A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics.
A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics.
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DOI：
10.1056/nejmoa1910993
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发表时间：
2019-12-12
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虽然已经开发出几种埃博拉病毒病的实验性治疗方法，但需要在随机对照试验的背景下评估最有希望的治疗方法的安全性和有效性。我们在2018年8月开始爆发埃博拉疫情的刚果民主共和国对四种埃博拉病毒病的研究性疗法进行了试验。所有年龄的埃博拉病毒RNA逆转录聚合酶链反应检测阳性的患者均被纳入研究。所有患者均接受标准治疗，并按1:1:1:1的比例随机分配至静脉注射三联单克隆抗体ZMapp（对照组）、抗病毒药物remdesivir、单克隆抗体MAb114或三联单克隆抗体REGN-EB3。REGN-EB3组是在较晚版本的方案中加入的，因此将这些患者的数据与加入REGN-EB3组（ZMapp亚组）时或之后入组的ZMapp组患者的数据进行比较。主要终点为28天死亡。从2018年11月20日至2019年8月9日，共有681名患者入组，当时数据和安全监测委员会建议在剩余的试验中仅将患者分配到MAb114和REGN-EB3组；该建议是基于一项中期分析的结果，该分析显示这些组在死亡率方面优于ZMapp和remdesivir。28天，MAb114组174例患者中有61例（35.1%）死亡，而ZMapp组169例患者中有84例（49.7%）死亡（P = 0.007）， REGN-EB3组155例患者中有52例（33.5%）死亡，而ZMapp亚组154例患者中有79例（51.3%）死亡（P = 0.002）。入院前症状持续时间较短，病毒载量、血清肌酐和转氨酶水平基线值较低，均与生存率提高相关。四个严重不良事件被认为可能与试验药物有关。在降低EVD死亡率方面，MAb114和REGN-EB3均优于ZMapp。可以在疾病暴发期间进行合乎科学和伦理的临床研究，并有助于为疫情应对提供信息。
Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial. We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase–polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days. A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P = 0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P = 0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs. Both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. Scientifically and ethically sound clinical research can be conducted during disease out-breaks and can help inform the outbreak response.