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

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 us...

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Autores principales: García-Vicuña, Rosario, Rodriguez-García, Sebastián C., Abad-Santos, Francisco, Bautista Hernández, Azucena, García-Fraile, Lucio, Barrios Blandino, Ana, Gutiérrez Liarte, Angela, Alonso-Pérez, Tamara, Cardeñoso, Laura, Alfranca, Aránzazu, Mejía-Abril, Gina, Sanz Sanz, Jesús, González-Alvaro, Isidoro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904894/
https://www.ncbi.nlm.nih.gov/pubmed/35280907
http://dx.doi.org/10.3389/fmed.2022.819621
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author García-Vicuña, Rosario
Rodriguez-García, Sebastián C.
Abad-Santos, Francisco
Bautista Hernández, Azucena
García-Fraile, Lucio
Barrios Blandino, Ana
Gutiérrez Liarte, Angela
Alonso-Pérez, Tamara
Cardeñoso, Laura
Alfranca, Aránzazu
Mejía-Abril, Gina
Sanz Sanz, Jesús
González-Alvaro, Isidoro
author_facet García-Vicuña, Rosario
Rodriguez-García, Sebastián C.
Abad-Santos, Francisco
Bautista Hernández, Azucena
García-Fraile, Lucio
Barrios Blandino, Ana
Gutiérrez Liarte, Angela
Alonso-Pérez, Tamara
Cardeñoso, Laura
Alfranca, Aránzazu
Mejía-Abril, Gina
Sanz Sanz, Jesús
González-Alvaro, Isidoro
author_sort García-Vicuña, Rosario
collection PubMed
description 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.
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spelling pubmed-89048942022-03-10 Subcutaneous IL-6 Inhibitor Sarilumab vs. Standard Care in Hospitalized Patients With Moderate-To-Severe COVID-19: An Open Label Randomized Clinical Trial García-Vicuña, Rosario Rodriguez-García, Sebastián C. Abad-Santos, Francisco Bautista Hernández, Azucena García-Fraile, Lucio Barrios Blandino, Ana Gutiérrez Liarte, Angela Alonso-Pérez, Tamara Cardeñoso, Laura Alfranca, Aránzazu Mejía-Abril, Gina Sanz Sanz, Jesús González-Alvaro, Isidoro Front Med (Lausanne) Medicine 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. Frontiers Media S.A. 2022-02-23 /pmc/articles/PMC8904894/ /pubmed/35280907 http://dx.doi.org/10.3389/fmed.2022.819621 Text en 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. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
García-Vicuña, Rosario
Rodriguez-García, Sebastián C.
Abad-Santos, Francisco
Bautista Hernández, Azucena
García-Fraile, Lucio
Barrios Blandino, Ana
Gutiérrez Liarte, Angela
Alonso-Pérez, Tamara
Cardeñoso, Laura
Alfranca, Aránzazu
Mejía-Abril, Gina
Sanz Sanz, Jesús
González-Alvaro, Isidoro
Subcutaneous IL-6 Inhibitor Sarilumab vs. Standard Care in Hospitalized Patients With Moderate-To-Severe COVID-19: An Open Label Randomized Clinical Trial
title Subcutaneous IL-6 Inhibitor Sarilumab vs. Standard Care in Hospitalized Patients With Moderate-To-Severe COVID-19: An Open Label Randomized Clinical Trial
title_full Subcutaneous IL-6 Inhibitor Sarilumab vs. Standard Care in Hospitalized Patients With Moderate-To-Severe COVID-19: An Open Label Randomized Clinical Trial
title_fullStr Subcutaneous IL-6 Inhibitor Sarilumab vs. Standard Care in Hospitalized Patients With Moderate-To-Severe COVID-19: An Open Label Randomized Clinical Trial
title_full_unstemmed Subcutaneous IL-6 Inhibitor Sarilumab vs. Standard Care in Hospitalized Patients With Moderate-To-Severe COVID-19: An Open Label Randomized Clinical Trial
title_short Subcutaneous IL-6 Inhibitor Sarilumab vs. Standard Care in Hospitalized Patients With Moderate-To-Severe COVID-19: An Open Label Randomized Clinical Trial
title_sort subcutaneous il-6 inhibitor sarilumab vs. standard care in hospitalized patients with moderate-to-severe covid-19: an open label randomized clinical trial
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904894/
https://www.ncbi.nlm.nih.gov/pubmed/35280907
http://dx.doi.org/10.3389/fmed.2022.819621
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