Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial

Authors

Jennifer Tom
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

Publication Date

3-1-2022

Journal

Critical Care Medicine

DOI

10.1097/CCM.0000000000005229

PMID

34612846

PMCID

PMC8855771

PubMedCentral® Posted Date

10-12-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Antibodies, Monoclonal, Humanized, Biomarkers, COVID-19, Double-Blind Method, Female, Humans, Inflammation Mediators, Length of Stay, Male, Patient Discharge, Prognosis, Respiration, Artificial, SARS-CoV-2, COVID-19 Drug Treatment

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.

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