A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection
PREVAIL II Writing Group, Multi-National PREVAIL II Study Team, Richard T Davey Jr, Lori Dodd, Michael A Proschan, James Neaton, Jacquie Neuhaus Nordwall, Joseph S Koopmeiners, John Beigel, John Tierney, H Clifford Lane, Anthony S Fauci, Moses B F Massaquoi, Foday Sahr, Denis Malvy, Jerry F Brown, Stephen B Kennedy, Gertrude Mulbah, Courtney Renken, Herbert Kallon, Reginald Cole, Komba Songu M’Briwa, Sekou Kanneh, Thomas Tucker, Adam Levine, Gino Strada, Oliver Morgan, Daouda Sissoko, Géraldine Colin, Sylvain Juchet, Xavier Anglaret, Joseph Akoi Bore, Raymond Koundouno, Sophie Duraffour, Stephan Gunther, Abdoul-Habib Beavogui, Alseny-Modet Camara, Jacques Kolie, Cecile Etienne, Claire Levy-Marchal, Yannick Ruaux-Morison, Keira Camara, Aguibou Barry, Abdoulaye Soumah, Andrea K Boggild, David R Boulware, Christopher J Kratochvil, Andre C Kalil, Philip Smith, Angela L Hewlett, Mark Kortepeter, Timothy Burgess, Scott Miller, Nahid Bhadelia, Colleen Kraft, Bruce Ribner, G Marshall Lyon III, Aneesh Mehta, Jay Varkey, Mark Mulligan, Susan Rogers, Cynthia Carpentieri, Elizabeth Higgs, Jamila Aboulhab, Jerome Pierson, Risa Eckes, Betsy Herpin, Susan Vogel, Laura McNay, Mary Smolskis, Lisa Hensley, Peter Jahrling, Nikki Gettinger, Kevin Barrett, Theresa Engel, Quy Ton, Matthew Kirchoff, Hope Pogemiller, Deborah Wentworth, Grace Kelly, Judith Zuckerman, Katherine Cone, Anthony Suffredini, Daniel Chertow, Tara Palmore, Mark Miller, Benjamin Bishop, Cynthia K Osborne, Laurie Lambert, Tara Perti, Liza Lindenberg, Jim Remington, Alejandra Miranda, Michelle Holshue, Travis Ready, Claire Gustin, Mona Patel, Catherine Groden, Susan Orsega, Jaewon Hong, Yiying Tsai, Ann Peterson, Meghan Schlosser, Jennifer Shepherd, Judith Brooks, Jerry Burge, Nancy Goldspiel, Lisa Tung, Maximilian Muenke, Tim Uyeki, Michael Montello, Lisa Cordes, Stacey McAdams, Vanessa Eccard, Molly Buehn, Leah McDonald, Tara Nyhuis, Larry Zeitlin, Miles Brennan, Kevin Whaley, Thomas Moench, PREVAIL II Writing Group, Multi-National PREVAIL II Study Team, Richard T Davey Jr, Lori Dodd, Michael A Proschan, James Neaton, Jacquie Neuhaus Nordwall, Joseph S Koopmeiners, John Beigel, John Tierney, H Clifford Lane, Anthony S Fauci, Moses B F Massaquoi, Foday Sahr, Denis Malvy, Jerry F Brown, Stephen B Kennedy, Gertrude Mulbah, Courtney Renken, Herbert Kallon, Reginald Cole, Komba Songu M’Briwa, Sekou Kanneh, Thomas Tucker, Adam Levine, Gino Strada, Oliver Morgan, Daouda Sissoko, Géraldine Colin, Sylvain Juchet, Xavier Anglaret, Joseph Akoi Bore, Raymond Koundouno, Sophie Duraffour, Stephan Gunther, Abdoul-Habib Beavogui, Alseny-Modet Camara, Jacques Kolie, Cecile Etienne, Claire Levy-Marchal, Yannick Ruaux-Morison, Keira Camara, Aguibou Barry, Abdoulaye Soumah, Andrea K Boggild, David R Boulware, Christopher J Kratochvil, Andre C Kalil, Philip Smith, Angela L Hewlett, Mark Kortepeter, Timothy Burgess, Scott Miller, Nahid Bhadelia, Colleen Kraft, Bruce Ribner, G Marshall Lyon III, Aneesh Mehta, Jay Varkey, Mark Mulligan, Susan Rogers, Cynthia Carpentieri, Elizabeth Higgs, Jamila Aboulhab, Jerome Pierson, Risa Eckes, Betsy Herpin, Susan Vogel, Laura McNay, Mary Smolskis, Lisa Hensley, Peter Jahrling, Nikki Gettinger, Kevin Barrett, Theresa Engel, Quy Ton, Matthew Kirchoff, Hope Pogemiller, Deborah Wentworth, Grace Kelly, Judith Zuckerman, Katherine Cone, Anthony Suffredini, Daniel Chertow, Tara Palmore, Mark Miller, Benjamin Bishop, Cynthia K Osborne, Laurie Lambert, Tara Perti, Liza Lindenberg, Jim Remington, Alejandra Miranda, Michelle Holshue, Travis Ready, Claire Gustin, Mona Patel, Catherine Groden, Susan Orsega, Jaewon Hong, Yiying Tsai, Ann Peterson, Meghan Schlosser, Jennifer Shepherd, Judith Brooks, Jerry Burge, Nancy Goldspiel, Lisa Tung, Maximilian Muenke, Tim Uyeki, Michael Montello, Lisa Cordes, Stacey McAdams, Vanessa Eccard, Molly Buehn, Leah McDonald, Tara Nyhuis, Larry Zeitlin, Miles Brennan, Kevin Whaley, Thomas Moench
Abstract
Background: Data from studies in nonhuman primates suggest that the triple monoclonal antibody cocktail ZMapp is a promising immune-based treatment for Ebola virus disease (EVD).
Methods: Beginning in March 2015, we conducted a randomized, controlled trial of ZMapp plus the current standard of care as compared with the current standard of care alone in patients with EVD that was diagnosed in West Africa by polymerase-chain-reaction (PCR) assay. Eligible patients of any age were randomly assigned in a 1:1 ratio to receive either the current standard of care or the current standard of care plus three intravenous infusions of ZMapp (50 mg per kilogram of body weight, administered every third day). Patients were stratified according to baseline PCR cycle-threshold value for the virus (≤22 vs. >22) and country of enrollment. Oral favipiravir was part of the current standard of care in Guinea. The primary end point was mortality at 28 days.
Results: A total of 72 patients were enrolled at sites in Liberia, Sierra Leone, Guinea, and the United States. Of the 71 patients who could be evaluated, 21 died, representing an overall case fatality rate of 30%. Death occurred in 13 of 35 patients (37%) who received the current standard of care alone and in 8 of 36 patients (22%) who received the current standard of care plus ZMapp. The observed posterior probability that ZMapp plus the current standard of care was superior to the current standard of care alone was 91.2%, falling short of the prespecified threshold of 97.5%. Frequentist analyses yielded similar results (absolute difference in mortality with ZMapp, -15 percentage points; 95% confidence interval, -36 to 7). Baseline viral load was strongly predictive of both mortality and duration of hospitalization in all age groups.
Conclusions: In this randomized, controlled trial of a putative therapeutic agent for EVD, although the estimated effect of ZMapp appeared to be beneficial, the result did not meet the prespecified statistical threshold for efficacy. (Funded by the National Institute of Allergy and Infectious Diseases and others; PREVAIL II ClinicalTrials.gov number, NCT02363322 .).
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Source: PubMed