In This Article
- A team of Massachusetts General Hospital clinician-researchers mobilized quickly during extraordinary circumstances to fast-track a study of a potential treatment for hospitalized patients with COVID-19
- The randomized, double-blind, placebo-controlled, multicenter clinical trial found that tocilizumab does not affect outcomes for hospitalized patients with COVID-19
- Although the trial results were negative, the team answered an important research question despite enormous challenges posed by the pandemic
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Amidst the initial surge of COVID-19, a group of Massachusetts General Hospital researchers mobilized to quickly launch a randomized, double-blind, placebo-controlled, multicenter clinical trial to test the immunosuppressant drug tocilizumab as a potential treatment for the disease.
Although the investigation ultimately found that tocilizumab did not reduce hospitalized patients' need for mechanical ventilation or prevent death, the trial did prove that research can be launched quickly and effectively, even in a pandemic.
"It was a time of incredible chaos, great unknowns and concern about whether we were going to have enough personal protective equipment for health care providers, concern about whether we were going to have enough ventilators for patients," says principal investigator John Stone, MD, MPH, a rheumatologist and the Edward A. Fox chair in Medicine at Mass General. "Superimposed on all of that, was the urgency to launch clinical trials to try to learn something about how to treat this disease. We needed information about how to help the patients, and we had no previous guidance on how to perform clinical trials in COVID-19."
Fast-Tracking a Trial During a Pandemic
Tocilizumab is a biologic medication approved by the U.S. Food and Drug Administration to treat adults with rheumatoid arthritis or giant cell arteritis (GCA), as well as children with certain types of arthritis. Dr. Stone led the worldwide clinical trial in 2017 (published in the New England Journal of Medicine) that resulted in the drug's use in GCA, the most common form of vasculitis.
"Tocilizumab inhibits interleukin-6 (IL-6). It binds to the IL-6 receptor and therefore prevents IL-6 from interacting with its receptor, making it physiologically inert," Dr. Stone says. "There was reason to believe that IL-6 might be playing a central role in COVID-19 pneumonia. Patients with COVID-19 and elevated levels of IL-6 were in a hyperinflammatory state and had greater risk of mechanical ventilation and death. So it made sense that tocilizumab might work in this disease."
To test that theory, Dr. Stone and a team of Mass General rheumatologists launched a rigorous trial during the height of the first surge of COVID-19 in Boston, from April through mid-June 2020. Steps that normally take months were condensed, sometimes to hours.
Almost immediately, Dr. Stone secured funding from the manufacturer of tocilizumab. Legal teams executed contracts in record time, then the researchers accelerated the creation of the study protocol, a database and consent forms. Institutional Review Board approval, which often takes months, was obtained rapidly.
Within a week, the study enrolled 30 patients. By the end of the second week, six additional hospitals and 90 more patients joined the effort. The team also pivoted instantly to accommodate a patient sample that was 45% Hispanic, with Spanish-speaking staff facilitating informed consent.
"I learned very early in my career that you need at least six months to launch a research project from a cold start. We couldn't have had a colder start than the one we had," Dr. Stone says. "It all happened very, very quickly. Then for the next 40 days, we worked harder than I think we have ever worked in our entire careers."
Negative Results Surprise Investigators
The study ultimately evaluated 243 hospitalized patients with:
- Confirmed infection with SARS-CoV-2
- High levels of inflammation
- At least two symptoms of pneumonia (fever greater than 38°C, pulmonary infiltrates and the need for supplemental oxygen)
Patients were randomized 2:1 to receive standard care plus either a single dose of tocilizumab (8 milligrams per kilogram of body weight) or one dose of a placebo (normal saline).
In a paper published in the New England Journal of Medicine, Dr. Stone's team reported no evidence that tocilizumab had any positive effect on the study group.
"Receipt of tocilizumab had no impact whatsoever on the patient's risk of being intubated or dying," Dr. Stone says. "It didn't decrease the duration of supplemental oxygen use. It didn't reduce the likelihood that they would progress. It didn't matter for any of the other secondary endpoints."
Reflecting on Negative Results and a Meaningful Research Endeavor
The team performed a multivariate analysis to look for confounding variables, but none of the efficacy measures assessed were statistically significant. "We were very surprised by our results. They definitely flew in the face of conventional wisdom at the time," Dr. Stone says. Subsequent trials of tocilizumab have confirmed the findings of this early trial from Mass General.
Although the tocilizumab trial had negative results, it had several positive outcomes: The findings answered an important question about treatment for hospitalized patients with COVID-19. And the study illustrated what can be accomplished by a determined research team.
"Everybody worked constantly, around the clock, to get things done. That's the only way that it could have happened," Dr. Stone says. "We were disappointed, of course, to have a negative trial, but we are very proud of what we did—conducting a rigorous trial under such difficult circumstances."
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