Sarilumab plus standard of care vs standard of care for the treatment of severe COVID-19: a phase 3, randomized, open-labeled, multi-center study (ESCAPE study)
Ilaria Mastrorosa, Roberta Gagliardini, Francesco Vladimiro Segala, Annalisa Mondi, Patrizia Lorenzini, Carlotta Cerva, Eleonora Taddei, Francesca Bai, Alessandra Vergori, Marcantonio Negri, Carmela Pinnetti, Stefania Cicalini, Rita Murri, Valentina Mazzotta, Marta Camici, Silvia Mosti, Teresa Bini, Gaetano Maffongelli, Alessia Beccacece, Eugenia Milozzi, Marco Iannetta, Silvia Lamonica, Marisa Fusto, Maria Maddalena Plazzi, Pier Sandrine Ottou, Miriam Lichtner, Massimo Fantoni, Massimo Andreoni, Loredana Sarmati, Roberto Cauda, Enrico Girardi, Emanuele Nicastri, Antonella D'arminio Monforte, Fabrizio Palmieri, Antonella Cingolani, Francesco Vaia, Andrea Antinori, Chiara Agrati, Massimo Andreoni, Andrea Antinori, Francesca Bai, Alessia Beccacece, Filippo Barreca, Maria Paola Bertuccio, Teresa Bini, Evangelo Boumis, Marta Camici, Roberto Cauda, Carlotta Cerva, Stefania Cicalini, Antonella Cingolani, Antonella D'arminio Monforte, Angela D'urso, Margherita De Masi, Federico De Zottis, Cosmo Del Borgo, Francesco Di Gennaro, Arianna Emiliozzi, Massimo Fantoni, Laura Fondaco, Marisa Fusto, Roberta Gagliardini, Francesca Giovannenze, Elisabetta Grilli, Marco Iannetta, Daniele Iodice, Miriam Lichtner, Patrizia Lorenzini, Gaetano Maffongelli, Erminia Masone, Barbara Massa, Ilaria Mastrorosa, Valentina Mazzotta, Paola Mencarini, Eugenia Milozzi, Annalisa Mondi, Silvia Mosti, Rita Murri, Marcantonio Negri, Emanuele Nicastri, Gian Piero Oliva, Giovanna Onnelli, Pier Sandrine Ottou, Pier Giorgio Pace, Fabrizio Palmieri, Jessica Paulicelli, Carmela Pinnetti, Maria Maddalena Plazzi, Loredana Sarmati, Francesco Vladimiro Segala, Chiara Sorace, Eleonora Taddei, Alessandra Vergori, Pietro Vitale
eClinicalMedicine, doi:10.1016/j.eclinm.2023.101895
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 h) plus standard of care (SOC) (arm A) or to continue SOC (arm B). Randomization was web-based. As post-hoc analyses, the participants were stratified according to baseline inflammatory parameters. The primary endpoint was analysed on the modified Intention-To-Treat population, including all the 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 and adjusted for severity of illness, 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 1.07 [0.8-1.5] in arm B; log-rank p = 0.50). After stratifying for inflammatory parameters, arm A showed higher probability of improvement than B without statistical significance in the strata with C reactive protein (CRP) < 7 mg/dL (88% [77-96] vs 79% [63-91], HR 1.55 [0.9-2.6]; log-rank p = 0.049) and in the strata 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 The efficacy of sarilumab in severe COVID-19 was not demonstrated both in the overall and in the stratified for severity analysis population. Exploratory analyses suggested that subsets of patients with lower CRP values or lower lymphocyte counts might have had benefit with sarilumab treatment, but this finding would require replication in other studies. The relatively low rate of concomitant corticosteroid use, could partially explain our results.
Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi. org/10.1016/j.eclinm.2023.101895 .
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