A Randomized Placebo-Controlled Trial of Sarilumab in Hospitalized Patients with Covid-19 (preprint)

BACKGROUNDSarilumab (anti-interleukin-6 receptor- monoclonal antibody) may attenuate the inflammatory response in Covid-19. METHODSWe performed an adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial of intravenous sarilumab 200 mg or 400 mg in adults hospitalized with Covid-19. The phase 3 primary analysis population (cohort 1) was patients with critical Covid-19 receiving mechanical ventilation (MV) randomized to sarilumab 400 mg or placebo. The primary end point for phase 3 was the proportion of patients with [≥]1-point improvement in clinical status from baseline to day 22. RESULTSFour-hundred fifty-seven (457) and 1365 patients were randomized and treated in phases 2 and 3, respectively. Among phase 3 critical patients receiving MV (n=289; 34.3% on corticosteroids), the proportion with [≥]1-point improvement in clinical status (alive not receiving MV) at day 22 was 43.2% in sarilumab 400 mg and 35.5% in placebo (risk difference [RD] +7.5%; 95% confidence interval [CI], -7.4 to 21.3; P=0.3261), representing a relative risk improvement of 21.7%. Day 29 all-cause mortality was 36.4% in sarilumab 400 mg versus 41.9% in placebo (RD -5.5%; 95% CI, -20.2 to 8.7; relative risk reduction 13.3%). In post hoc analyses pooling phase 2 and 3 critical patients receiving MV, the hazard ratio (HR) for death in sarilumab 400 mg compared with placebo was 0.76 (95% CI, 0.51 to 1.13) overall, improving to 0.49 (95% CI, 0.25 to 0.94) in patients receiving corticosteroids at baseline. CONCLUSIONIn hospitalized patients with Covid-19 receiving MV, numerical benefits with sarilumab did not achieve statistical significance, but benefit may be greater in patients receiving corticosteroids. A larger study is required to confirm this observed numerical benefit. (ClinicalTrials.gov number, NCT04315298)

Baseline SARS-CoV-2 Viral Load Is Associated with Disease Severity and Clinical Outcomes in Hospitalised Patients with COVID-19: Post-Hoc Analyses of a Phase 2/3 Multicentre Trial (preprint)

Background: Elucidating the relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load and clinical outcomes is critical for understanding COVID-19.Methods: SARS-CoV-2 levels were analysed by quantitative real-time polymerase chain reaction (RT-qPCR) of naso- or oro-pharyngeal swab specimens collected at baseline and clinical outcomes were recorded over 60 days from 1362 COVID-19 hospitalised patients enrolled in a multi-center, randomized, placebo-controlled phase II/III trial of sarilumab for COVID-19 (NCT04315298).Findings: In post-hoc analyses, higher baseline viral load, measured by both RT-qPCR cycle threshold (Ct) and log10 copies/mL, was associated with greater supplemental oxygenation requirements and disease severity at study entry. Higher baseline viral load was associated with higher mortality, lower likelihood of improvement in clinical status and supplemental oxygenation requirements, and lower rates of hospital discharge. Viral load was not impacted by sarilumab treatment over time compared with placebo.Interpretation: These data support viral load as an important determinant of clinical outcomes in hospitalized patients with COVID-19 requiring supplemental oxygen or assisted ventilation.Trial Registration: NCT04315298Funding Statement: Supported by Regeneron Pharmaceuticals, Inc. and Sanofi. Certain aspects of this project have been funded in whole or in part with federal funds from the Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number: HHSO100201700020C.Declaration of Interests: All authors are employees or employees and shareholders of Regeneron Pharmaceuticals, Inc.Ethics Approval Statement: The local institutional review board or ethics committee at each centre oversaw trial conduct and documentation. All patients provided written informed consent before participation. Ethics approval was obtained from the following ethics review boards: WCG IRB, Puyallup, WA (IRB00000533); Oregon Health & Science University, Portland, OR (MOD00027616); Institutional Review Board University of Florida, Gainesville, FL (IRB202000779); Columbia University, Human Research Protection Office and IRBs, New York, NY (IRB-AAAS9615); Johns Hopkins Medicine, Office of Human Subjects Research, IRB, Baltimore, MD (IRB00246576/CIR00058074); NYU School Of Medicine, New York, NY (I20-00351_MOD03); Northwestern University IRB, Chicago, IL (STU00212239-MOD0012); Westchester Medical Center, NY Medical College, Office of Research Administration, Valhalla, NY (IRBReg#00000428); Portland Health and Services IRB Providence – St. Johns, Portland, OR (MOD2020001024); Cornell Weill Medicine IRB, New York, NY (IRB00009419); Providence St. Joseph IRB, Renton, WA (MOD2020001029); Providence Health and Services IRB, Portland, OR (MOD2020000519); Ascension St. John Hospital, Tulsa, OK (IRB#00001980); Geisinger IRB, Danville, PA (IRB#0008345).