Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial
Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial
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DOI：
10.1016/s0140-6736(20)31022-9
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发表时间：
2020-05-16
期刊：
影响因子：
168.9
通讯作者：
Wang, Chen
中科院分区：
文献类型：
--
作者：
Wang, Yeming;Zhang, Dingyu;Wang, Chen
背景：目前还没有特定的抗病毒药物被证明对2019年重症冠状病毒病患者有效(新冠肺炎)。核苷类似物前药雷米地韦(GS-5734)体外对包括SARS-CoV-2在内的致病性动物和人类冠状病毒具有抑制作用，在动物模型上对中东呼吸综合征冠状病毒、SARS-CoV-1和SARS-CoV-2复制有抑制作用。方法采用随机、双盲、安慰剂对照、多中心的方法，在湖北省10家医院进行试验，中国。符合资格的病人包括已获实验室证实感染SARS-CoV-2而需入院治疗的成年人(年龄18岁)，由发病至入院相隔12天或以下，室内空气中氧饱和度达94%或以下，或动脉血氧分压与吸入氧分压的比率为300毫米汞或以下，以及经放射学证实的肺炎。患者被随机分成2：1的比例静脉注射雷米昔韦(第一天200毫克，第二-10天100毫克，每天一次输注)或相同剂量的安慰剂输注10天。患者被允许同时使用洛比那韦-利托那韦、干扰素和皮质类固醇。主要终点是截至第28天的临床改善时间，定义为从随机化到临床状态(从1=出院到6=死亡)的6分顺序量表中下降两个水平的点的时间(以天为单位)或活着出院，以先到者为准。初步分析是在意向治疗(ITT)人群中进行的，安全性分析是在所有开始分配治疗的患者中进行的。这项试验在ClinicalTrials.gov注册，NCT04257656。结果在2020年2月6日至2020年3月12日期间，237名患者被纳入并随机分配到一个治疗组(158名服用瑞培韦，79名服用安慰剂)；安慰剂组中有一名患者在随机分组后退出，不包括在ITT人群中。雷米西韦的使用与临床改善的时间差异无关(风险比1.23[95%可信区间0.87-1.75])。虽然没有统计学意义，但在症状持续时间在10天或更短的患者中，接受瑞希韦的患者的临床改善时间在数字上比接受安慰剂的患者快(风险比1.52[0.95-2.43])。在155名瑞希韦接受者中有102人(66%)报告了不良事件，而在78名安慰剂接受者中有50人(%)报告了不良事件。18名(12%)患者因不良反应而提前停药，而早期停止服用安慰剂的患者为4名(5%)。在这项针对因严重新冠肺炎入院的成年患者的研究中，瑞美昔韦与统计上显著的临床益处无关。然而，早期治疗的患者临床改善时间的数字缩短需要在更大规模的研究中得到证实。版权所有(C)2020爱思唯尔有限公司。保留所有权利。
Background No specific antiviral drug has been proven effective for treatment of patients with severe coronavirus disease 2019 (COVID-19). Remdesivir (GS-5734), a nucleoside analogue prodrug, has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models.Methods We did a randomised, double- blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China. Eligible patients were adults (aged >= 18 years) admitted to hospital with laboratory-confirmed SARS- CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2-10 in single daily infusions) or the same volume of placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status ( from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. Primary analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who started their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04257656.Findings Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment group (158 to remdesivir and 79 to placebo); one patient in the placebo group who withdrew after randomisation was not included in the ITT population. Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1.23 [95% CI 0.87-1.75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1.52 [0.95-2.43]). Adverse events were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early.Interpretation In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. Copyright (c) 2020 Elsevier Ltd. All rights reserved.