From ICUs to the labs, Brown faculty go all in to help COVID-19 patients.
When COVID-19 started to make its way into the US in early 2020, Jeff Bailey, MD, PhD, associate professor of pathology and laboratory medicine, thought back to his time in Liberia. In 2013 and 2014, he responded to the West African Ebola outbreak, work for which he was given the Britney Gengel International Humanitarian Award by the Red Cross.
“People presumed things were getting done by others because they seemed like the obvious things to do,” he says. “We later found out that everyone was thinking about the obvious things, but no one was doing them.”
Bailey, who is also a practicing physician in transfusion medicine and coagulation at The Miriam and Rhode Island hospitals, didn’t want the same thing to happen when a different pandemic reached their doorstep. So since March, he has headed the COVID research task force for Brown, coordinating the University-wide effort to better understand, treat, and manage COVID-19.
“People across Brown started to think ‘how can I bring my expertise to bear, and how could that be impactful?’” he says.
As the task force reviewed proposals for COVID-related research, not only did they look for projects that might seem obvious to researchers and academics at The Warren Alpert Medical School, but they stretched across the University to review and then fund COVID-19 investigations in disciplines like engineering and computer science.
In total, Brown awarded $350,000 to 15 teams of faculty in early April, on projects designed to quickly develop solutions to impact the world’s response to the pandemic. They also got permissions to convert basic research labs to safely handle COVID-19-related research, and worked to create the Lifespan/Brown COVID-19 Biobank based at Rhode Island Hospital. Patients coming into emergency departments there and at The Miriam were asked to donate blood samples for research to create the biorepository. Researchers statewide can apply to use samples from patients who tested positive or negative for the virus. The project worked so well that Brown helped an organization in Nebraska set up a similar biorepository plan.
“Helping to solve society’s most crucial problems is one of the University’s highest priorities,” Provost Richard M. Locke, PhD, and Vice President of Research Jill Pipher, PhD, announced at the time. “With the world in crisis, we are inspired to see the Brown community coming together to be part of the leading edge of COVID-19 research.”
HELP WANTED
Many of the Brown-funded grants were aimed at making an immediate and direct impact on helping Rhode Island and Rhode Islanders. For example, researchers in the School of Engineering used their grant money to speed up production of ventilators through a new design that used 3D printing and off-the-shelf parts that could be made quickly and locally. An engineering team also studied how airflow inside passenger cars could affect airborne COVID-19 transmission, figuring out the best and worst open window configurations to prevent the potential spread of the virus among passengers in the same car if one person is infected.
A group from the Department of Computer Science used their grant to develop an artificial intelligence platform to differentiate COVID-19 from viral pneumonia on a chest CT scan and use that information to identify early-stage patients who are likely to transition to severe COVID-19.
Grants went to community-based initiatives too. A team from the Brown Center for Biomedical Informatics, for example, established an inter-institutional informatics infrastructure to support COVID-19 research in Rhode Island through electronic health data, digital health technology, and data science techniques.
Another group from the Department of Molecular Biology, Cell Biology, and Biochemistry worked to develop a sample unit for a potential COVID-19 home testing kit.
“Brown has a special responsibility to make valuable contributions to Rhode Island through our research and service, and advance innovation in our home community, and these funded projects will do that,” Locke and Pipher wrote.
COMPASSIONATE CARE
In the spring Brown researchers joined a nationwide initiative to give critically ill COVID-19 patients convalescent plasma.
The idea has been around since the 1918 influenza pandemic, when doctors gave sick patients plasma from those who had already recovered from that century’s most deadly virus. Their theory was that the transfusion would help sick patients struggling to mount their own antibody defense by giving them the antibodies of someone else who already made it through to the other side.
It was a Hail Mary pass, but one with pedigree. When Emil von Behring did the same thing in 1901, treating diphtheria with antibodies from animals who had recovered from the disease, he won the Nobel Prize. It also had successfully treated bacterial infections like pneumococcus and meningococcus, and viral infections like measles and mumps. More recently, it had some success in treating patients with H1N1 flu and Ebola.
Doctors in 2020 found themselves in a similar situation as their colleagues in 1918: with no proven treatment for COVID-19, and a vaccine far off on the horizon, they looked to treating patients with the plasma of those who had already survived it.
“We knew this was going to be one of the few possibilities for treating folks early on in the pandemic,” says Ralph Rogers MD’14 RES’17 F’19, associate professor of medicine and an infectious diseases specialist with Brown Medicine. He served as principal investigator for Brown on the nationwide project, initiated by a self-organized group of investigators from more than 50 institutions. In it, patients with severe or life-threatening COVID-19 were given convalescent plasma, with the hope that it would increase survival rates and reduce the time they spent in ICUs, on ventilators, or both.
While plasma treatment has already proved safe in treating severe bleeding and reversing overdoses of anticoagulants, and had shown some effectiveness in treating Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS), its hadn’t been tested on COVID-19 patients before because there hadn’t been COVID-19 patients before.
But given the severity of illness of many patients, and the fatality rate of those already in ICUs and on ventilators, researchers sought a blanket “compassionate use” authorization from the FDA, Rogers says, to allow for the rapid availability of the potential therapy before its efficacy was established.
“Often that takes the form of an individual patient emergency use authorization [EUA]. This is like that, but on a much larger scale,” he says. Researchers agreed to abide by a protocol developed by the Mayo Clinic, which worked with the FDA on regulatory issues.
The logistics were challenging: potential donors had to be recruited and needed to meet strict eligibility criteria; blood centers had to be willing to collect and process a blood product categorized as an investigational drug; and hospital blood banks and local research oversight bodies had to agree to participate.
“In our community,” Rogers says, “we were lucky to have support from the Rhode Island Blood Center and our hospital blood bank leadership, who quickly recognized the importance and urgency of this effort and worked seamlessly together to help bring this therapy to our patients.”
Despite the hurdles, plasma was generally available to give the same day it was needed. Rogers says they gave the first infusion on April 15, less than two weeks after the FDA authorization was in place; as of July, they had treated 93 patients. Brown was only the third center (after New York and Houston) to describe outcomes with convalescent plasma as compared to a matched control group, Rogers says.
In August the FDA issued an EUA for the use of convalescent plasma for inpatients under different guidelines, which, at press time, had halted its use locally. Questions of its efficacy still remain. Though more than 70,000 patients across the US received the transfusions, most were not administered in randomized controlled trials, according to Rogers.
“CP [convalescent plasma]use remains a hot-button issue,” Rogers wrote in an email in September. “In theory, CP has always been a ‘stopgap’ passive immunotherapy.” Citing clinical trials of other therapies now underway—including a study of monoclonal antibodies in inpatients led by Eleftherios Mylonakis, MD, PhD, chief of the Division of Infectious Diseases at Rhode Island and The Miriam hospitals—Rogers added, “the window for CP use seems as though it is closing.”
GOING GLOBAL
Brown faculty are involved in two other trials of convalescent plasma, giving Rhode Island a footprint as part of global initiatives to find COVID-19 treatments. These trials—which, because they’re being conducted with outpatients, were not affected by the FDA’s recent decision on CP use—not only are helping the world’s scientific community better understand how to treat COVID-19, they also brought lifesaving treatments to Rhode Island patients.
Knowing when to give patients convalescent plasma, and how effective it might be in different phases of the illness, were the key points of these studies, which are being run by Adam C. Levine, MD, MPH, associate professor of emergency medicine and director of the Division of Global Emergency Medicine. Both studies are part of multi-center trials led by Johns Hopkins.
In one, a phase two clinical trial, CP is given to individuals who have had high-risk exposure to COVID-19, like if they live with someone who has tested positive for the virus or if they’re a health care worker. These subjects are enrolled in the trial and randomized to convalescent plasma or standard plasma before they show any signs or symptoms. The goal is to see if giving antibodies to people exposed to COVID-19 can work as prophylactic treatment, to prevent an infection from taking hold.
“Given that so much transmission happens within a household, and we don’t really have a way to prevent that, and frontline workers are putting themselves at risk, this could be a powerful way to prevent those infections,” says Levine, who also worked in Liberia during the Ebola outbreak in 2014. He adds that if this kind of preventive measure works, it can also help health care workers—especially older individuals at high risk for COVID-19 complications—feel more confident about continuing to do their jobs.
In a second study, also a phase two clinical trial, participants who recently tested positive for COVID-19 and are experiencing mild symptoms are treated with CP in their first week of disease to see if it prevents them from developing severe illness.
“Based on what we know about convalescent plasma from other diseases and from this disease, it’s probably more likely to be effective early in the course of the disease, before the viral load is too high,” Levine says. “Then the antibodies have the best shot at neutralizing what is there.”
By early September the nationwide trial had enrolled more than 100 patients, Levine says, and they had started enrolling non-English speakers, “which has been one of our biggest impediments to enrolling in Rhode Island.”
While all these trials are important at a time when no other treatment options are available, Rogers hopes this information won’t be needed in the future, and will eventually seem as dated as shirtwaists and beaver hats.
“In theory, it’s a moot point because what we’re using now will hopefully be replaced by something better,” says Rogers, like Mylonakis’ study of the more refined monoclonal antibodies. Instead of relying on plasma from COVID-19 survivors for a supply of antibodies, the antibodies would be made in a lab, where they could be mass produced. Monoclonal antibodies are already a common cancer treatment, and could become the first line of both offense and defense against COVID-19.
REDEPLOYING REMDESIVIR
Karen Tashima, MD, professor of medicine, calls remdesivir a “drug looking for a disease to treat.” The antiviral was developed in 2009 by Gilead Sciences in hopes of treating RNA-based viruses that could spark global pandemics. It didn’t work as well as antibodies for Ebola in a 2014 study, despite showing activity against Ebola, Marburg, SARS, and MERS viruses in the lab.
“Why not try it for COVID-19?” asks Tashima, who is the director of clinical trials at the immunology center at Lifespan and clinical research site leader for The Miriam Hospital.
That’s exactly what she and her colleagues did as part of a global phase two clinical trial. In it, 397 people hospitalized for COVID-19 were given remdesivir for five or 10 days. The goal was to help determine how long patients should be given the drug.
Researchers found that in patients who didn’t require ventilators, remdesivir given for five days was just as effective as when it was given for 10 days. These findings were published in the New England Journal of Medicine in late May, and the trial has since expanded to nearly 6,000 patients.
“We can’t say how effective it was in this study because it was not compared to a placebo, but we know that after five days, people had very few adverse reactions, and that five days is just as good as 10 days for patients who are not intubated,” says Tashima, whose previous work has focused mostly on HIV drug clinical trials. These results can stop patients from getting medication in doses they don’t need, especially a medication that at times has been in short supply. (In a published placebo-controlled study, patients receiving remdesivir recovered more quickly than those receiving placebo.)
The study was conducted at the height of the spring outbreak, and brought a potential treatment into Rhode Island’s hospitals that might not have been available otherwise. “We really wanted to have a treatment available to patients in Rhode Island because what else could we do?” she says. “We wanted to have something to give patients that wasn’t just supportive care. We wanted to be able to offer this drug.”
This is an “all hands on deck” situation, Tashima adds, with researchers and health care professionals who had no experience in clinical trials getting up to speed quickly. “My colleagues in infectious disease really learned how to be clinical trials investigators overnight,” she says. They also had to iron out what are normally standard processes, like how to get consent forms signed by infectious patients when they’re not supposed to bring paper into their treatment rooms, or obtaining consent from family members when patients couldn’t consent themselves.
Tashima says they made sure to have doctors fluent in Spanish on their team, and consent forms in Spanish, to ensure Spanish speakers could be enrolled in the trial too—key since COVID-19 has disproportionally affected Black and Latinx Americans. With 170 participants in the Ocean State, she says, “We ended up being the third-highest enroller globally and in the US.”
Now Tashima is calling on hundreds of Rhode Islanders to sign up for a new study, one that’s an even bigger deal: in September she was named site investigator for a phase three, placebo-controlled clinical trial of a COVID-19 vaccine, and she began recruiting volunteers. Once again, the smallest state is poised to play a significant role in fighting the pandemic. “Little Rhode Island has made a big impact,” she says. “I’m really proud of that.”
