it.” 

In that Phase II trial, described in a study published in the journal Lancet Neurology, Sheth and his team found that IV glyburide did not reduce the number of emergency surgeries in the Phase II trial, though it did show promise in improving patient outcomes. 

“If you look at a lot of successful trials in any area of medicine — and this is certainly true in stroke where few things have succeeded — trials are neutral a lot of the time,” he said. “There’s also another term that I use called ‘instructive trials,’ meaning that your top line result might be negative, especially when you are navigating an area where there has not been any success before, and in doing every trial, you’re learning something. You’re learning about the patient population, you’re learning about the drug, you’re learning about where you are likely to have a big effect.” 

The Phase II findings were promising enough that Remedy Pharmaceuticals, which then owned rights to glyburide, partnered with the biotechnology company Biogen to launch a Phase III trial to test its efficacy. Sheth’s longtime partners in these trials include W. Taylor Kimberly at Massachusetts General Hospital and Sven Jacobson of Remedy Pharmaceuticals.

Known as CHARM — referring to cerebral oedema after large hemispheric stroke — the Phase III, double-blind, placebo-controlled, randomized trial was conducted across 143 acute stroke centers in 21 countries between 2018 and 2023. 

The CHARM trial was more complicated than the previous trials because it not only involved hundreds of patients from around the world but also took place during the COVID-19 pandemic. Additionally, there had been some internal leadership changes at Biogen, which had acquired the rights to glyburide from Remedy, and Biogen decided to pull out of stroke treatment before the CHARM trial fully finished. (Remedy now owns the rights again). Fortunately, Sheth and his team had already enrolled the vast majority of patients in the trial and were able to continue following their progress and finish collecting high-quality data. 

The findings were published in Lancet Neurology in December 2024. Like the Phase II trial, CHARM’s primary result was neutral, though they found promising signals of drug efficacy. “The big takeaway is that we don’t know yet if it is effective or not effective,” Sheth said. “We need to do more testing. We keep learning.”

The results may not be enough to get IV glyburide approved by the U.S. Food and Drug Administration (FDA) yet. But Sheth and his team have gotten more insight into the population the drug might work for, and who it might not, ahead of their next Phase III trial. Based on the CHARM trial, they observed that IV glyburide worked really well in patients who either received a clot-busting drug called tissue plasminogen activator (tPA) or had a minimally invasive procedure to remove blood clots known as a mechanical thrombectomy.

This past June, Sheth and his collaborators published a series of analyses in the Annals of Neurology about those specific patient subgroups and concluded that IV glyburide might help improve outcomes for patients with large strokes, especially among mechanical thrombectomy patients. 

This specific result will serve as the basis for a new trial that is in the review process at NIH StrokeNet, a stroke trials network designed to serve as the primary infrastructure and pipeline for new and exciting potential treatments for patients with stroke and those at risk for stroke. Currently a principal investigator for the NIH proposal, Sheth is designing a framework to test if IV glyburide works for patients undergoing mechanical thrombectomy. He hopes IV glyburide is approved for NIH funding in the next year or two.

“In the world of stroke, it probably stands with maybe two or three other drugs in the world that are this advanced in terms of potentially becoming an acute stroke treatment,” said Sheth. “This kind of innovation wouldn’t be possible without the partnership between Yale, the NIH, and the industry.”

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