A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics

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. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.).

Figure 1.. Cumulative Incidence of Death.

Shown are Kaplan–Meier estimates of the cumulative incidence of death. Panel A shows the estimates in the overall population, Panel B the estimates in patients who had a nucleoprotein cycle-threshold (Ct) value of 22 or less at baseline (corresponding to a high viral load), and Panel C the estimates in patients who had a Ct value of more than 22 at baseline (corresponding to a low viral load).

Figure 2.. Time to Viral Clearance.

Panel A shows the time to the first negative result for Ebola virus (EBOV) nucleoprotein on reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay in all groups, with deaths imputed as the worst time. The dots indicate individual patients, the triangles indicate patients who were enrolled before January 2019 when the protocol was revised to add the REGN-EB3 group, and the horizontal bars indicate the group means. The black hashed bar in the remdesivir group indicates that the median time was not observed because more than 50% of patients in this group died before the first negative result. Data are not shown for one patient in the ZMapp group and one patient in the REGN-EB3 group who did not have a first negative result before day 28 but who had a negative result at days 48 and 41, respectively. Panel B shows the values for EBOV nucleoprotein as determined on RT-PCR, according to day of the trial. The symbols indicate the median, and the vertical bars indicate the interquartile range.