Patients

From November 20, 2018, to August 9, 2019, a total of 681 patients were enrolled and underwent randomization at Ebola treatment centers in Beni (335 patients), Butembo (243 patients), Katwa (46 patients), and Mangina (57 patients). Eight patients were excluded from the final analysis: 1 patient was later found to have been ineligible because of a false positive EVD result on RT-PCR assay, and 7 patients underwent randomization during a 2-week period when ZMapp was unavailable because of compromised cold-chain conditions. Of the remaining 673 participants, 169 were assigned to receive ZMapp, 175 to receive remdesivir, 174 to receive MAb114, and 155 to receive REGN-EB3. A total of 154 patients were assigned to the ZMapp group after the REGN-EB3 group had been added (the ZMapp subgroup), and data from these patients were used in the comparison of REGN-EB3 with ZMapp (Fig. S1).

Table 1. Table 1. Baseline Demographic and Clinical Characteristics of the Trial Population.

Most patients (74.4%) were 18 years of age or older, 12.8% were 6 to 17 years of age, and 12.8% were 5 years of age or younger, of whom 0.7% were neonates (≤7 days old). A total of 55.6% patients were female, of whom 6.1% were pregnant at the time of EVD diagnosis (Table 1).

The mean (±SD) baseline nucleoprotein Ct value was 24.0±5.6, and 42.1% of patients had a baseline value of 22.0 or lower. Patients were enrolled within an average of 5.5 days after the onset of symptoms. The most commonly reported baseline symptoms were diarrhea (in 53.8% of the patients), fever (in 51.4%), abdominal pain (in 46.4%), headache (in 44.4%), and vomiting (in 39.4%) (Table S2). Malaria coinfection was identified in 57 of 557 patients (10.2%). Patient-reported information regarding vaccination status (i.e., whether the patient had received the rVSVΔG-ZEBOV-GP vaccine) was available for 620 patients; of these, 155 (25.0%) reported that they received the vaccine. Among patients who reported that they had been vaccinated, 38.7% reported that they had received the vaccination at least 10 days before enrollment.

The mean baseline serum creatinine level was 2.5±2.9 mg per deciliter (221±256 μmol per liter), the mean aspartate aminotransferase level was 668±700 U per liter, and the mean alanine aminotransferase level was 379±464 U per liter. The mean baseline creatinine and aspartate aminotransferase values were higher in the ZMapp and remdesivir groups than in the other two groups. However, the baseline creatinine level was not recorded in 18.6% of patients, aspartate aminotransferase level was not recorded in 40.6%, and alanine aminotransferase level was not recorded in 18.1%. In addition, 70.1% of the available baseline samples indicated some degree of hemolysis.

Mortality

On August 9, 2019, when 681 patients had been enrolled, the data and safety monitoring board conducted an interim analysis on data from 499 patients and, on the basis of two observations, recommended terminating random assignment to ZMapp and remdesivir. First, results in the REGN-EB3 group crossed an interim boundary for efficacy with respect to a surrogate end point for death at 28 days that took into account outcomes in all patients with at least 10 days of follow-up (Fig. S3). Second, an analysis of mortality showed that there was a clear separation between the MAb114 and REGN-EB3 groups and the ZMapp and remdesivir groups (Fig. S4).

Table 2. Table 2. Comparison of Death at 28 Days According to Treatment Group.

A total of 673 patients were included in the primary analyses. At 28 days, death had occurred in 290 patients (43.1%) overall, in 18.8% of patients with a low viral load (Ct value >22.0), and in 76.1% with a high viral load (Ct value ≤22.0) (Table 2).

Figure 1. 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).

Table 3. Table 3. Logistic-Regression Analyses for Death at 28 Days.

Table 4. Table 4. Multivariate Logistic-Regression Analyses for Death at 28 Days in the 371 Patients Who Had Data Available for All Variables.

The percentage of patients who died was lower in the MAb114 group and in the REGN-EB3 group than in the ZMapp group (Figure 1 and Table 2). The difference between the MAb114 and the ZMapp groups was −14.6 percentage points (95% confidence interval [CI], −25.2 to −1.7; P=0.007); the difference between the REGN-EB3 group and the ZMapp subgroup was −17.8 percentage points (95% CI, −28.9 to −2.9; P=0.002); and the difference between the remdesivir and ZMapp groups was 3.4 percentage points (95% CI, −7.2 to 14.0). (Fig. S5 shows the differences in mortality in the remdesivir, MAb114, and REGN-EB3 groups relative to the ZMapp group according to Ct value, age, sex, and site.) The survival benefits seen in the MAb114 and REGN-EB3 groups were also seen in sensitivity analyses adjusted for potential baseline imbalances (Table 3 and Table 4 and Table S3).

Secondary Efficacy End Points

Figure 2. 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.

In an analysis of the time to the first negative result on RT-PCR assay for EBOV nucleoprotein, in which patients who had died were considered as not having had viral clearance, the time to the first negative result was shorter in the MAb114 and REGN-EB3 groups than in the ZMapp group (median in the MAb114 group, 16 days; median in the REGN-EB3 group, 15 days; median in the ZMapp group, 27 days) (Figure 2). Among patients in the remdesivir group, the estimated median time was more than 28 days because mortality exceeded 50%.

Prognostic Variables

A longer duration of symptoms before treatment was associated with significantly worse outcomes. Of note, 19% of patients who arrived at the treatment center within 1 day after the reported onset of symptoms died, as compared with 47% of patients who arrived after they had had symptoms for 5 days (Table S4). The odds of death increased by 11% (95% CI, 5 to 16) for each day after the onset of symptoms that the patient did not present to the treatment center (Table 3).

The odds of death were lower among patients with lower viral loads (odds ratio per unit increase in Ct value, 0.66; 95% CI, 0.62 to 0.71) and higher among patients with higher levels of creatinine (odds ratio per 1 mg per deciliter increase, 1.43; 95% CI, 1.31 to 1.56), aspartate aminotransferase (odds ratio per 100 U per liter increase, 1.15; 95% CI, 1.11 to 1.20), and alanine aminotransferase (odds ratio per 100 U per liter increase, 1.43; 95% CI, 1.33 to 1.54). A multivariate logistic-regression analysis showed that the duration of symptoms at enrollment, baseline nucleoprotein Ct value, and serum creatinine level all remained significant prognostic indicators of death (Table 4). Across all models, the effect estimates of treatment with MAb114 and REGN-EB3 remained significant (Table 3 and Table 4).

The percentage of patients who died was lower among those who reported that they had received the rVSV∆G-ZEBOV-GP vaccine than among those who reported no vaccination (27.1% [42 of 155 patients] vs. 48.4% [225 of 465]). However, patients who reported vaccination were also more likely to have had fewer days of illness before enrollment, higher baseline nucleoprotein Ct values, and lower levels of alanine aminotransferase (Table S5).

Safety

At least 98% of the patients received the infusions according to protocol (Table S6). A total of 29 serious adverse events were determined by trial investigators to be potentially related to the trial drugs (Table S7). However, after adjudication by an independent pharmacovigilance committee, four events in three patients, all of which resulted in death, were determined to be possibly related to a trial drug: one patient in the ZMapp group had worsening of gastrointestinal symptoms; one patient in the ZMapp group had periinfusional hypotension and hypoxia that responded to resuscitation after treatment interruption but that resulted in death within 24 hours; and one patient in the remdesivir group had hypotension that resulted in cessation of a loading dose of remdesivir and that was followed rapidly by cardiac arrest. However, even in these cases, the deaths could not readily be distinguished from underlying fulminant EVD itself.

Delays in Treatment Administration

The mean time from randomization to administration of the first infusion was somewhat longer in the ZMapp and remdesivir groups than in the MAb114 and REGN-EB3 groups. (Table S8 and Fig. S6 provide a summary of the time from randomization to the first infusion according to trial group and site, and Table S9 provides the results of a sensitivity analysis of outcomes that excluded data from patients with delays of more than 6 hours.) Twelve patients were enrolled but died before receiving the first infusion: one in the ZMapp group, three in the remdesivir group, three in the MAb114 group, and five in the REGN-EB3 group.