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A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics.
The New England Journal of Medicine ( IF 70.670 ) Pub Date : 2019-11-27 , DOI: 10.1056/nejmoa1910993
Sabue Mulangu,Lori E Dodd,Richard T Davey,Olivier Tshiani Mbaya,Michael Proschan,Daniel Mukadi,Mariano Lusakibanza Manzo,Didier Nzolo,Antoine Tshomba Oloma,Augustin Ibanda,Rosine Ali,Sinaré Coulibaly,Adam C Levine,Rebecca Grais,Janet Diaz,H Clifford Lane,Jean-Jacques Muyembe-Tamfum,,Billy Sivahera,Modet Camara,Richard Kojan,Robert Walker,Bonnie Dighero-Kemp,Huyen Cao,Philippe Mukumbayi,Placide Mbala-Kingebeni,Steve Ahuka,Sarah Albert,Tyler Bonnett,Ian Crozier,Michael Duvenhage,Calvin Proffitt,Marc Teitelbaum,Thomas Moench,Jamila Aboulhab,Kevin Barrett,Kelly Cahill,Katherine Cone,Risa Eckes,Lisa Hensley,Betsey Herpin,Elizabeth Higgs,Julie Ledgerwood,Jerome Pierson,Mary Smolskis,Ydrissa Sow,John Tierney,Sumathi Sivapalasingam,Wendy Holman,Nikki Gettinger,David Vallée,Jacqueline Nordwall,

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.).
更新日期:2019-12-13

 

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