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Review 2: "Tocilizumab in Hospitalized Patients With COVID-19 Pneumonia"

An anti-interleukin-6 antibody, tocilizumab, was found to have no significant differences in mortality or clinical outcomes at day 28, but shorter median time to hospital discharge, compared with placebo in a rigorously conducted randomized control trial.

Published onOct 16, 2020
Review 2: "Tocilizumab in Hospitalized Patients With COVID-19 Pneumonia"
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key-enterThis Pub is a Review of
Tocilizumab in Hospitalized Patients With COVID-19 Pneumonia

BACKGROUND COVID-19 is associated with immune dysregulation and hyperinflammation. Tocilizumab is an anti-interleukin-6 receptor antibody. METHODS Patients hospitalized with severe COVID-19 pneumonia receiving standard care were randomized (2:1) to double-blinded intravenous tocilizumab 8 mg/kg or placebo. The primary outcome measure was clinical status on a 7-category ordinal scale at day 28 (1, discharged/ready for discharge; 7, death). RESULTS Overall, 452 patients were randomized; the modified-intention-to-treat population included 294 tocilizumab-treated and 144 placebo-treated patients. Clinical status at day 28 was not statistically significantly improved for tocilizumab versus placebo (P=0.36). Median (95% CI) ordinal scale values at day 28: 1.0 (1.0 to 1.0) for tocilizumab and 2.0 (1.0 to 4.0) for placebo (odds ratio, 1.19 [0.81 to 1.76]). There was no difference in mortality at day 28 between tocilizumab (19.7%) and placebo (19.4%) (difference, 0.3% [95% CI, -7.6 to 8.2]; nominal P=0.94). Median time to hospital discharge was 8 days shorter with tocilizumab than placebo (20.0 and 28.0, respectively; nominal P=0.037; hazard ratio 1.35 [95% CI 1.02 to 1.79]). Median duration of ICU stay was 5.8 days shorter with tocilizumab than placebo (9.8 and 15.5, respectively; nominal P=0.045). In the safety population, serious adverse events occurred in 34.9% of 295 patients in the tocilizumab arm and 38.5% of 143 in the placebo arm. CONCLUSIONS In this randomized placebo-controlled trial in hospitalized COVID-19 pneumonia patients, tocilizumab did not improve clinical status or mortality. Potential benefits in time to hospital discharge and duration of ICU stay are being investigated in ongoing clinical trials.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.



Consideration of the timing of anti-interleukin-6 receptor treatment in coronavirus disease 2019 (COVID-19) pneumonia

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a serious global health threat. SARS-CoV-2 infection is associated with a high risk of mortality, causing severe vasculitis and blood coagulation that can lead to severe respiratory failure and multiple organ damage. Immunological analysis of COVID-19 patients shows that SARS-CoV-2 infection elicits a cytokine storm, suggesting possible efficacy of anti-cytokine therapies. Interleukin-6 (IL-6) is involved in the immune response to SARS-CoV-2 infection, and the results of small size cohort studies have reported that anti-IL-6 receptor antibody, tocilizumab, showed efficacy in treating COVID-19 patients.

Phase III results of the COVACTA trial did not show improvement in patient mortality, but a benefit was observed with shortened duration of intensive care unit stay compared to placebo treatment. Moreover, the COVACTA trial proved the safety of tocilizumab in COVID-19 treatment, which indicates a lower risk of secondary infection. However, while some trials of anti-IL-6 drugs, including sarilumab and tocilizumab, did not prove their efficacy, further benefits of these drugs were later observed in retrospective studies.

Emerging evidence from numerous retrospective studies have provided insights into the pathogenesis of SARS-CoV-2 infection and the effect of IL-6 signaling inhibition on this disease. The cytokine storm induced by COVID-19 is formed by IL-6 trans-signaling in the endothelium, in which IL-6 acts on endothelial cells to promote release of pro-inflammatory cytokines and a protein called plasminogen activator inhibitor-1 (PAI-1), which causes small blood clots in vessels throughout the body, including in the lungs. After tocilizumab treatment, serum levels of PAI-1 and C-reactive protein (CRP), which is controlled by IL-6 in severe COVID-19 patients, were significantly reduced and some clinical symptoms improved. Additionally, a small-scale retrospective study provided evidence of the potential efficacy of tocilizumab treatment in COVID-19 patients during the early stages of hospitalization.

Thus, proper timing of tocilizumab treatment is likely to be crucial for its efficacy in controlling COVID-19. Although the COVACTA trial did not meet the primary outcome, trials to prove the efficacy of tocilizumab should be continued with appropriate strategies.

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