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Tocilizumab in Hospitalized Patients With Severe COVID-19 Pneumonia
Quick Takes
- Tocilizumab is a monoclonal antibody against interleukin-6, a cytokine thought to be central to the hyperinflammatory phase of COVID-19.
- In noncritically ill patients with severe COVID-19, tocilizumab was not effective at improving the clinical status or reducing mortality compared to placebo.
- Biomarkers of inflammation are likely more sensitive measures that could help define patients who would benefit from targeting the inflammatory pathways in COVID-19.
Study Questions:
Is a single intravenous infusion of tocilizumab effective at improving the clinical status of noncritically ill patients hospitalized for severe coronavirus disease 2019 (COVID-19) pneumonia?
Methods:
In this multicenter trial involving 62 hospitals across nine countries in Europe and North America, adult patients with severe COVID-19 pneumonia defined as having an oxygen saturation of ≤93% or PaO2/FiO2 <300 mm Hg were randomized 2:1 to intravenous tocilizumab (8 mg/kg for one dose) or placebo. A second dose of tocilizumab could be administered if clinical status did not improve. Patients were excluded if they had evidence of a secondary infection or if they were being treated with another investigational agent. The primary outcome was clinical status at day 28 on an ordinal scale ranging from 1 (discharged or ready for discharge) to 7 (death) in the modified intention-to-treat population, which included all the patients who had received at least one dose of tocilizumab or placebo.
Results:
A total of 438 (294 in the tocilizumab group and 144 in the placebo group) were included in the primary analysis. Over two thirds of the participants (70%) were men, 15% were Black, and the mean age was 60 years. There was no difference in the level of interleukin-6 (IL-6) between arms (mean 200 ng/L). Less patients in the tocilizumab arm received corticosteroids compared to the placebo arm (19% vs. 29%). The incidence of mechanical ventilation was similar in both arms (38%). There was no significant difference in clinical status at 28 days between the tocilizumab and placebo arms (between-group difference, −1.0; 95% confidence interval [CI], −2.5 to 0; p = 0.31). Mortality at day 28 was 19.7% in the tocilizumab group and 19.4% in the placebo group (weighted difference, 0.3 percentage points [95% CI, –7.6 to 8.2; p = 0.94]). There was a trend towards lower hospitalization days with tocilizumab (median of 20 compared to 28) compared to placebo. There were no statistically significant differences in serious adverse events between both groups.
Conclusions:
The use of tocilizumab did not result in better clinical status or lower mortality at 28 days compared to placebo in noncritically ill patients hospitalized for severe COVID-19.
Perspective:
The tocilizumab trials (and every other trial of COVID-19) exemplify the challenges in finding a silver bullet for COVID-19. It has become evident that COVID-19 is a heterogeneous disease with significant variability in clinical course and different phases; an acute viral phase and hyperinflammatory phase—which does not occur in every patient. The effectiveness of current therapies such as remdesivir and glucocorticoids has been shown to be highly sensitive to the clinical status of the patient. Tocilizumab targets IL-6—a cytokine thought to be central to the hyperinflammatory phase; however, elevated IL-6 was not a criterion for enrollment in this trial. This was less restrictive in its definition of severe COVID-19, with the intent of evaluating whether tocilizumab would be broadly effective in patients with COVID-19 pneumonia. Large high-quality observational studies such as STOP-COVID and the REMAP-CAP trial suggest benefit of tocilizumab in the critically ill subgroup of patients with COVID-19, likely due to the selection of those in a hyperinflammatory phase of the disease. Biomarkers of inflammation are likely more sensitive measures that could help define patients who would benefit from targeting the inflammatory pathways in COVID-19.
Clinical Topics: COVID-19 Hub, Prevention
Keywords: Biomarkers, Coronavirus, COVID-19, Critical Illness, Cytokines, Glucocorticoids, Inflammation, Interleukin-6, Patient Discharge, Pneumonia, Primary Prevention, Respiration, Artificial
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