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.
Trial registration: ClinicalTrials.gov NCT04320615 NCT04363736 .
【초록키워드】 coronavirus disease, Neutrophils, Monocytes, Coronavirus disease 2019, Europe, Biomarker, Biomarkers, Lymphocytes, Hospitalized, Mortality, Trial, randomization, mechanical ventilation, Tocilizumab, Pneumonia, antibody, interleukin-6, C-reactive protein, D-dimer, ferritin, Platelets, outcome, lactate dehydrogenase, observational study, clinical outcomes, Predictive value, clinical status, Clinical outcome, Randomized, interleukin, modeling, phase 3 trial, Patient, death, Placebo, receptor, multicenter, prognostic, placebo-controlled, Ordinal Scale, Lactate, retrospective, Interaction, Analysis, double-blind, Predictive, (interleukin-6, standard care, severe coronavirus disease, Exploratory analysis, hospital discharge, dimer, North America, candidate, seven-category ordinal scale, Multiple, binomial, Effect, measurement, additional sensitivity analyses, COVACTA, Randomly, evaluated, receiving, assigned, were measured, ferritin level, patients hospitalized, treatment with tocilizumab, 【제목키워드】 Controlled,