Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2293-2303 |
| Number of pages | 11 |
| Journal | New England Journal of Medicine |
| Volume | 381 |
| Issue number | 24 |
| DOIs | |
| State | Published - Dec 12 2019 |
Bibliographical note
Funding Information:From Institut National de Recherche Bio-médicale, Democratic Republic of Congo (S.M., O.T.M., D.M., M.L.M., D.N., A.T.O., A.I., R.A., J.-J.M.-T.); the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (L.E.D., R.T.D., M.P., H.C.L.); the Alliance for International Medical Action, Dakar, Senegal (S.C.); International Medical Corps, Los Angeles (A.C.L.); Epicentre, Médecins sans Frontières, Paris (R.G.); and the World Health Organization, Geneva (J.D.). The full names, academic degrees, and affiliations of the members of the PALM Writing Group are listed in the Appendix. Address reprint requests to Dr. Lane at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr., Rm. 4-1479, MSC 1460, Bethesda, MD 20892-1504, or at clane@niaid.nih.gov.
Funding Information:
Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.
Funding Information:
Supported primarily by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). In-kind support and cosponsorship were provided by the national government of the Democratic Republic of Congo (DRC) and the African Coalition for Epidemic Research, Response, and Training. Logistic support was provided by the World Health Organization (WHO). Some funding for NIAID was provided by the National Cancer Institute through a contract (HHSN261200800001E) with Leidos Biomedical Research and subcontracts to the Mitchell Group. The Biomedical and Advanced Research and Development Authority of the U.S. Department of Health and Human Services provided financial support for the production of ZMapp (contract number, HHSO100201400009C) and REGN-EB3 (contract number, HHSO100201700016C). NIAID and the Defense Advanced Research Projects Agency of the U.S. Department of Defense provided financial support for the production and provision of MAb114. Mapp Biopharmaceutical provided ZMapp, Gilead Sciences provided remdesivir, and NIAID provided MAb114 to the project. Regeneron Pharmaceuticals provided financial support for the provision of REGN-EB3 to the project.
Funding Information:
The trial was jointly approved by the ethics board at the University of Kinshasa and the institu- tional review board at the National Institute of Allergy and Infectious Diseases (NIAID) and was overseen by an independent data and safety monitoring board. Trial staff at participating Ebola treatment centers included staff from the Alliance for International Medical Action (ALIMA), International Medical Corps (IMC), Médecins sans Frontières (MSF), and the DRC Ministry of Health. Written informed consent was obtained from all patients or their legal guardians, and assent forms were obtained for children according to local standards and requirements. Full details about the trial design, conduct, oversight, and analyses are provided in the protocol and the Supplementary Appendix, both available with the full text of this article at NEJM.org. The PALM Writing Group performed the primary data analyses, wrote the manuscript, and, on behalf of the PALM Study Group, vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. The Office of Clinical Research Policy and Regulatory Operations of the Division of Clinical Research of the NIAID is the holder of the Investigational New Drug application (125530) from the Food and Drug Administration. The Biomedical and Advanced Research and Development Authority of the U.S. Department of Health and Human Services provided financial support for the production of ZMapp and REGN-EB3. NIAID and the Defense Advanced Research Projects Agency of the U.S. Department of Defense provided financial support for the production and provision of MAb114.
Publisher Copyright:
Copyright © 2019 Massachusetts Medical Society.
