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Review 3: "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 3: "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
Description

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.

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Review:

This is a well written research article on a critical topic, one of unusually high importance to biomedical research today. The authors have made a strong case for the benefit of Tocilizumab in the reduction of the number of days to hospital discharge/ready for discharge and duration of ICU. The study population is well-defined. This reviewer is not an expert in the evaluation of statistical analyses. The statistical methods used seem to be appropriate. However, for a more definitive evaluation, the editor may rely on their own judgement or another reviewer.

The following suggestions would improve the manuscript:
1. In Table 1, it would help to provide breakdown of ‘Symptoms at diagnosis’ by comorbidities (that are already listed). The added information would provide a better understanding of whether certain symptoms are more or less prevalent in certain comorbidities.
2. In Figure 2 (A & B), under ‘Patients remaining at risk’ it would improve readability if % values of patients, in addition to the number provided, are also provided.

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