REMAP-CAP, COVACTA trials show mixed results for IL-6 blockade in COVID-19
medwireNews: Findings from the REMAP-CAP trial indicate that add-on treatment with tocilizumab or sarilumab may be beneficial for critically ill patients with COVID-19, whereas COVACTA suggests comparable outcomes with tocilizumab versus placebo in those with severe COVID-19 pneumonia.
Interleukin (IL)-6 is “[o]ne of the prime candidates for mediating inflammation in Covid-19,” and targeting the cytokine is attractive because “there are already approved agents that block either the cytokine or its receptor,” say Eric Rubin (Harvard TH Chan School of Public Health, Boston, Massachusetts, USA) and colleagues in an editorial accompanying the trial publications in The New England Journal of Medicine.
REMAP-CAP included 803 critically ill COVID-19 patients from 113 sites across six countries who were admitted to an intensive care unit (ICU) and receiving pulmonary or cardiovascular support. Within 24 hours of commencing organ support, participants were randomly assigned to receive a single dose of intravenous tocilizumab 8 mg/kg (with a second dose 12–24 hours later at the discretion of the treating physician), intravenous sarilumab 400 mg, or no additional treatment, alongside local standard care.
From baseline to day 21, participants given tocilizumab (n=353) or sarilumab (n=48) had a significantly higher median number of organ support-free days than those in the control group (n=402), at 10 and 11 versus zero, respectively. The adjusted odds ratios (ORs) compared with control were 1.64 for tocilizumab and 1.76 for sarilumab.
The researchers also found that in-hospital mortality rates were lower with tocilizumab or sarilumab versus control, at 27% for the pooled IL-6 receptor inhibitor group compared with 36% for the control arm. The adjusted ORs for in-hospital survival were significant for both tocilizumab and sarilumab versus placebo, at 1.64 and 2.01, respectively.
Consistent with previous trials of IL-6 inhibitors for COVID-19, there was “no increased incidences of serious adverse events” with tocilizumab or sarilumab, say the REMAP-CAP investigators. There were nine serious adverse events (AEs) in the tocilizumab group, none in the sarilumab group, and 11 in the control arm.
“We have to find the right patient and the right time”
In the COVACTA study, conducted at 62 hospitals in nine countries, 438 patients hospitalized with severe COVID-19 pneumonia were randomly assigned to receive tocilizumab 8 mg/kg (n=294; one dose with another after 8–24 hours at the discretion of the treating physician) or placebo (n=144) in addition to standard care.
Ivan Rosas (Baylor College of Medicine, Houston, Texas, USA) and co-investigators found that the primary outcome of clinical status on an ordinal scale at day 28 was not significantly different in the tocilizumab and placebo arms, with median values of 1.0 (indicating discharged or ready for discharge) and 2.0 (non-ICU hospitalization without supplemental oxygen), respectively.
In addition, 28-day mortality rates did not significantly differ among patients given tocilizumab versus placebo (19.7 vs 19.4%), but the researchers caution that “the trial was not powered for this outcome.” Rates of serious AEs were comparable in the tocilizumab and placebo arms, at 34.9% and 38.5%, respectively.
“How can we make sense of these disparate results?” ask the editorialists.
They note that the trials had differences in “enrollment criteria, the time at which anti–interleukin-6 therapy was initiated (relative both to the time of infection and to the severity of inflammation), the primary outcome, and background care.”
“All inflammation may not be the same: patients with severe disease at initial presentation may have a different pathogenesis than those in whom inflammatory disease develops later, which suggests that the timing of treatment may be crucial in understanding responses”, they continue.
Rubin and colleagues also note that background therapy may have contributed to the apparently contradictory results, with “[o]nly a minority” of COVACTA participants receiving glucocorticoid therapy (19.4–28.5%), compared with more than 90% in REMAP-CAP.
“Interleukin-6 blockade plus glucocorticoids, acting in different ways, may be additive or synergistic,” they say.
The editorialists conclude: “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.”
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2021 Springer Healthcare Ltd, part of the Springer Nature Group
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