tetano
Editor, Senior Moderator
N Engl J Med
. 2021 Feb 25.
doi: 10.1056/NEJMoa2028700. Online ahead of print.
Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia
Ivan O Rosas[SUP] 1 [/SUP], Norbert Br?u[SUP] 1 [/SUP], Michael Waters[SUP] 1 [/SUP], Ronaldo C Go[SUP] 1 [/SUP], Bradley D Hunter[SUP] 1 [/SUP], Sanjay Bhagani[SUP] 1 [/SUP], Daniel Skiest[SUP] 1 [/SUP], Mariam S Aziz[SUP] 1 [/SUP], Nichola Cooper[SUP] 1 [/SUP], Ivor S Douglas[SUP] 1 [/SUP], Sinisa Savic[SUP] 1 [/SUP], Taryn Youngstein[SUP] 1 [/SUP], Lorenzo Del Sorbo[SUP] 1 [/SUP], Antonio Cubillo Gracian[SUP] 1 [/SUP], David J De La Zerda[SUP] 1 [/SUP], Andrew Ustianowski[SUP] 1 [/SUP], Min Bao[SUP] 1 [/SUP], Sophie Dimonaco[SUP] 1 [/SUP], Emily Graham[SUP] 1 [/SUP], Balpreet Matharu[SUP] 1 [/SUP], Helen Spotswood[SUP] 1 [/SUP], Larry Tsai[SUP] 1 [/SUP], Atul Malhotra[SUP] 1 [/SUP]
Affiliations
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.).
. 2021 Feb 25.
doi: 10.1056/NEJMoa2028700. Online ahead of print.
Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia
Ivan O Rosas[SUP] 1 [/SUP], Norbert Br?u[SUP] 1 [/SUP], Michael Waters[SUP] 1 [/SUP], Ronaldo C Go[SUP] 1 [/SUP], Bradley D Hunter[SUP] 1 [/SUP], Sanjay Bhagani[SUP] 1 [/SUP], Daniel Skiest[SUP] 1 [/SUP], Mariam S Aziz[SUP] 1 [/SUP], Nichola Cooper[SUP] 1 [/SUP], Ivor S Douglas[SUP] 1 [/SUP], Sinisa Savic[SUP] 1 [/SUP], Taryn Youngstein[SUP] 1 [/SUP], Lorenzo Del Sorbo[SUP] 1 [/SUP], Antonio Cubillo Gracian[SUP] 1 [/SUP], David J De La Zerda[SUP] 1 [/SUP], Andrew Ustianowski[SUP] 1 [/SUP], Min Bao[SUP] 1 [/SUP], Sophie Dimonaco[SUP] 1 [/SUP], Emily Graham[SUP] 1 [/SUP], Balpreet Matharu[SUP] 1 [/SUP], Helen Spotswood[SUP] 1 [/SUP], Larry Tsai[SUP] 1 [/SUP], Atul Malhotra[SUP] 1 [/SUP]
Affiliations
- PMID: 33631066
- DOI: 10.1056/NEJMoa2028700
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.).