Dr. John Marshall is the Canadian lead investigator in the REMAP-CAP trial, and a key player in the World Health Organization (WHO) SOLIDARITY trial, both of which are global trials evaluating treatments for COVID-19.
Dr. Marshall, Professor of Surgery at the University of Toronto, and Trauma Surgeon and Intensivist at St. Michael’s Hospital, is a global expert in ICU-acquired infections like pneumonia, and a veteran of the H1N1 and SARS pandemics. He is the founding chair of the International Forum for Acute Care Trialists (InFACT), and a leader in the design of clinical trials and pandemic preparedness. He also co-chairs the WHO Clinical Characterization and Management Working Group which was formed in February 2020 in Geneva.
Leading the REMAP-CAP trial at St. Michael’s Hospital
Over the past eight years, the global critical care research community has worked to build a research platform to expedite research in the face of future pandemic need. That future is now, and the REMAP-CAP platform is ready for the challenge.
Experience with SARS and H1N1 convinced Dr. Marshall and his colleagues that in order to respond adequately to the next pandemic, it was necessary to have trial architecture up and running before the pandemic arrived. In 2011, St. Michael’s Hospital hosted an international meeting that brought together 100 researchers, clinicians, government officials and funding agency representatives from around the world to talk about pandemic research preparedness. The idea for REMAP-CAP (Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community Acquired Pneumonia) resulted from this meeting and the trial launched in December 2019 at St. Michael’s Hospital, with funding from the Canadian Institutes of Health Research (CIHR).
The study uses a novel trial design known as a platform trial that can analyze multiple interventions simultaneously, update its design in response to evolving results, and integrate those results into clinical practice. Dr. Marshall explains that is a “living, continuously evolving study”. REMAP-CAP was created so that in the event of a future pandemic of a respiratory pathogen – such as COVID-19 –researchers would be able to evaluate the most relevant treatment options quickly.
In the current COVID-19 pandemic, the goal is to generate evidence that will reduce morbidity in severely ill patients with COVID-19. With the novel design of REMAP-CAP, and the number of trial participants likely to enroll over the next few months, Dr. Marshall says actionable data will be generated “in a matter of months, as opposed to years, which is what the usual clinical trial timeline is.”
Involvement in the WHO SOLIDARITY trial
In the face of the escalating COVID-19 pandemic, the WHO announced the launch of a large, international study of potential coronavirus therapies, called the SOLIDARITY trial. Canada was one of the first countries to jump on board through the Canadian Treatments for COVID-19 (CATCO) study, sponsored by Sunnybrook Health Sciences Centre. More than 70 Canadian research sites have signed up to participate in CATCO.
CATCO is currently comparing lopinavir-ritonavir, a combination of antiviral agents used to treat HIV, against the standard of care, with other interventions to be added shortly. Dr. Marshall views SOLIDARITY/CATCO as the grand umbrella trial coordinating global research efforts. “REMAP-CAP studies the sickest COVID-19 patients while CATCO guides the study of anti-viral interventions” he said. “The important thing is that we are all of the view that this requires an integrated global response.”
Dr. Marshall’s co-chair on the WHO Committee Clinical Characterization Working Group, Dr. Srinivas Murthy of the University of British Columbia, is the lead investigator of the CATCO trial. Data collected from participating hospitals will be submitted to a central repository managed by the WHO.
Ontario is a leader in the global research response
Through the REMAP-CAP and CATCO studies, and multiple others occurring across the province, Ontario, and St. Michael’s in particular, has proven itself a leader in the global research response to COVID-19. As Dr. Marshall puts it, “St. Michael’s Hospital is the lead for REMAP-CAP trial and Ontario is the hub of clinical trials activity in Canada.”
“CTO has assumed a vital role in expediting and facilitating clinical research,” commented Dr. Marshall. Both the REMAP-CAP trial and the CATCO trial are part of CTO Stream and are two of many COVID-19 trials within the program. Clinical Trials Ontario (CTO) is committed to helping move COVID-19 studies forward as quickly as possible. Through CTO’s programming, CTO Stream, the Trial Site Network, and QuickSTART, CTO is able to help identify collaborators across the province and assist in managing study start-up at each of these centers.
Learning Lessons and Adapting
There have been major strides made in the research response to pandemics since the H1N1 pandemic. “We have come a long way, if you compare where we are now to where we were in the H1N1 pandemic. In 2009, there were a number of clinical trials that began during that pandemic, but they were small, not integrated well, and slow to get started,” said Dr. Marshall. “In this pandemic, people were conducting clinical trials as early as they were treating patients.”
Dr. Marshall is also surprised at the public’s response to the role of research in ending the pandemic. “People are saying research is just as important as patient care. There is a sense that we are going to collaborate and we are going to share data. Not only are we going to generate information quickly about COVID-19, we are going to fundamentally change the way we do research and the way we think about integration of research into clinical practice coming out of this.”
However, Dr. Marshall is certain there are still lessons to be learned from the response to the current pandemic. “The one that I am really concerned about right now is that as the pandemic ramps up, we are at risk of focusing on interventions that benefit high income countries whereas the burden of illness is going to be in low and middle income countries.”
Dr. Marshall worries how devastating this pandemic will be in those countries. However, he is already working on a solution. Working through InFACT, Dr. Marshall and the REMAP-CAP team are looking at whether they can adapt the platform so that it could be used in resource-limited settings. He hopes to get a version of the trial up and running throughout Latin America, Africa and Southeast Asia. “It’s a huge challenge but I think it’s important to try.”