A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics

By S. Mulangu, L. Dodd, R. Davey, Olivier Tshiani Mbaya, Michael Proschan, Daniel Mukadi, Mariano Lusakibanza Manzo, Didier Nzolo, Antoine Tshomba Oloma, Augustin Ibanda and 41 more. New England Journal of Medicine, 2019

1,321 citations recorded by the source corpus.

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 out-breaks and can help inform the outbreak response.

Subfields: Emergency Medical Services, Infectious Diseases, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/662b0c832abd8436a22a441f16ae2aaad773650a

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Infectious Diseases

In Public Health, Environmental and Occupational Health

Jun Zheng

Citations in the corpus

The convalescent sera option for containing COVID-19. (2020, neutral): “These considerations were invoked recently with the decision to use mAbs in the treatment of Ebola virus disease (32).”
Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial (2020, background): “19 Intra venous remdesivir was studied for treatment of Ebola virus disease, in which it was adequately tolerated but less effective than several monoclonal antibody therapeutics, 20 and has been used on the basis of individual compas sionate use over the past several months in patients with COVID-1”
A Review of SARS-CoV-2 and the Ongoing Clinical Trials (2020, background): “Although it has not been shown to be effective against Ebola in this trial, it proved its safety for humans, which allowed it to enter clinical trials immediately in the conditions of COVID-19 emergency [43] .”
SARS-CoV-2: an Emerging Coronavirus that Causes a Global Threat (2020, background): “When compared with SARS-CoV and MERS-CoV, the nucleotide sequences of SARS-CoV-2 showed a higher homology with that of SARS-CoV while was relatively poor with that of MERS-CoV [19].”
Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability (2020, methodology): “Indeed, therapeutic antibody cocktails with a variety of specificities have been used successfully against Ebola virus disease (7) and are being tested widely in clinical trials for HIV-1 (28).”
Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the COVID-19 Pandemic (2020, neutral): “Whereas extensive CV toxicities and medication interactions have yet to be reported, prior evaluation of this drug during the Ebola outbreak did note the development of hypotension and subsequent cardiac arrest after loading dose in 1 patient (among 175 total) (79).”
Novel 2019 coronavirus structure, mechanism of action, antiviral drug promises and rule out against its treatment (2020, background): “Mulangu et al(Proschan et al., 2019) have conducted a trial of four investigational therapies for Ebola virus diseased patients.”