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Safety and Efficacy of Dupilumab for the Treatment of Hospitalized Patients with Moderate to Severe COVID 19: A Phase IIa Trial

BACKGROUND: A profound need remains to develop further therapeutics for treatment of those hospitalized with COVID-19. Based on data implicating the type 2 cytokine interleukin (IL)-13 as a significant factor leading to critical COVID-19, this trial was designed to assess dupilumab, a monoclonal ant...

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Autores principales: Sasson, Jennifer, Donlan, Alexandra N., Ma, Jennie Z., Haughey, Heather M., Coleman, Rachael, Nayak, Uma, Mathers, Amy J., Laverdure, Sylvain, Dewar, Robin, Jackson, Patrick E. H., Heysell, Scott K., Sturek, Jeffrey M., Petri, William A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8996634/
https://www.ncbi.nlm.nih.gov/pubmed/35411349
http://dx.doi.org/10.1101/2022.03.30.22273194
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author Sasson, Jennifer
Donlan, Alexandra N.
Ma, Jennie Z.
Haughey, Heather M.
Coleman, Rachael
Nayak, Uma
Mathers, Amy J.
Laverdure, Sylvain
Dewar, Robin
Jackson, Patrick E. H.
Heysell, Scott K.
Sturek, Jeffrey M.
Petri, William A.
author_facet Sasson, Jennifer
Donlan, Alexandra N.
Ma, Jennie Z.
Haughey, Heather M.
Coleman, Rachael
Nayak, Uma
Mathers, Amy J.
Laverdure, Sylvain
Dewar, Robin
Jackson, Patrick E. H.
Heysell, Scott K.
Sturek, Jeffrey M.
Petri, William A.
author_sort Sasson, Jennifer
collection PubMed
description BACKGROUND: A profound need remains to develop further therapeutics for treatment of those hospitalized with COVID-19. Based on data implicating the type 2 cytokine interleukin (IL)-13 as a significant factor leading to critical COVID-19, this trial was designed to assess dupilumab, a monoclonal antibody that blocks IL-13 and IL-4 signaling, for treatment of inpatients with COVID-19. METHODS: We conducted a phase IIa randomized double-blind placebo-controlled trial to assess the safety and efficacy of dupilumab plus standard of care versus placebo plus standard of care in mitigating respiratory failure and death in those hospitalized with COVID-19. Subjects were followed prospectively for 60 days. The primary endpoint was the proportion of patients alive and free of invasive mechanical ventilation at 28 days. FINDINGS: Forty eligible subjects were enrolled from June to November of 2021. There was no difference in adverse events nor in ventilator free survival at day 28 between study arms. However, for the secondary endpoint of mortality at day 60, subjects randomized to dupilumab had a higher survival rate compared to the placebo group (89.5% vs 76.2%, adjusted HR 0.05, 95% CI: 0.0–0.72, p=0.03). There were fewer subjects admitted to the ICU in the dupilumab group compared to placebo (33.3% vs 66.7%; adjusted HR 0.44, 95% CI: 0.09–2.09, p=0.30). Lastly, we saw downstream evidence of IL-4 and IL-13 signaling blockade in the dupilumab group through analysis of immune biomarkers over time. INTERPRETATION: Dupilumab was well tolerated and improved 60-day survival in patients hospitalized with moderate to severe COVID-19. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, NCT04920916. FUNDING: Virginia Biosciences Health Research Corporation, PBM C19, Henske Family Foundation, National Institutes of Health, National Cancer Institute
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spelling pubmed-89966342022-04-12 Safety and Efficacy of Dupilumab for the Treatment of Hospitalized Patients with Moderate to Severe COVID 19: A Phase IIa Trial Sasson, Jennifer Donlan, Alexandra N. Ma, Jennie Z. Haughey, Heather M. Coleman, Rachael Nayak, Uma Mathers, Amy J. Laverdure, Sylvain Dewar, Robin Jackson, Patrick E. H. Heysell, Scott K. Sturek, Jeffrey M. Petri, William A. medRxiv Article BACKGROUND: A profound need remains to develop further therapeutics for treatment of those hospitalized with COVID-19. Based on data implicating the type 2 cytokine interleukin (IL)-13 as a significant factor leading to critical COVID-19, this trial was designed to assess dupilumab, a monoclonal antibody that blocks IL-13 and IL-4 signaling, for treatment of inpatients with COVID-19. METHODS: We conducted a phase IIa randomized double-blind placebo-controlled trial to assess the safety and efficacy of dupilumab plus standard of care versus placebo plus standard of care in mitigating respiratory failure and death in those hospitalized with COVID-19. Subjects were followed prospectively for 60 days. The primary endpoint was the proportion of patients alive and free of invasive mechanical ventilation at 28 days. FINDINGS: Forty eligible subjects were enrolled from June to November of 2021. There was no difference in adverse events nor in ventilator free survival at day 28 between study arms. However, for the secondary endpoint of mortality at day 60, subjects randomized to dupilumab had a higher survival rate compared to the placebo group (89.5% vs 76.2%, adjusted HR 0.05, 95% CI: 0.0–0.72, p=0.03). There were fewer subjects admitted to the ICU in the dupilumab group compared to placebo (33.3% vs 66.7%; adjusted HR 0.44, 95% CI: 0.09–2.09, p=0.30). Lastly, we saw downstream evidence of IL-4 and IL-13 signaling blockade in the dupilumab group through analysis of immune biomarkers over time. INTERPRETATION: Dupilumab was well tolerated and improved 60-day survival in patients hospitalized with moderate to severe COVID-19. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, NCT04920916. FUNDING: Virginia Biosciences Health Research Corporation, PBM C19, Henske Family Foundation, National Institutes of Health, National Cancer Institute Cold Spring Harbor Laboratory 2022-05-19 /pmc/articles/PMC8996634/ /pubmed/35411349 http://dx.doi.org/10.1101/2022.03.30.22273194 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Sasson, Jennifer
Donlan, Alexandra N.
Ma, Jennie Z.
Haughey, Heather M.
Coleman, Rachael
Nayak, Uma
Mathers, Amy J.
Laverdure, Sylvain
Dewar, Robin
Jackson, Patrick E. H.
Heysell, Scott K.
Sturek, Jeffrey M.
Petri, William A.
Safety and Efficacy of Dupilumab for the Treatment of Hospitalized Patients with Moderate to Severe COVID 19: A Phase IIa Trial
title Safety and Efficacy of Dupilumab for the Treatment of Hospitalized Patients with Moderate to Severe COVID 19: A Phase IIa Trial
title_full Safety and Efficacy of Dupilumab for the Treatment of Hospitalized Patients with Moderate to Severe COVID 19: A Phase IIa Trial
title_fullStr Safety and Efficacy of Dupilumab for the Treatment of Hospitalized Patients with Moderate to Severe COVID 19: A Phase IIa Trial
title_full_unstemmed Safety and Efficacy of Dupilumab for the Treatment of Hospitalized Patients with Moderate to Severe COVID 19: A Phase IIa Trial
title_short Safety and Efficacy of Dupilumab for the Treatment of Hospitalized Patients with Moderate to Severe COVID 19: A Phase IIa Trial
title_sort safety and efficacy of dupilumab for the treatment of hospitalized patients with moderate to severe covid 19: a phase iia trial
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8996634/
https://www.ncbi.nlm.nih.gov/pubmed/35411349
http://dx.doi.org/10.1101/2022.03.30.22273194
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