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.

中文翻译：

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在一项随机对照试验中使用 Tocilizumab 治疗的 2019 年冠状病毒病患者的预后和预测生物标志物*

目标： 

探索在 2019 冠状病毒病肺炎患者的回顾性观察研究中确定的候选预后和预测生物标志物（白细胞介素 6、C 反应蛋白、乳酸脱氢酶、铁蛋白、淋巴细胞、单核细胞、中性粒细胞、d-二聚体和血小板）tocilizumab是一种抗白细胞介素 6 受体抗体，使用 COVACTA 试验的数据对因严重冠状病毒病 2019 肺炎住院的患者进行试验。

设计： 

来自多中心、随机、双盲、安慰剂对照的 3 期试验的探索性分析。

环境： 

北美和欧洲的医院。

患者： 

因严重冠状病毒病 2019 肺炎住院的成人接受标准护理。

干涉： 

随机分配 2:1 至 IV tocilizumab 8 mg/kg 或安慰剂。

测量和主要结果： 

在托珠单抗组的 295 名患者和安慰剂组的 142 名患者中测量了候选生物标志物。评估的疗效结果是第 28 天的七类有序量表（1，出院；7，死亡）、死亡率、出院时间和机械通气（如果未随机接受）的临床状态。预后和预测性生物标志物是使用比例赔率、二项式或精细灰色模型以及其他敏感性分析进行连续评估。安慰剂组的模型显示，除乳酸脱氢酶和d-二聚体外，所有候选生物标志物都对第 28 天的死亡率、机械通气、临床状态和出院时间等临床结果有很强的预后作用。在tocilizumab中建模与安慰剂相比，手臂显示铁蛋白对死亡率（预测交互作用， p = 0.03）、机械通气（预测交互作用，p = 0.01）和临床状态（预测交互作用，p = 0.02）的第 28 天临床结果的预测价值。

结论： 

COVACTA 证实了多种生物标志物对临床结果的预后。铁蛋白被确定为托珠单抗对 COVACTA 患者人群影响的预测性生物标志物；在第 28 天，与安慰剂相比，高铁蛋白水平与托珠单抗更好的临床结果相关。