Yale study finds lower dose of COVID-19 drug is effective
A new Yale-UBC study finds that a decreased dosage of tocilizumab can effectively treat severe cases of COVID-19 and reduce supply shortages.
In response to the ongoing COVID-19 pandemic, a new study conducted by researchers at Yale and the University of British Columbia found that a lower-than-recommended dose of a common COVID-19 medication was effective at treating severe cases of the virus, providing a cost-effective option to address shortages of the drug.
The study, published in the journal Lancet Regional Health, found that reducing the dosage of the medication tocilizumab from a weight-based standard to a 400 milligram fixed dose was similarly effective at reducing inflammation and mortality associated with COVID-19. Given shortages of tocilizumab around the world, the researchers also found lower dosages to be a cost-effective option for tocilizumab distribution.
“My thinking was that, if we just give everyone 400 milligrams, then you almost double the supply [of tocilizumab],” said Luke Chen, a hematologist at the University of British Columbia and one of the study’s co-authors. “You still get the same anti-inflammatory response in the short term — and so you probably get the effect that you need for COVID. You’ll almost double the number of patients who can actually get the medication.”
In the early days of the pandemic, Chen noted, many patients who died of COVID-19 had suffered from a “pathological immune response” so that even once they had cleared the virus, their immune responses were causing inflammation that led to organ failure and death. Tocilizumab is a monoclonal antibody that inhibits an immune protein called interleukin-6, helping suppress the adverse immune response to COVID-19.
According to Chen, even though the “general wisdom was that you don’t give someone with an active infection an immunosuppressive medication,” research from the past year suggested that by suppressing the body’s immune response, tocilizumab decreases COVID-19 mortality from 35 percent to 28 percent. The medication contributes to lower blood pressure, decreased fever and diminished inflammation.
However, once tocilizumab was identified as an effective treatment for severe COVID-19, demand for the medication skyrocketed, creating a worldwide shortage. While supply chain issues did not notably impact the United States, Europe, Asia and Canada struggled to keep up with demand.
“We knew that we’d be running low on tocilizumab for several months because this is a drug that’s a monoclonal antibody,” Chen said. “So, it’s not like a small molecule pill, it’s an injection medication. And there are only one or two facilities in the world to produce it.”
To maximize Canada’s limited supply of tocilizumab, researchers at the University of British Columbia were keen to explore the effectiveness of a reduced dosage of tocilizumab.
The existing eight milligram per kilogram weight-based recommendation, Chen said, was based on studies of rheumatoid arthritis, where sustained high concentrations of the medication are required to chronically suppress inflammation.
“You have to maintain a minimum concentration over the month to control inflammation,” Chen said. “But COVID is not a chronic inflammatory illness — and so you probably only need to control the inflammation for a week or two.”
Since COVID-19 is more acute, the researchers hypothesized that a halved dosage may be effective enough, while doubling the availability of tocilizumab.
To test their hypothesis, the researchers recruited 152 patients with COVID-19. Out of the group, 40 received the recommended eight milligram per kilogram dosage of tocilizumab, 59 received a fixed decrease dose of 400 milligrams and 53 in a control group received the medication dexamethasone. In both tocilizumab groups, the researchers found that C-reactive proteins, a biomarker for inflammation, decreased by over 90 percent within five days, compared with a 48 percent decrease for the control group.
Meanwhile, the researchers found no difference in COVID-19 mortality or length of hospital stays between the dosage groups, suggesting that the decreased dosage may be an effective therapy for severe COVID-19 given a limited supply.
The University of British Columbia team also collaborated with George Goshua, a third-year hematology fellow at the Yale School of Medicine and a co-lead author of the study, to examine the cost-effectiveness of the two tocilizumab treatment strategies: treating all patients with a 400mg dosage versus allocating a full dosage to a randomly selected half.
Goshua’s analysis found that, taking into account factors including mortality, length of hospital stay and hospitalization costs, the use of 400 milligram doses is a cost-effective approach to distributing tocilizumab in the Canadian healthcare system, where limited supply of tocilizumab is a reality.
“[Tocilizumab] was studied at the 800-milligram dose and that’s what it should be used at, as long as there’s enough supply,” Goshua said. “I think [this study] is more so notable for other countries in the world, where there are going to be and where there have been supply issues.”
In a nationalized health care setting like Canada, Goshua continued, costs “are under much greater scrutiny than they are in the U.S.” And for a medication like tocilizumab, which is sold for roughly $1000 for 400 milligrams, better understanding the cost-effectiveness of a lower dosage brought “a lot of added value” to the study, according to Chen.
Although the researchers noted this specific study had a one-time focus, the collaborators at Yale and the University of British Columbia hope to continue exploring the relationship between COVID-19 and the endothelium — the cells that line the inside of blood vessels. Chen hopes that “it’s the first of a number of ongoing collaborations between UBC and Yale.”
“We have yet to determine whether, and to what extent, the initial dysregulation of the immune system or the subsequent therapeutic intervention is associated with post-COVID recovery,” Sophie Stukas, an associate research scientist at the University of British Columbia and one of the co-lead authors of the paper, wrote to the News. “To try and answer some of these questions, we are aiming to follow this patient group through the post COVID recovery clinic.”