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

Crit Care Med. 2022 Mar 1;50(3):398-409. 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.

Trial registration: ClinicalTrials.gov NCT04320615 NCT04363736.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Biomarkers
  • COVID-19 / drug therapy*
  • COVID-19 / epidemiology*
  • COVID-19 / mortality
  • Double-Blind Method
  • Female
  • Humans
  • Inflammation Mediators / metabolism
  • Length of Stay
  • Male
  • Patient Discharge
  • Prognosis
  • Respiration, Artificial
  • SARS-CoV-2

Substances

  • Antibodies, Monoclonal, Humanized
  • Biomarkers
  • Inflammation Mediators
  • tocilizumab

Supplementary concepts

  • COVID-19 drug treatment

Associated data

  • ClinicalTrials.gov/NCT04320615
  • ClinicalTrials.gov/NCT04363736