Dr. Derek Angus, professor and chair, Department of Critical Care Medicine at Pitt and UPMC, is pictured during a news conference Thursday. Photo by the University of Pittsburgh

With their consent, patients at UPMC Chautauqua could participate in a trial that results in finding a treatment for COVID-19.

Dr. Derek Angus, professor and chair, Department of Critical Care Medicine at Pitt and UPMC, talked recently about UPMC’s efforts to lead an international clinical trial supported by artificial intelligence. Before COVID-19 emerged, Angus and international collaborators had developed a platform, called REMAP-Community Acquired Pneumonia (REMAP-CAP) designed to find optimal treatments for severe pneumonia both in non-pandemic and pandemic settings. When COVID-19 began circulating, REMAP-CAP was adapted to incorporate additional treatment regimens specifically targeting the SARS-CoV-2 virus. The international team describes the REMAP-CAP platform in a manuscript published Thursday in the Annals of the American Thoracic Society (AnnalsATS).

“How this works is when a patient is admitted with severe COVID-19 o any of our institutions, if they consent to participate in the trial, they’re immediately assigned randomly to different recipes of treatments,” Angus said. “Only one of those recipes has only the standard care in it. And nearly all the recipes are including at least one of these active therapies. Furthermore then the trial continues to update over time. Doing this at the point of care saves time.. It’s specifically designed in a way that makes it efficient in the setting of COVID-19 when everyone is under PPE and everyone is trying to do things quickly. We have to have this happen efficiently and safely. UPMC REMAP-COVID then learns on the fly using a built-in artificial intelligence engine such that within this combination of therapies, those treatments that are doing the best, even while the trial is still running, the trial then changes the odds towards getting those treatments more frequently so the poor-performing therapies are discarded quickly and essentially our physicians are always betting on the winning horse.”

UPMC-REMAP-COVID19 will open across UPMC’s 40-hospital system and begin with multiple treatments tested simultaneously in different combinations — including hydroxychloroquine, steroids and medications called immunomodulators that alter the responsiveness of the immune system. If new drugs need to be tested, they are simply rolled into the platform as study amendments, rather than tested in separate free-standing trials. All participants will receive the current standard of care, and most also will receive one, two or three of the experimental treatment options. This means that, at launch, only 12.5% of participants will be strictly assigned to the placebo arm of the trial and, within weeks, researchers expect that about 99% of patients will be receiving one or more active therapies specifically targeting COVID-19.

Because the UPMC-REMAP-COVID19 platform is connected to the worldwide REMAP-CAP, the trial learns from the entire international experience. REMAP-CAP is enrolling patients with COVID-19 in North America, Europe, Australia and New Zealand, and expanding rapidly.

“This trial ties into an international trial that we helped design and lead,” Angus said. “Just to give you a flavor of how this trial is being perceived, the chief medical officer of the British National Health Service last week sent out a letter encouraging every hospital in Britain to participate in this trial. We feel we need a big tent approach in the United States. We’ve heard from government and regulatory authorities from public health authorities and from major foundations that are all endorsing that these types of adaptive platform trials are the way to try to learn efficiently in the midst of this pandemic.”

UPMC officials recently discussed a clinical trial they are ready to undertake regarding a potential vaccine for COVID-19. Researchers were able to work quickly on the vaccine because they had done some work during earlier coronavirus epidemics, including SARS. Funding dried up when research on those earlier disease vaccines was ready to proceed to clinical trials, and Angus said a similar problem happened when doctors researching the H1N1 flu virus, a novel influenza virus otherwise known as the swine flu, researchers tried to take treatment approaches into a clinical trial setting. Funding wasn’t the problem, but the disease disappeared from a region very quickly, meaning there were no patients to participate in a clinical trial. The H1N1 situation prompted research into how to better conduct clinical trials during a pandemic when doctors and patients need to decide on a course of treatment quickly.

“The world moved rapidly to identify the virus in H1N1,” Angus said. “Within weeks the basic science of the virus was totally understood and yet the entire worldwide clinical research community couldn’t find any therapies for H1N1. Everyone scrambled to do traditional clinical trials and by the time they got them up and running H1N1 had left their region and gone somewhere else. I was part of a group of scientists from around the world who sat afterwards and said what did we do wrong and how can we do this better?”

That question led the doctors to receive funding from the British Embassy to host a meeting in Pittsburgh in 2012 to devise a better structure to ask clinical questions during future pandemics. From those talks, REMAP was born.

How quickly the REMAP clinical trial confirms an optimal treatment for COVID-19 depends on how many patients enroll. Angus said it typically takes several hundred patients. As therapies work, however, they will be pushed to the forefront of the clinical trial, which means answers will come more quickly than in a typical randomized clinical trial and more patients will benefit from the emerging therapies in real time.

“What you’re asking is when does the uncertainty switch from being uncertain to completely known,” Angus said in response to a reporter’s question. “To completely know an answer with a high degree of certainty can still take weeks or months depending on how rapidly patients are enrolled. But with every notch in the reduction in uncertainty, the trial then converts that reduction in uncertainty into improved odds for the patient. So even before we’ve got the end trial result we’re already offering opportunities where on average patients will be doing better inside the trial than outside of it.”