Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial*
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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.
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SciScore for 10.1101/2020.12.23.20247379: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Consent: Informed consent was obtained for all enrolled patients.
IRB: The protocol was reviewed and approved by all appropriate institutional review boards and ethics committees (see Appendix 1 for the complete list).Randomization Statistical analysis: Biomarkers were assessed in the modified intention-to-treat population (any randomly assigned patients who received study medication). Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see N…
SciScore for 10.1101/2020.12.23.20247379: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Consent: Informed consent was obtained for all enrolled patients.
IRB: The protocol was reviewed and approved by all appropriate institutional review boards and ethics committees (see Appendix 1 for the complete list).Randomization Statistical analysis: Biomarkers were assessed in the modified intention-to-treat population (any randomly assigned patients who received study medication). Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Another limitation of this study is that laboratory values were measured locally, which, notably, entails more variability than uniform test runs in a central laboratory. Local laboratory results for ferritin, however, were confirmed by retesting all samples at a central laboratory using an in vitro diagnostic method (Roche Cobas). In conclusion, markers of hyperinflammation, macrophage activation, and dysregulated immune cells appear to be important prognostic biomarkers in COVID-19. Ferritin, as an acute-phase protein and a macrophage activation marker, might have potential as a predictive biomarker to help identify patients with severe COVID-19 who respond to tocilizumab. Results from ongoing studies of tocilizumab in COVID-19 are needed to validate these findings.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04320615 Completed A Study to Evaluate the Safety and Efficacy of Tocilizumab i… NCT04363736 Completed A Study to Investigate Intravenous Tocilizumab in Participan… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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