A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics

被引：1063

作者：

Mulangu, Sabue ^{[1
]}

Dodd, Lori E. ^{[2
]}

Davey, Richard T., Jr. ^{[2
]}

Mbaya, Olivier Tshiani ^{[1
]}

Proschan, Michael ^{[2
]}

Mukadi, Daniel ^{[1
]}

Manzo, Mariano Lusakibanza ^{[1
]}

Nzolo, Didier ^{[1
]}

Oloma, Antoine Tshomba ^{[1
]}

Ibanda, Augustin ^{[1
]}

Ali, Rosine ^{[1
]}

Coulibaly, Sinare ^{[3
]}

Levine, Adam C. ^{[4
]}

Grais, Rebecca ^{[5
]}

Diaz, Janet ^{[6
]}

Lane, H. Clifford ^{[2
]}

Muyembe-Tamfum, Jean-Jacques ^{[1
]}

Sivahera, Billy ^{[7
]}

Camara, Modet ^{[7
]}

Kojan, Richard ^{[7
]}

Walker, Robert ^{[8
]}

Dighero-Kemp, Bonnie ^{[9
]}

Cao, Huyen ^{[10
]}

Mukumbayi, Philippe ^{[11
]}

Mbala-Kingebeni, Placide ^{[11
]}

Ahuka, Steve ^{[11
]}

Albert, Sarah ^{[12
]}

Bonnett, Tyler ^{[12
]}

Crozier, Ian ^{[12
]}

Duvenhage, Michael ^{[12
]}

Proffitt, Calvin ^{[12
]}

Teitelbaum, Marc ^{[12
]}

Moench, Thomas ^{[13
]}

Aboulhab, Jamila ^{[14
]}

Barrett, Kevin ^{[14
]}

Cahill, Kelly ^{[14
]}

Cone, Katherine ^{[14
]}

Eckes, Risa ^{[14
]}

Hensley, Lisa ^{[14
]}

Herpin, Betsey ^{[14
]}

Higgs, Elizabeth ^{[14
]}

Ledgerwood, Julie ^{[14
]}

Pierson, Jerome ^{[14
]}

Smolskis, Mary ^{[14
]}

Sow, Ydrissa ^{[14
]}

Tierney, John ^{[14
]}

Sivapalasingam, Sumathi ^{[15
]}

Holman, Wendy ^{[16
]}

Gettinger, Nikki ^{[17
]}

Vallee, David ^{[17
]}

机构：

[1] Inst Natl Rech Biomed, Kinshasa, DEM REP CONGO

[2] NIAID, NIH, 10 Ctr Dr,Rm 4-1479,MSC 1460, Bethesda, MD 20892 USA

[3] Alliance Int Med Act, Dakar, Senegal

[4] Int Med Corps, Los Angeles, CA USA

[5] Epictr Med Sans Frontieres, Paris, France

[6] WHO, Geneva, Switzerland

[7] Alliance Int Med Act, Dakar, Senegal

[8] Biomed Adv Res & Dev Author, Washington, DC USA

[9] Battelle Mem Inst, Columbus, OH USA

[10] Gilead, Foster City, CA USA

[11] Inst Natl Rech Biomed, Kinshasa, DEM REP CONGO

[12] Leidos, Reston, VA USA

[13] Mapp Biopharmaceut, San Diego, CA USA

[14] NIAID, North Bethesda, MD USA

[15] Regeneron, Tarrytown, NY USA

[16] Ridgeback Biotherapeut, Miami, FL USA

[17] Mitchell Grp, Seventeen Mile Rocks, Qld, Australia

[18] Univ Minnesota, Minneapolis, MN 55455 USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2019年 / 381卷 / 24期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1056/NEJMoa1910993

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：2293 / 2303

页数：11

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