Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia A Randomized Clinical Trial
Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia A Randomized Clinical Trial
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DOI：
10.1001/jamainternmed.2020.6820
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发表时间：
2020-10-20
影响因子：
39
通讯作者：
Ravaud, Philippe
中科院分区：
文献类型：
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作者：
Hermine, Olivier;Mariette, Xavier;Ravaud, Philippe
严重肺炎伴炎症过度和白细胞介素-6升高是冠状病毒疾病的常见表现2019（COVID-19）。目的确定托珠单抗（TCZ）是否能改善因中重度COVID-19肺炎住院患者的预后。设计、设置和参与者本研究是一项队列嵌入式、治疗者发起的、多中心、开放标签、在2020年3月31日至2020年4月18日期间，对需要至少3 L/min氧气但没有通气或入住重症监护室的COVID-19和中度或重度肺炎患者进行了一项随机临床试验，随访28天。从法国9所大学医院招募患者。分析是在意向治疗的基础上进行的，没有纠正多重次要outcome.INTERVENTIONS患者随机分配接受TCZ，8毫克/公斤，静脉加日常护理的第1天和第3天，如果有临床指征（TCZ组）或仅接受日常护理（UC组）。住院治疗包括抗生素，抗病毒药，皮质类固醇，血管加压药的支持，和anticoagulants. Main结局和措施的主要结果是得分高于5分的世界卫生组织10点临床进展量表（WHO-CPS）在第4天和生存，而不需要通气（包括无创通气）在第14天。次要结果是第7天和第14天WHO-CPS评分评估的临床状态、总生存率、出院时间、氧供应独立时间、生物学因素如C反应蛋白水平和不良事件。TCZ组1例患者撤回知情同意，未纳入分析。在130例患者中，42例为女性（32%），中位（四分位距）年龄为64（57.1-74.3）岁。在TCZ组中，12例患者在第4天的WHO-CPS评分大于5，而UC组为19例（中位后验绝对风险差[ARD] -9.0%; 90%可信区间[CrI]，-21.0至3.1），ARD阴性的后验概率为89.0%，未达到95%预定的疗效阈值。第14天，12% TCZ组需要无创通气（NIV）或机械通气（MV）或死亡的患者少于UC组（95% CI -28%至4%）（24%对36%，中位后验风险比[HR] 0.58; 90% CrI，0.33-1.00），HR小于1的后验概率为95.0%，达到预定义的有效性阈值。MV或死亡的HR为0.58（90%CrI，0.30至1.09）。第28天，TCZ组7例患者死亡，UC组8例患者死亡（校正HR，0.92; 95% CI 0.33-2.53）。TCZ组和UC组分别有20例（32%）和29例（43%）患者发生严重不良事件（P = .21）。结论和相关性在这项对需要氧气支持但未入住重症监护室的COVID-19和肺炎患者进行的随机临床试验中，TCZ在第4天并未将WHO-CPS评分降低至低于5分，但可能降低了NIV的风险，MV，或第14天死亡。第28天死亡率无差异，需要进一步研究证实这些初步结果。
IMPORTANCE Severe pneumonia with hyperinflammation and elevated interleukin-6 is a common presentation of coronavirus disease 2019 (COVID-19).OBJECTIVE To determine whether tocilizumab (TCZ) improves outcomes of patients hospitalized with moderate-to-severe COVID-19 pneumonia.DESIGN, SETTING, AND PARTICPANTS This cohort-embedded, investigator-initiated, multicenter, open-label, bayesian randomized clinical trial investigating patients with COVID-19 and moderate or severe pneumonia requiring at least 3 L/min of oxygen but without ventilation or admission to the intensive care unit was conducted between March 31, 2020, to April 18, 2020, with follow-up through 28 days. Patients were recruited from 9 university hospitals in France. Analyses were performed on an intention-to-treat basis with no correction for multiplicity for secondary outcomes.INTERVENTIONS Patients were randomly assigned to receive TCZ, 8 mg/kg, intravenously plus usual care on day 1 and on day 3 if clinically indicated (TCZ group) or to receive usual care alone (UC group). Usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants.MAIN OUTCOMES AND MEASURES Primary outcomes were scores higher than 5 on the World Health Organization 10-point Clinical Progression Scale (WHO-CPS) on day 4 and survival without need of ventilation (including noninvasive ventilation) at day 14. Secondary outcomes were clinical status assessed with the WHO-CPS scores at day 7 and day 14, overall survival, time to discharge, time to oxygen supply independency, biological factors such as C-reactive protein level, and adverse events.RESULTS Of 131 patients, 64 patients were randomly assigned to the TCZ group and 67 to UC group; 1 patient in the TCZ group withdrew consent and was not included in the analysis. Of the 130 patients, 42 were women (32%), and median (interquartile range) age was 64 (57.1-74.3) years. In the TCZ group, 12 patients had a WHO-CPS score greater than 5 at day 4 vs 19 in the UC group (median posterior absolute risk difference [ARD] -9.0%; 90% credible interval [CrI], -21.0 to 3.1), with a posterior probability of negative ARD of 89.0% not achieving the 95% predefined efficacy threshold. At day 14, 12% (95% CI -28% to 4%) fewer patients needed noninvasive ventilation (NIV) or mechanical ventilation (MV) or died in the TCZ group than in the UC group (24% vs 36%, median posterior hazard ratio [HR] 0.58; 90% CrI, 0.33-1.00), with a posterior probability of HR less than 1 of 95.0%, achieving the predefined efficacy threshold. The HR for MV or death was 0.58 (90% CrI, 0.30 to 1.09). At day 28, 7 patients had died in the TCZ group and 8 in the UC group (adjusted HR, 0.92; 95% CI 0.33-2.53). Serious adverse events occurred in 20 (32%) patients in the TCZ group and 29 (43%) in the UC group (P = .21).CONCLUSIONS AND RELEVANCE In this randomized clinical trial of patients with COVID-19 and pneumonia requiring oxygen support but not admitted to the intensive care unit, TCZ did not reduce WHO-CPS scores lower than 5 at day 4 but might have reduced the risk of NIV, MV, or death by day 14. No difference on day 28 mortality was found. Further studies are necessary for confirming these preliminary results.