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Rosas IO, Brau N, Waters M, et al. Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia. N Engl J Med. 2021 Feb 25. doi: 10.1056/NEJMoa2028700. (Original study)

BACKGROUND: Coronavirus disease 2019 (Covid-19) is associated with immune dysregulation and hyperinflammation, including elevated interleukin-6 levels. The use of tocilizumab, a monoclonal antibody against the interleukin-6 receptor, has resulted in better outcomes in patients with severe Covid-19 pneumonia in case reports and retrospective observational cohort studies. Data are needed from randomized, placebo-controlled trials.

METHODS: In this phase 3 trial, we randomly assigned patients who were hospitalized with severe Covid-19 pneumonia in a 2:1 ratio receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight) or placebo. Approximately one quarter of the participants received a second dose of tocilizumab or placebo 8 to 24 hours after the first dose. 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: Of the 452 patients who underwent randomization, 438 (294 in the tocilizumab group and 144 in the placebo group) were included in the primary and secondary analyses. The median value for clinical status on the ordinal scale at day 28 was 1.0 (95% confidence interval [CI], 1.0 to 1.0) in the tocilizumab group and 2.0 (non-ICU hospitalization without supplemental oxygen) (95% CI, 1.0 to 4.0) in the placebo group (between-group difference, -1.0; 95% CI, -2.5 to 0; P = 0.31 by the van Elteren test). In the safety population, serious adverse events occurred in 103 of 295 patients (34.9%) in the tocilizumab group and in 55 of 143 patients (38.5%) in the placebo group. 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; nominal P = 0.94).

CONCLUSIONS: In this randomized trial involving hospitalized patients with severe Covid-19 pneumonia, the use of tocilizumab did not result in significantly better clinical status or lower mortality than placebo at 28 days. (Funded by F. Hoffmann-La Roche and the Department of Health and Human Services; COVACTA ClinicalTrials.gov number, NCT04320615.).

Related DynaMed Topics

Discipline Area Score
Hospital Doctor/Hospitalists 7 / 7
Internal Medicine 7 / 7
Infectious Disease 6 / 7
Intensivist/Critical Care 6 / 7
Respirology/Pulmonology 6 / 7
Comments from MORE raters

Infectious Disease rater

According to other trials (Recovery and REMAP-CAP), the negative results in this one seem to be explained by the type of patients (not enough severe, treated later in their clinical course, and mainly without steroids) and the smaller sample size. Tocilizumab seems a good option but added to corticosteroids in critical/ICU patients.

Infectious Disease rater

This is the 4th paper on tocilzumab and similar agents for COVID-19. Also, NIH and IDSA guidelines have been updated on this topic. Each paper alone has limited impact because they have contradictory results. A combined review of 2 or more studies would be useful to clinicians who are confused by what in an initial reading may appear as contradictory results.

Intensivist/Critical Care rater

Here`s the problem: There have been 5 or 6 recent studies published on tocilizumab in COVID. Like this one, some are negative and others such as REMAP are positive. Clinicians are uncertain how to proceed.

Intensivist/Critical Care rater

This article along with the recovery trial may change the way COVID is treated. It's important on its own and with the two studies combined, they are practice-changing for ICUs.

Respirology/Pulmonology rater

This RCT finds no mortality benefit for severe Covid-19 infections using tocilizumab. Faster recovery and shorter ICU time was suggested but will need more study. Outside of a study protocol, tocilizumab should not be part of standard care for Covid-19.

Respirology/Pulmonology rater

Anti-IL 6 therapy is commonly used in treating hospitalized patients with COVID-19 infection. This analysis suggests that although the therapy did not increase adverse effects, the therapy did not reduce severity or change mortality in participants with moderate-severe infection.
Comments from EvidenceAlerts subscribers

Dr. Isa Kilicaslan (4/1/2021 2:23 PM)

This COVACTA trial is an international multicenter study from 62 hospitals in Europe and North America (Canada, Denmark, France, Germany, Italy, Netherlands, Spain, United Kingdom, and America). It is also a randomized, double-blind, placebo-controlled study. In the methods section, serious cases of COVID pneumonia are defined as PCR +, evidence of bilateral chest infiltrates, and a blood oxygen satıration of 93% or less. It was also stated that the patients took low-dose glucocorticoids. Therefore, the results of the study are reliable. In this study, it was reported that there was no evidence that tocilizumab reduced efficacy or mortality. Thanks to the authors for this work. However, tocilizumab in patients with severe COVID pneumonia is still unclear.