by Tom, Jennifer; Bao, Min; Tsai, Larry; Qamra, Aditi;
Summers, David; Carrasco-Triguero, Montserrat; McBride, Jacqueline;
Rosenberger, Carrie M.; Lin, Celia J. F.; Stubbings, William; Blyth, Kevin G.;
Carratalà , Jordi; François, Bruno; Benfield, Thomas; Haslem, Derrick; Bonfanti,
Paolo; van der Leest, Cor H.; Rohatgi, Nidhi; Wiese, Lothar; Luyt, Charles Edouard;
Kheradmand, Farrah; Rosas, Ivan O.; Cai, Fang
Critical Care Medicine: March 2022 -
Volume 50 - Issue 3 - p 398-409
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.
