Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia

Authors

Ivan O Rosas
Norbert Bräu
Michael Waters
Ronaldo C Go
Bradley D Hunter
Sanjay Bhagani
Daniel Skiest
Mariam S Aziz
Nichola Cooper
Ivor S Douglas
Sinisa Savic
Taryn Youngstein
Lorenzo Del Sorbo
Antonio Cubillo Gracian
David J De La Zerda
Andrew Ustianowski
Min Bao
Sophie Dimonaco
Emily Graham
Balpreet Matharu
Helen Spotswood
Larry Tsai
Atul Malhotra

Publication Date

4-22-2021

Journal

The New England Journal of Medicine

DOI

10.1056/NEJMoa2028700

PMID

33631066

PMCID

PMC7953459

PubMedCentral® Posted Date

2-25-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Adult, Aged, Antibodies, Monoclonal, Humanized, COVID-19, Double-Blind Method, Female, Hospital Mortality, Hospitalization, Humans, Infusions, Intravenous, Intensive Care Units, Male, Middle Aged, Receptors, Interleukin-6, Respiration, Artificial, Treatment Failure, COVID-19 Drug Treatment

Abstract

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.)

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