A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics
Sabue Mulangu1, Lori E Dodd1, Richard T Davey1
1From Institut National de Recherche Biomédicale, 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 affiliations of the members of the PALM Writing Group are as follows: the Alliance for International Medical Action (B.S., M.C., R.K.); the Biomedical Advanced Research and Development Authority (R.W.); Battelle (B.D.-K.); Gilead (H.C.); Institut National de Recherche Biomédicale (P.M., P.M.-K., S. Ahuka); Leidos (S. Albert, T.B., I.C., M.D., C.P., M.T.); Mapp Biopharmaceutical (T.M.); the National Institute of Allergy and Infectious Diseases (J.A., K.B., K. Cahill, K. Cone, R.E., L.H., B.H., E.H., J.L., J.P., M.S., Y.S., J.T.); Regeneron (S.S.); Ridgeback Biotherapeutics (W.H.); the Mitchell Group (N.G., D.V.); and University of Minnesota (J.N.).
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.).
Insights
Two investigational Ebola virus disease (EVD) therapies, MAb114 and REGN-EB3, significantly reduced mortality compared to ZMapp. Clinical trials during outbreaks are vital for effective response.
Area of Science:
- Infectious Diseases
- Virology
- Clinical Trials
Background:
- Ebola virus disease (EVD) requires effective therapeutics.
- Previous experimental treatments for EVD needed rigorous evaluation in controlled trials.
Purpose of the Study:
- To assess the safety and efficacy of four investigational EVD therapies.
- To compare MAb114 and REGN-EB3 against ZMapp and remdesivir in a randomized controlled trial.
Main Methods:
- A randomized controlled trial involving 681 patients in the Democratic Republic of Congo.
- Patients received standard care plus one of four treatments: ZMapp, remdesivir, MAb114, or REGN-EB3.
- The primary endpoint was 28-day mortality.
Main Results:
- MAb114 and REGN-EB3 demonstrated superior efficacy in reducing EVD mortality compared to ZMapp.
- Mortality rates were 35.1% for MAb114 and 33.5% for REGN-EB3, versus 49.7% and 51.3% for ZMapp groups.
- Lower viral load and creatinine levels correlated with improved survival; four serious adverse events were potentially drug-related.
Conclusions:
- MAb114 and REGN-EB3 are superior to ZMapp for treating EVD.
- Conducting ethical and scientifically sound clinical research during outbreaks is crucial for informing public health responses.
