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

Abstract

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.

A Quantitative Systems Pharmacology Model of the Pathophysiology and Treatment of COVID-19 Predicts Optimal Timing of Pharmacological Interventions

“…Del Valle et al, in a large study of > 1400 COVID-19 patients, found a threshold of 70 pg/mL of plasma IL-6 levels at hospitalization could independently predict disease severity and mortality. A recent, RCT evaluating the efficacy of Tocilizumab in >300 subjects further showed plasma IL-6 levels were significantly correlated with baseline clinical severity and were also a significant predictive biomarker for clinical severity through Day 28 of the trial [46,47]. To translate the plausible population to the incidence of hospitalization reported in outpatient clinical trials, a threshold of 40 pg/mL is employed for plasma IL-6 levels, corresponding to a value closer to the lower tail of the plasma IL-6 distribution observed in hospitalized patients with mild-moderate COVID-19 severity [46,47].…”

“…A recent, RCT evaluating the efficacy of Tocilizumab in >300 subjects further showed plasma IL-6 levels were significantly correlated with baseline clinical severity and were also a significant predictive biomarker for clinical severity through Day 28 of the trial [46,47]. To translate the plausible population to the incidence of hospitalization reported in outpatient clinical trials, a threshold of 40 pg/mL is employed for plasma IL-6 levels, corresponding to a value closer to the lower tail of the plasma IL-6 distribution observed in hospitalized patients with mild-moderate COVID-19 severity [46,47]. Moreover, given the uncertainty in using a plasma biomarker as an indicator of a hard-end point such as hospitalization, we conservatively apply this threshold to the peak IL-6 levels attained at any point over the entire time-course of the simulated infection.…”

“…Moreover, our results also act as a proof of concept for the relatively simple approach we employed to translate the QSP model outputs to disease severity metrics. As more mechanistic information becomes available, the QSP model lends itself to the incorporation of clinical information on additional biomarkers, such as ferritin and CRP, which are preliminarily implemented in the model [47]. More sophisticated probabilistic approaches, e.g.…”

“…In doing so, we adopt a parsimonious approach and treat plasma IL-6 as the key biomarker correlated to disease severity. Numerous clinical studies provide evidence for a link between increasing plasma IL-6 levels and COVID-19 disease severity and prognosis [46][47][48][49]. Del Valle et al, in a large study of > 1400 COVID-19 patients, found a threshold of 70 pg/mL of plasma IL-6 levels at hospitalization could independently predict disease severity and mortality.…”

A close‐up view of dynamic biomarkers in the setting of COVID‐19: Striking focus on cardiovascular system

“…According to the results, it has been revealed that the high levels of ferritin, as a predictive value, but not CRP reduction, were directly associated with improved clinical outcomes in TCZ recipients compared with the placebo group at day 28. 82 , 83 Moreover, the effect of subcutaneous injection of single dose sarilumab is also being conducted to evaluate possible benefits compared to the standard of care in the early stages of the disease. Even so, data have not been published yet.…”