Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia

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.).

Figure 1. Enrollment and Outcomes.

One patient who was assigned to the placebo group received tocilizumab; this patient was included in the placebo group for analyses performed in the modified intention-to-treat population (mITT) and in the tocilizumab group for analyses performed in the safety population. One patient in each trial group died after they had withdrawn from the trial; therefore, for these patients, death is not listed as the reason for discontinuation. Pao₂:Fio₂ denotes the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, Spo₂ oxygen saturation, ULN upper limit of the normal range, and WHO World Health Organization.

Figure 2. Changes in Clinical Status and Hospital Discharge.

Panel A shows the time until improvement from baseline by at least two categories on the seven-category ordinal scale that was used to assess the patients’ clinical status. Panel B shows the number of days until hospital discharge or readiness for discharge by day 28. Data in Panels A and B are plotted as 1 minus the Kaplan–Meier estimator. Data for patients who discontinued the trial or were lost to follow-up for any reason were censored (indicated by hatch marks) at the time of their last ordinal-scale assessment. Data for patients who died were censored at day 28. Panel C shows the patients’ clinical status as assessed on the seven-category ordinal scale at day 28, according to the category at baseline. Categories on the ordinal scale were as follows: 1, discharged or ready for discharge; 2, hospitalization in a non–intensive care unit (ICU) without supplemental oxygen; 3, non–ICU hospitalization with supplemental oxygen; 4, ICU or non–ICU hospitalization with noninvasive ventilation or high-flow oxygen; 5, ICU hospitalization with mechanical ventilation; 6, ICU hospitalization with extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; and 7, death. Data in category 6 include a patient who died on trial day 1 but had been assigned to category 6 on that day before receiving placebo.