The New England Journal of Medicine yesterday published two studies on the effectiveness of the interleukin-6 receptor antagonists tocilizumab and sarilumab in severely ill adult COVID-19 patients, one finding a benefit to a combination of the two drugs and the other showing no benefit with tocilizumab alone.
Early treatment with combo may be key
The first study, led by researchers at Imperial College London as part of an ongoing international platform trial, involved randomly assigning 803 patients in 113 intensive care units (ICUs) in six countries to receive tocilizumab, sarilumab, or usual care from April (tocilizumab) and June (sarilumab) through November 2020.
Median number of organ support–free days was 10 in the group receiving tocilizumab (353 patients), 11 in the sarilumab group (48 patients), and 0 in the control group (402 patients). Both monoclonal antibodies showed effectiveness in improving 90-day survival, time to ICU and hospital release, and World Health Organization ordinal clinical status scale on day 14.
Mean adjusted cumulative odds ratios were 1.64 for tocilizumab patients (95% credible interval [CI], 1.25 to 2.14) and 1.76 for sarilumab (95% CI, 1.17 to 2.91) compared with controls, for posterior probabilities of superiority to control greater than 99.9% and 99.5%, respectively.
At 90 days, the pooled monoclonal antibody groups had better survival than controls (hazard ratio, 1.61 (95% CI, 1.25 to 2.08) and a posterior probability of survival greater than 99.9%. Secondary analyses also supported the effectiveness of the drugs.
All except three patients were on respiratory support at study randomization, including oxygen through high-flow nasal cannulae (29%), noninvasive ventilation (42%), and invasive mechanical ventilation (29%). Of the tocilizumab patients, 92% received one dose, and 29% received a second dose at their clinician's discretion. Over 80% of patients also received glucocorticoids.
Nine serious adverse events occurred among the tocilizumab patients, including one secondary bacterial infection, five bleeding events, two cardiac events, and one instance of vision deterioration. In the control group, 11 serious adverse events were reported, including four bleeding events and seven thromboses (blood clots).
Tocilizumab and sarilumab both inhibit receptors for interleukin-6, an inflammatory agent released in response to infection. Both drugs are often used to treat rheumatoid arthritis. The authors noted that previous trials of tocilizumab and sarilumab have had mixed results.
The researchers said that all patients were enrolled within 24 hours of starting organ support. "This may be an important factor to maximize effectiveness: treating critically ill patients early, while any developing organ dysfunction may be more reversible," they wrote.
No improved clinical status with monotherapy
In the second study, a phase 3 clinical trial, a team led by a researcher from Baylor College of Medicine assigned 438 hospitalized adult patients with severe COVID-19 pneumonia in a 2-to-1 ratio to receive either a single dose of intravenous tocilizumab or a placebo. The trial took place at 62 hospitals in 9 countries in Europe and North America from Apr 3 to May 28, 2020.
About one fourth of patients received a second dose of tocilizumab or placebo 8 to 24 hours after the first. The placebo group didn't require ICU care or supplemental oxygen.
The investigators found that tocilizumab didn't significantly improve clinical status or lower death rates over placebo at 28 days. Among the 294 patients in the tocilizumab group, median clinical status on an ordinal scale (with 1 indicating past or impending hospital release and 7 indicating death) was 1.0, compared with 2.0 in the 144 patients in the placebo group (between-group difference, -1.0).
"We found no significant difference in clinical status between the tocilizumab group and the placebo group at day 28," the researchers said. "No mortality benefit was associated with the use of tocilizumab, although the trial was not powered for this outcome."
Serious adverse events occurred in 34.9% of patients in the tocilizumab group and in 38.5% in the placebo group. Among the tocilizumab group, 19.7% died, compared with 19.4% in those receiving placebo (weighted difference, 0.3 percentage points).
The authors called for future trials of tocilizumab to focus more narrowly on different stages of the disease or enroll more patients to allow further stratification based on disease severity and other baseline factors. "The need for effective treatments for patients with severe Covid-19 pneumonia continues to be a major challenge at this point in the pandemic," they wrote.
Conflicting results difficult to interpret
In a commentary in the same journal, Eric Rubin, MD, PhD; Dan Longo, MD; and Lindsey Baden, MD, all of Harvard University, said that the two trials' contradictory results could have been due to differences in enrollment criteria, time of initiation of the drugs, the primary outcome, background care, types of inflammation, the periods over which the two trials were conducted, and their use of glucocorticoids.
In contrast to the first trial, only a small proportion of patients in the second trial received glucocorticoids because they weren't considered standard care at the time.
"One particularly notable change has been that patients with severe disease, the targets of therapy in most of these trials, now almost universally receive glucocorticoids, since these drugs were shown in July 2020 to reduce mortality," the authors wrote. "Interleukin-6 blockade plus glucocorticoids, acting in different ways, may be additive or synergistic. Alternatively, the use of glucocorticoids may simply be a marker for other changes in treatment that have occurred during the course of the epidemic."
They added that when trial results change as underlying treatments evolve, as they did in this case and often do in platform trials, they can be difficult to understand. "For now, we are left with evidence of benefit from interleukin-6 inhibitors, at least under some circumstances, but how to best use them remains unclear," Rubin and colleagues concluded.