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Review 1: "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 1: "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:

The work presented by Rosas and colleagues investigated the use of the anti-interleukin-6 antibody, tocilizumab, to improve outcomes in patients with severe COVID-19 pneumonia. Using a randomized double-blind clinical trial design that enrolled 452 patients, the investigators found no significant differences in mortality between the placebo and treatment groups. Additionally, there were no significant improvements in the clinical status of patients as categorized by an ordinal scale of clinical outcomes (0-7), and no significant difference in adverse events between treated and untreated patients. The technical quality of the work was high and the conclusions of the manuscript are well-formed by appropriate analyses and supportive data.

With the rapid increase of clinical trials to repurpose existing drugs to improve outcomes for patients with COVID-19, this manuscript stands out as having high-quality data due to the appropriate clinical trial design. The randomized double-blind approach is correct for this type of study and the patients were well randomized, adding confidence to the results found. Data analyses included the van Elteren test on the primary outcome of clinical status on day 28, and additional odds ratios, Cox proportional hazard tests and data presented as Kaplan-Meier plots for secondary outcomes, all of which are appropriate for data of this nature. Though the primary endpoint defined by the authors was not met, the additional analysis on time to discharge is valuable and further studies on this outcome would be worth investigating.

Minor improvements to this manuscript:

1. Appendix 1 is not referenced in the manuscript.

2. Consider omitting the p-value from the Kaplan-Meier plots because they are not a robust statistical measure in this case. The Cox proportional hazards ratios and p-values in the results section are more appropriate measures.

3. Table 2 has inconsistent vertical borders across rows. Please unify.

4. The authors should consider a side-by-side histogram of the placebo versus tocilizumab groups of ordinal scale outcomes on day 28. This might better compare the distribution of outcomes than a stacked bar chart.

5. The final number of patients experiencing hypersensitivity in safety data seems higher for the treatment arm. Could the authors please comment on this?

6. Please add how many patients did or did not require a second infusion as stated in the protocol. Were the analyses of these patients any different?

7. Do the authors plan to examine demographic predictors of the outcomes in the future?

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