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 burden. The relatively low rate of concomitant corticosteroid use, could partially explain our results.Trial Registration Details: The study is registered in the European Union Clinical Trials Register (Eudract Number: 2020- 177 001390-76).Funding Information: This study was supported by INMI “Lazzaro Spallanzani” Ricerca Corrente Linea 1 on emerging and reemerging infections, funded by Italian Ministry of Health.Declaration of Interests: Andrea Antinori has served as a paid consultant to Gilead Sciences, Janssen-Cilag, Merck, GlaxoSmithKline, Astra Zeneca, Roche, and ViiV Healthcare and received research institutional grants from Gilead Sciences, Janssen-Cilag and ViiV Healthcare and received payment or honoraria from Gilead Science and ViiV Healthcare and received support for attending meetings and/or travel from ViiV Healthcare and AbbVie. Marta Camici received institutional grant, support for attending meetings and/or travel and speakers’ honoraria from Gilead Sciences. Stefania Cicalini reports consulting fees paid to self from ViiV Healthcare, Jansen-Cilag, Merck Sharp and Dohme, Gilead Sciences; payment or honoraria from ViiV Healthcare, Jansen-Cilag, Merck Sharp and Dohme, and Gilead Sciences. Roberta Gagliardini reports payments to their institution from Gilead Sciences, speakers’ honoraria/educational activities for ViiV Healthcare, Merck Sharp and Dohme and Gilead Sciences, support for attending meetings and/or travel from ViiV Healthcare, advisor for Theratechnologies, Janssen-Cilag and Gilead Sciences. Ilaria Mastrorosa received institutional grant and support for attending meetings and/or travel from Gilead Sciences. Annalisa Mondi received speakers’ honoraria from Gilead Sciences and ViiV Healthcare and participated in advisory boards sponsored by ViiV Healthcare. Carmela Pinnetti received personal fee from Gilead-Sciences for a case presentation and a travel grant from Gilead and served on an advisory board for Janssen-Cilag. Alessandra Vergori received institutional grant from Gilead Sciences, speakers’ honoraria/educational activities for Merck Sharp and Dohme, ViiV Healthcare and Janssen Cilag, advisor for JanssenCilag. The other co-authors declare no conflicts of interests for this work.Ethics Approval Statement: The original protocol (Escape Study version 2.2, May 5, 2020) was approved by the Scientific Committee of the Italian Drug Agency (AIFA) and by the Ethical Committee of the Lazzaro Spallanzani Institute, as National Review Board for COVID-19 pandemic in Italy (approval number 152/2020), and by the ethics committee of the National Institute for Infectious Diseases L. Spallanzani IRCCS and the institutional review boards at each participating hospital. An amendment to the original protocol (Escape Study version 3.0, October 6, 2020) was made in order to extend the duration of recruitment (from 6 to 12 months) and to allow the use of corticosteroids and/or antiviral agents as SOC, according to decision of clinical investigator and current guidelines. It was approved on November 6, 2020 (approval number 205/2020). The study was conducted in accordance with the European Union Clinical Practice Standards, with ICH Good Clinical Practice (GCP) and with the ethical principles expressed in Declaration of Helsinki and its amendments. The clinical study was performed under the regulations of AIFA and of the Italian Ministry of Health. Before entering the study, all patients, gave their written or verbal informed consent (version 3.1. November 13, 2020). All data have been collected anonymously into the Electronic Case Report Forms (eCRF); subjects were identified by numeric codes only, password protected.