Dataset Information

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

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.

SUBMITTER: Tom J

PROVIDER: S-EPMC8855771 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Tom Jennifer J Bao Min M Tsai Larry L Qamra Aditi A Summers David D Carrasco-Triguero Montserrat M McBride Jacqueline J Rosenberger Carrie M CM Lin Celia J F CJF Stubbings William W Blyth Kevin G KG Carratalà Jordi J François Bruno B Benfield Thomas T Haslem Derrick D Bonfanti Paolo P van der Leest Cor H CH Rohatgi Nidhi N Wiese Lothar L Luyt Charles Edouard CE Kheradmand Farrah F Rosas Ivan O IO Cai Fang F

Critical care medicine 20220301 3

<h4>Objectives</h4>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.<h4>Design ...[more]

PMID: 34612846

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Project description:ObjectiveTo determine whether tocilizumab improves clinical outcomes for patients with severe or critical coronavirus disease 2019 (covid-19).DesignRandomised, open label trial.SettingNine hospitals in Brazil, 8 May to 17 July 2020.ParticipantsAdults with confirmed covid-19 who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers (C reactive protein, D dimer, lactate dehydrogenase, or ferritin). The data monitoring committee recommended stopping the trial early, after 129 patients had been enrolled, because of an increased number of deaths at 15 days in the tocilizumab group.InterventionsTocilizumab (single intravenous infusion of 8 mg/kg) plus standard care (n=65) versus standard care alone (n=64).Main outcome measureThe primary outcome, clinical status measured at 15 days using a seven level ordinal scale, was analysed as a composite of death or mechanical ventilation because the assumption of odds proportionality was not met.ResultsA total of 129 patients were enrolled (mean age 57 (SD 14) years; 68% men) and all completed follow-up. All patients in the tocilizumab group and two in the standard care group received tocilizumab. 18 of 65 (28%) patients in the tocilizumab group and 13 of 64 (20%) in the standard care group were receiving mechanical ventilation or died at day 15 (odds ratio 1.54, 95% confidence interval 0.66 to 3.66; P=0.32). Death at 15 days occurred in 11 (17%) patients in the tocilizumab group compared with 2 (3%) in the standard care group (odds ratio 6.42, 95% confidence interval 1.59 to 43.2). Adverse events were reported in 29 of 67 (43%) patients who received tocilizumab and 21 of 62 (34%) who did not receive tocilizumab.ConclusionsIn patients with severe or critical covid-19, tocilizumab plus standard care was not superior to standard care alone in improving clinical outcomes at 15 days, and it might increase mortality.Trial registrationClinicalTrials.gov NCT04403685.

Project description:No therapeutics have been proven effective yet for the treatment of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To assess the efficacy and safety of Triazavirin therapy for COVID-19, we conducted a randomized, double-blinded controlled trial involving hospitalized adult patients with COVID-19. Participants were enrolled from ten sites, and were randomized into two arms of the study with a ratio of 1:1. Patients were treated with Triazavirin 250 mg versus a placebo three or four times a day for 7 d. The primary outcome was set as the time to clinical improvement, defined as normalization of body temperature, respiratory rate, oxygen saturation, cough, and absorption of pulmonary infection by chest computed tomography (CT) until 28 d after randomization. Secondary outcomes included individual components of the primary outcome, the mean time and proportion of inflammatory absorption in the lung, and the conversion rate to a repeated negative SARS-CoV-2 nucleic acid test of throat swab sampling. Concomitant therapeutic treatments, adverse events, and serious adverse events were recorded. Our study was halted after the recruitment of 52 patients, since the number of new infections in the participating hospitals decreased greatly. We randomized 52 patients for treatment with Triazavirin (n = 26) or a placebo (n = 26). We found no differences in the time to clinical improvement (median, 7 d versus 12 d; risk ratio (RR), 2.0; 95% confidence interval (CI), 0.7-5.6; p = 0.2), with clinical improvement occurring in ten patients in the Triazavirin group and six patients in the placebo group (38.5% versus 23.1%; RR, 2.1; 95% CI, 0.6-7.0; p = 0.2). All components of the primary outcome normalized within 28 d, with the exception of absorption of pulmonary infection (Triazavirin 50.0%, placebo 26.1%). Patients in the Triazavirin group used less frequent concomitant therapies for respiratory, cardiac, renal, hepatic, or coagulation supports. Although no statistically significant evidence was found to indicate that Triazavirin benefits COVID-19 patients, our observations indicated possible benefits from its use to treat COVID-19 due to its antiviral effects. Further study is required for confirmation.

Dataset Information

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

Objectives

Design

Setting

Patients

Intervention

Measurements and main results

Conclusions

Publications

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

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