Subcutaneous IL-6 Inhibitor Sarilumab vs. Standard Care in Hospitalized Patients With Moderate-To-Severe COVID-19: An Open Label Randomized Clinical Trial

Abstract

Background: The use of IL-6 blockers in COVID-19 hospitalized patients has been associated with a reduction in mortality compared to standard care. However, many uncertainties remain pertaining to optimal intervention time, administration schedule, and predictors of response. To date, data on the use of subcutaneous sarilumab is limited and no randomized trial results are available.

Methods: Open label randomized controlled trial at a single center in Spain. We included adult patients admitted with microbiology documented COVID-19 infection, imaging confirmed pneumonia, fever and/or laboratory evidence of inflammatory phenotype, and no need for invasive ventilation. Participants were randomly assigned to receive sarilumab, a single 400 mg dose in two 200 mg subcutaneous injections, added to standard care or standard care, in a 2:1 proportion. Primary endpoints included 30-day mortality, mean change in clinical status at day 7 scored in a 7-category ordinal scale ranging from death (category 1) to discharge (category 7), and duration of hospitalization. The primary efficacy analysis was conducted on the intention-to-treat population.

Results: A total of 30 patients underwent randomization: 20 to sarilumab and 10 to standard care. Most patients were male (20/30, 67%) with a median (interquartile range) age of 61.5 years (56-72). At day 30, 2/20 (10%) patients died in the sarilumab arm vs. none (0/10) in standard care (Log HR 15.11, SE 22.64; p = 0.54). At day 7, no significant differences were observed in the median change in clinical status (2 [0-3]) vs. 3 [0-3], p = 0.32). Median time to discharge (days) was similar (7 [6-11] vs. 6 [4-12]; HR 0.65, SE 0.26; p = 0.27). No significant differences were detected in the rate of progression to invasive and noninvasive mechanical ventilation.

Conclusions and relevance: Our pragmatic pilot study has failed to demonstrate the benefit of adding subcutaneous sarilumab to standard care for mortality by 30 days, functional status at day 7, or hospital stay. Findings herein do not exclude a potential effect of sarilumab in severe COVID-19 but adequately powered blinded randomized phase III trials are warranted to assess the impact of the subcutaneous route and a more selected target population.

Trial registration: www.ClinicalTrials.gov, Identifier: NCT04357808.

Keywords: COVID-19; IL-6; IL-6 blockade; IL-6 receptor inhibitors; randomized controlled trial; sarilumab; subcutaneous; subcutaneous route.

Conflict of interest statement

RG-V reported receiving educational grants support from Lilly, Janssen, Pfizer, Roche, Sanofi, honoraria for presentations for Lilly, Sanofi, advisory boards for Lilly, Pfizer, Sanofi, nonfinancial support from Lilly, Pfizer, and Sanofi, all outside the present work. IG-A reported Roche provided him data for research, honoraria for presentations for Lilly, Roche, Sanofi, advisory boards for Lilly, Sanofi, non-financial support from Abbvie, BMS, MSD, Novartis, Pfizer and Roche, outside the present work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 García-Vicuña, Rodriguez-García, Abad-Santos, Bautista Hernández, García-Fraile, Barrios Blandino, Gutiérrez Liarte, Alonso-Pérez, Cardeñoso, Alfranca, Mejía-Abril, Sanz Sanz and González-Alvaro.

Figures

Figure 1

Flow chart of the study.

Figure 2

Evolution of clinical status in COVID-19 patients from baseline to day 14 according to the 7-category ordinal scale. Data are shown as the percentage of patients at each ordinal point in the sarilumab + standard care (SAR; n = 20) and standard care (SC; n = 10) groups, displayed as boxes with the different hues ranging from black (1 = death) to white (7 = discharge) scale.

Figure 3

Evolution of partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) throughout study visits. Patients are grouped depending on (A) allocated interventions: standard care (SC) or sarilumab (SAR) and (B) level of serum interleukin-6 (IL-6) at randomization (cut-off for high levels ≥ 30 pg/ml). Two patients died and their last observed value was carried forward. IL-6 levels at randomization were available only in 24 patients; high IL-6 levels were observed in 3 patients from the SAR group and 1 patient from the SC group. Data are shown as interquartile ranges (p75 upper edge of the box, p25 lower edge, p50 midline) as well as the p95 (line above box) and p5 (line below). Dots represent outliers. Statistical significance was determined with the Mann–Whitney U test.

Figure 4

Evolution of laboratory parameters throughout study visits. (A) C reactive Protein; (B) Total lymphocyte count; (C) Lactate dehydrogenase; (D) Ferritin; (E) Creatinin. Patients from standard care (SC; white boxes) and sarilumab (SAR; gray boxes). Only values available at each time point is shown and results are displayed as the interquartile range (p75 upper edge of the box, p25 lower edge, p50 midline) as well as the p95 (line above box) and p5 (line below). Dots represent outliers.