Sarilumab treatment of hospitalised patients with severe or critical COVID-19: a multinational, randomised, adaptive, phase 3, double-blind, placebo-controlled trial

Lescure, F.-X.; Honda, H.; Fowler, R. A.; Sloane Lazar, J.; Shi, G.; Wung, P.; Patel, N.; Hagino, O.

Background: Elevated proinflammatory cytokines have been associated with 2019 coronavirus disease (COVID-19) severity. We assessed efficacy and safety of sarilumab, an interleukin-6 receptor inhibitor, in severe (requiring supplemental oxygen by nasal canula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods: This was a 60-day, randomised, double-blind, placebo-controlled, multinational trial in patients hospitalised with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomised 2:2:1 to intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. The primary endpoint was time to >=2-point clinical improvement (7-point scale; range: 1 [death] to 7 [not hospitalised]). The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This trial is registered with ClinicalTrials.gov (NCT04327388). Findings: Between March 28 and July 3, 2020, 420 patients were randomised; 416 received treatment (placebo, n=84; sarilumab 200 mg, n=159; sarilumab 400 mg, n=173). At day 29, there were no significant differences in median (95% CI) time to >=2-point improvement between placebo (12.0 [9.0-15.0] days) and sarilumab groups (200 mg: 10.0 [9.0-12.0] days, p=0.96, log-rank test; 400 mg: 10.0 [9.0-13.0] days, p=0.34) or in proportions of patients alive (placebo, 91.7%; sarilumab 200 mg, 89.9%, p=0.63; sarilumab 400 mg, 91.9%, p=0.85). At day 29, there were numerical, nonsignificant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +9%, 95% CI -7.7 to 25.5, p=0.25) for critical patients. There were no unexpected safety signals. Interpretation: This trial did not demonstrate efficacy of sarilumab in patients hospitalised with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding: Sanofi and Regeneron Pharmaceuticals, Inc.