tetano
Editor, Senior Moderator
Crit Care Med
. 2021 Oct 6.
doi: 10.1097/CCM.0000000000005229. Online ahead of print.
Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial
Jennifer Tom[SUP] 1 [/SUP], Min Bao, Larry Tsai, Aditi Qamra, David Summers, Montserrat Carrasco-Triguero, Jacqueline McBride, Carrie M Rosenberger, Celia J F Lin, William Stubbings, Kevin G Blyth, Jordi Carratalà, Bruno François, Thomas Benfield, Derrick Haslem, Paolo Bonfanti, Cor H van der Leest, Nidhi Rohatgi, Lothar Wiese, Charles Edouard Luyt, Farrah Kheradmand, Ivan O Rosas, Fang Cai
Affiliations
Abstract
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.
. 2021 Oct 6.
doi: 10.1097/CCM.0000000000005229. Online ahead of print.
Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial
Jennifer Tom[SUP] 1 [/SUP], Min Bao, Larry Tsai, Aditi Qamra, David Summers, Montserrat Carrasco-Triguero, Jacqueline McBride, Carrie M Rosenberger, Celia J F Lin, William Stubbings, Kevin G Blyth, Jordi Carratalà, Bruno François, Thomas Benfield, Derrick Haslem, Paolo Bonfanti, Cor H van der Leest, Nidhi Rohatgi, Lothar Wiese, Charles Edouard Luyt, Farrah Kheradmand, Ivan O Rosas, Fang Cai
Affiliations
- PMID: 34612846
- DOI: 10.1097/CCM.0000000000005229
Abstract
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.