Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia

Abstract

Background: Coronavirus disease 2019 (Covid-19) pneumonia is often associated with hyperinflammation. Despite the disproportionate incidence of Covid-19 among underserved and racial and ethnic minority populations, the safety and efficacy of the anti-interleukin-6 receptor antibody tocilizumab in patients from these populations who are hospitalized with Covid-19 pneumonia are unclear.

Methods: We randomly assigned (in a 2:1 ratio) patients hospitalized with Covid-19 pneumonia who were not receiving mechanical ventilation to receive standard care plus one or two doses of either tocilizumab (8 mg per kilogram of body weight intravenously) or placebo. Site selection was focused on the inclusion of sites enrolling high-risk and minority populations. The primary outcome was mechanical ventilation or death by day 28.

Results: A total of 389 patients underwent randomization, and the modified intention-to-treat population included 249 patients in the tocilizumab group and 128 patients in the placebo group; 56.0% were Hispanic or Latino, 14.9% were Black, 12.7% were American Indian or Alaska Native, 12.7% were non-Hispanic White, and 3.7% were of other or unknown race or ethnic group. The cumulative percentage of patients who had received mechanical ventilation or who had died by day 28 was 12.0% (95% confidence interval [CI], 8.5 to 16.9) in the tocilizumab group and 19.3% (95% CI, 13.3 to 27.4) in the placebo group (hazard ratio for mechanical ventilation or death, 0.56; 95% CI, 0.33 to 0.97; P = 0.04 by the log-rank test). Clinical failure as assessed in a time-to-event analysis favored tocilizumab over placebo (hazard ratio, 0.55; 95% CI, 0.33 to 0.93). Death from any cause by day 28 occurred in 10.4% of the patients in the tocilizumab group and 8.6% of those in the placebo group (weighted difference, 2.0 percentage points; 95% CI, -5.2 to 7.8). In the safety population, serious adverse events occurred in 38 of 250 patients (15.2%) in the tocilizumab group and 25 of 127 patients (19.7%) in the placebo group.

Conclusions: In hospitalized patients with Covid-19 pneumonia who were not receiving mechanical ventilation, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival. No new safety signals were identified. (Funded by Genentech; EMPACTA ClinicalTrials.gov number, NCT04372186.).

Figure 1. Enrollment, Randomization, and Follow-up.

The modified intention-to-treat population included all the patients who underwent randomization and received tocilizumab or placebo. Patients may have been excluded for more than one reason. A total of 389 patients underwent randomization, and 388 patients had data that could be evaluated. (One patient underwent randomization before local institutional review board approval of the trial site. This patient did not receive tocilizumab or placebo, and no further data were collected.) One patient who was randomly assigned to the placebo group received tocilizumab and was included in the tocilizumab group in the safety population. The 2 patients who had another reason for discontinuation of placebo were transferred to other facilities. Patients who completed day 28 of the trial before discharge or were discharged before day 28 were considered to have completed the trial. Percentages shown are for the modified intention-to-treat population. ALT denotes alanine aminotransferase, AST aspartate aminotransferase, BIPAP bilevel positive airway pressure, CPAP continuous positive airway pressure, HIV human immunodeficiency virus, SpO₂ oxygen saturation as measured by pulse oximetry, TB tuberculosis, and ULN the upper limit of the normal range.

Figure 2. Time to Mechanical Ventilation or Death by Day 28 in the Modified Intention-to-Treat Population.

The cumulative proportion of patients was estimated with the Kaplan–Meier method and compared in the two groups with the use of the stratified log-rank test. The stratified Cox proportional-hazards model was used to estimate the hazard ratio and 95% confidence interval. Data on patients who did not receive mechanical ventilation or who died on or before day 28 were censored at day 28 or the date of the last available follow-up, whichever occurred first.