Sarilumab Plus Standard of Care Versus Standard of Care for the Treatment of Severe COVID-19: A Phase 3, Randomized, Open-Labeled, Multi-Center Study (ESCAPE Study)

Background: Among interleukin-6 inhibitors suggested for use in COVID-19, there are few robust evidences for the efficacy of sarilumab. Herein, we evaluated the efficacy and safety of sarilumab in severe COVID-19. Methods: In this phase 3, open-labeled, randomized clinical trial, conducted at 5 Italian hospitals, adults with severe COVID-19 pneumonia (excluding mechanically ventilated) were randomized 2:1 to receive intravenous sarilumab (400 mg, repeatable after 12 hours) plus standard of care (SOC) (arm A) or to continue SOC (arm B). Randomization was web-based. As post-hoc analyses, participants were stratified according to baseline inflammatory parameters. The primary endpoint was analysed on the modified Intention-To-Treat population, including all randomized patients who received any study treatment (sarilumab or SOC). It was time to clinical improvement of 2 points on a 7-points ordinal scale, from baseline to day 30. We used Kaplan Meier method and log-rank test to compare the primary outcome between two arms, and Cox regression stratified by clinical center to estimate the hazard ratio (HR). The trial was registered with EudraCT (2020-001390-76). Findings: Between May 2020 and May 2021, 191 patients were assessed for eligibility, of whom, excluding nine dropouts, 176 were assigned to arm A (121) and B (55). At day 30, no significant differences in the primary endpoint were found (88% [95% CI 81-94] in arm A vs 85% [74-93], HR 1.08 [0.8-1.6] in arm B;log-rank p=0.50). After stratifying for inflammatory parameters, the probability of improvement was greater in arm A than B, for the strata with C reactive protein <7 mg/dL (88% [77-96] vs 79% [63- 91], HR 1.55 [0.9-2.6];log-rank p=0.049) and with lymphocytes <870/mmc (90% [79-96]) vs (73% [55-89], HR 1.53 [0.9-2.7];log-rank p=0.058). Overall, 39/121 (32%) AEs were reported in arm A and 14/55 (23%) in B (p=0.195), while serious AEs were 22/121 (18%) and 7/55 (11%), respectively (p=0.244). There were no treatment-related deaths. Interpretation: Efficacy of sarilumab in severe COVID-19 was not demonstrated both in overall and in stratified for severity analysis population, even if some benefits were shown at an early stage of the disease with lower inflammatory burde