尽管已经开发了几种针对埃博拉病毒病(EVD)的实验性疗法,最有希望的疗法的安全性和有效性需要在随机的背景下进行评估,对照试验。
我们在刚果民主共和国进行了一项针对EVD的四种研究性疗法的试验,爆发于2018年8月开始。招募了在逆转录酶-聚合酶链反应测定中埃博拉病毒RNA阳性结果的任何年龄的患者。所有患者均接受标准治疗,并以1:1:1:1的比例随机分配给静脉内施用三联单克隆抗体ZMapp(对照组),抗病毒剂Remdesivir,单一单克隆抗体MAb114或三重单克隆抗体REGN-EB3。REGN-EB3组是在协议的更高版本中添加的,因此,我们将这些患者的数据与加入REGN-EB3组(ZMapp亚组)时或之后纳入的ZMapp组患者的数据进行了比较.主要终点是28天的死亡。
从2018年11月20日至2019年8月9日,共招募了681名患者,当时数据和安全性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;该建议基于中期分析的结果,该结果显示这些组在死亡率方面优于ZMapp和remesivir。28天,MAb114组174例患者中有61例(35.1%)死亡,与ZMapp组169人中的84人(49.7%)相比(P=0.007),在REGN-EB3组的155人中有52人(33.5%),ZMapp亚组154人中有79人(51.3%)(P=0.002)。入院前症状持续时间较短,病毒载量和血清肌酐和转氨酶水平的基线值较低,均与生存率提高相关。四个严重不良事件被认为与试验药物潜在相关。
MAb114和REGN-EB3在降低EVD死亡率方面均优于ZMapp。在疾病暴发期间可以进行科学和道德上合理的临床研究,并可以帮助告知暴发响应。(由国家过敏和传染病研究所等资助;PALMClinicalTrials.gov编号,NCT03719586。).
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 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.).