Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial
Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc..
OBJECTIVES: To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia.
DESIGN: Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial.
SETTING: Hospitals in North America and Europe.
PATIENTS: Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care.
INTERVENTION: Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo.
MEASUREMENTS AND MAIN RESULTS: Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomization) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Modeling in the placebo arm showed all candidate biomarkers except lactate dehydrogenase and d-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modeling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction, p = 0.03), mechanical ventilation (predictive interaction, p = 0.01), and clinical status (predictive interaction, p = 0.02) compared with placebo.
CONCLUSIONS: Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28.
| Errataetall: |
CommentIn: Crit Care Med. 2022 Mar 1;50(3):510-513. - PMID 35191872 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:50 |
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| Enthalten in: |
Critical care medicine - 50(2022), 3 vom: 01. März, Seite 398-409 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tom, Jennifer [VerfasserIn] |
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| Links: |
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| Themen: |
Antibodies, Monoclonal, Humanized |
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| Anmerkungen: |
Date Completed 02.03.2022 Date Revised 06.02.2024 published: Print ClinicalTrials.gov: NCT04320615, NCT04363736 CommentIn: Crit Care Med. 2022 Mar 1;50(3):510-513. - PMID 35191872 Citation Status MEDLINE |
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| doi: |
10.1097/CCM.0000000000005229 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial |
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| 500 | |a Date Completed 02.03.2022 | ||
| 500 | |a Date Revised 06.02.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a ClinicalTrials.gov: NCT04320615, NCT04363736 | ||
| 500 | |a CommentIn: Crit Care Med. 2022 Mar 1;50(3):510-513. - PMID 35191872 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. | ||
| 520 | |a OBJECTIVES: To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia | ||
| 520 | |a DESIGN: Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial | ||
| 520 | |a SETTING: Hospitals in North America and Europe | ||
| 520 | |a PATIENTS: Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care | ||
| 520 | |a INTERVENTION: Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo | ||
| 520 | |a MEASUREMENTS AND MAIN RESULTS: Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomization) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Modeling in the placebo arm showed all candidate biomarkers except lactate dehydrogenase and d-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modeling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction, p = 0.03), mechanical ventilation (predictive interaction, p = 0.01), and clinical status (predictive interaction, p = 0.02) compared with placebo | ||
| 520 | |a CONCLUSIONS: Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28 | ||
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