BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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 outbreaks and can help inform the outbreak response. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.).

中文翻译：

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埃博拉病毒疾病治疗的随机对照试验。


背景虽然已经开发了几种针对埃博拉病毒病（EVD）的实验性疗法，但最有希望的疗法的安全性和有效性需要在随机对照试验的背景下进行评估。方法 我们在刚果民主共和国对埃博拉病毒病的四种研究疗法进行了试验，该国于 2018 年 8 月爆发埃博拉病毒病。逆转录酶聚合酶链反应检测中埃博拉病毒 RNA 呈阳性的任何年龄的患者被录取了。所有患者均接受标准护理，并以 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）、抗病毒药物瑞德西韦、单克隆抗体 MAb114 或三联单克隆抗体雷根-EB3。 REGN-EB3 组是在协议的较新版本中添加的，因此这些患者的数据与在添加 REGN-EB3 组时或之后入组的 ZMapp 组患者的数据进行了比较（ZMapp 亚组） 。主要终点是 28 天时死亡。结果 2018年11月20日至2019年8月9日期间，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将患者仅分配到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 和瑞德西韦。 28 天时，MAb114 组 174 名患者中有 61 名患者死亡（35.1%），而 ZMapp 组 169 名患者中有 84 名患者死亡（49.7%）（P = 0.007），155 名患者中有 52 名患者死亡（33.5%）。在 REGN-EB3 组中，与 ZMapp 亚组 154 例中的 79 例 (51.3%) 相比 (P = 0.002)。 入院前症状持续时间较短以及病毒载量、血清肌酐和转氨酶水平基线值较低均与生存率的提高相关。四种严重不良事件被判断可能与试验药物有关。结论 MAb114 和 REGN-EB3 在降低埃博拉病毒病死亡率方面均优于 ZMapp。可以在疾病爆发期间进行科学且符合伦理的临床研究，并有助于为疫情应对提供信息。 （由国家过敏和传染病研究所等资助；PALM ClinicalTrials.gov 编号，NCT03719586。）。