TY - JOUR
T1 - A randomized, controlled trial of Ebola virus disease therapeutics
AU - PALM Writing Group
AU - Mulangu, Sabue
AU - Dodd, Lori E.
AU - Davey, Richard T.
AU - Mbaya, Olivier Tshiani
AU - Proschan, Michael
AU - Mukadi, Daniel
AU - Manzo, Mariano Lusakibanza
AU - Nzolo, Didier
AU - Oloma, Antoine Tshomba
AU - Ibanda, Augustin
AU - Ali, Rosine
AU - Coulibaly, Sinaré
AU - Levine, Adam C.
AU - Grais, Rebecca
AU - Diaz, Janet
AU - Clifford Lane, H.
AU - Muyembe-Tamfum, Jean Jacques
AU - Sivahera, Billy
AU - Camara, Modet
AU - Kojan, Richard
AU - Walker, Robert
AU - Dighero-Kemp, Bonnie
AU - Cao, Huyen
AU - Mukumbayi, Philippe
AU - Mbala-Kingebeni, Placide
AU - Ahuka, Steve
AU - Albert, Sarah
AU - Bonnett, Tyler
AU - Crozier, Ian
AU - Duvenhage, Michael
AU - Proffitt, Calvin
AU - Teitelbaum, Marc
AU - Moench, Thomas
AU - Aboulhab, Jamila
AU - Barrett, Kevin
AU - Cahill, Kelly
AU - Cone, Katherine
AU - Eckes, Risa
AU - Hensley, Lisa
AU - Herpin, Betsey
AU - Higgs, Elizabeth
AU - Ledgerwood, Julie
AU - Pierson, Jerome
AU - Smolskis, Mary
AU - Sow, Ydrissa
AU - Tierney, John
AU - Sivapalasingam, Sumathi
AU - Holman, Wendy
AU - Gettinger, Nikki
AU - Nordwall, Jacqueline
N1 - Publisher Copyright:
Copyright © 2019 Massachusetts Medical Society.
PY - 2019/12/12
Y1 - 2019/12/12
N2 - 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.
AB - 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.
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U2 - 10.1056/NEJMoa1910993
DO - 10.1056/NEJMoa1910993
M3 - Article
C2 - 31774950
AN - SCOPUS:85076449492
SN - 0028-4793
VL - 381
SP - 2293
EP - 2303
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 24
ER -