Effect of interleukin-6 receptor antagonists in critically ill adult patients with COVID-19 pneumonia: two randomised controlled trials of the CORIMUNO-19 Collaborative Group

Abstract

Background: Our objective was to determine whether anti-interleukin (IL)-6 receptors improve outcomes of critically ill patients with coronavirus disease 2019 (COVID-19) pneumonia. We report on two cohort-embedded, investigator-initiated, multicentre, open-label, Bayesian randomised controlled clinical trials.

Methods: Patients were randomly assigned to receive either usual care (UC) or UC+tocilizumab (TCZ) 8 mg·kg^-1 (TOCI-2 trial) or UC or UC+sarilumab (SARI) 200 mg (SARI-2 trial), both intravenously on day 1 and, if clinically indicated, on day 3.

Results: Between 31 March and 20 April 2020, 97 patients were randomised in the TOCI-2 trial, to receive UC (n=46) or UC+TCZ (n=51). At day 14, numbers of patients who did not need noninvasive ventilation (NIV) or mechanical ventilation (MV) and were alive with TCZ or UC were similar (47% versus 42%; median posterior hazard ratio (HR) 1.19, 90% credible interval (CrI) 0.71-2.04), with a posterior probability of HR >1 of 71.4%. Between 27 March and 4 April 2020, 91 patients were randomised in the SARI-2 trial, to receive UC (n=41) or UC+SARI (n=50). At day 14, numbers of patients who did not need NIV or MV and were alive with SARI or UC were similar (38% versus 33%; median posterior HR 1.05, 90% CrI 0.55-2.07), with a posterior probability of HR >1 of 54.9%. Overall, the risk of death up to day 90 was: UC+TCZ 24% versus UC 30% (HR 0.67, 95% CI 0.30-1.49) and UC+SARI 29% versus UC 39% (HR 0.74, 95% CI 0.35-1.58). Both TCZ and SARI increased serious infectious events.

Conclusion: In critically ill patients with COVID-19, anti-IL-6 receptors did not significantly increase the number of patients alive without any NIV or MV by day 14.

FIGURE 1

Flowchart. a) TOCI-2 protocol (treatment with tocilizumab (TCZ)+usual care versus usual care). b) SARI-2 protocol (treatment with sarilumab (SARI)+usual care versus usual care). IQR: interquartile range.

FIGURE 2

Occurrence of events during follow-up. Kaplan–Meier cumulative estimates of probability of the primary outcome (removal of device (mechanical ventilation, high-flow oxygen (HFO) or noninvasive ventilation (NIV) support)) and death up to day 14 for a) TOCI-2 (treatment with tocilizumab) and b) SARI-2 (treatment with sarilumab); and overall survival for c) TOCI-2 (tocilizumab arm compared with usual care arm) and d) SARI-2 (sarilumab arm compared with usual care arm).