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Randomized Controlled Trial
. 2016 Oct 13;375(15):1448-1456.
doi: 10.1056/NEJMoa1604330.

A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection

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Free PMC article
Randomized Controlled Trial

A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection

PREVAIL II Writing Group et al. N Engl J Med. .
Free PMC article

Abstract

Background: Data from studies in nonhuman primates suggest that the triple monoclonal antibody cocktail ZMapp is a promising immune-based treatment for Ebola virus disease (EVD).

Methods: Beginning in March 2015, we conducted a randomized, controlled trial of ZMapp plus the current standard of care as compared with the current standard of care alone in patients with EVD that was diagnosed in West Africa by polymerase-chain-reaction (PCR) assay. Eligible patients of any age were randomly assigned in a 1:1 ratio to receive either the current standard of care or the current standard of care plus three intravenous infusions of ZMapp (50 mg per kilogram of body weight, administered every third day). Patients were stratified according to baseline PCR cycle-threshold value for the virus (≤22 vs. >22) and country of enrollment. Oral favipiravir was part of the current standard of care in Guinea. The primary end point was mortality at 28 days.

Results: A total of 72 patients were enrolled at sites in Liberia, Sierra Leone, Guinea, and the United States. Of the 71 patients who could be evaluated, 21 died, representing an overall case fatality rate of 30%. Death occurred in 13 of 35 patients (37%) who received the current standard of care alone and in 8 of 36 patients (22%) who received the current standard of care plus ZMapp. The observed posterior probability that ZMapp plus the current standard of care was superior to the current standard of care alone was 91.2%, falling short of the prespecified threshold of 97.5%. Frequentist analyses yielded similar results (absolute difference in mortality with ZMapp, -15 percentage points; 95% confidence interval, -36 to 7). Baseline viral load was strongly predictive of both mortality and duration of hospitalization in all age groups.

Conclusions: In this randomized, controlled trial of a putative therapeutic agent for EVD, although the estimated effect of ZMapp appeared to be beneficial, the result did not meet the prespecified statistical threshold for efficacy. (Funded by the National Institute of Allergy and Infectious Diseases and others; PREVAIL II ClinicalTrials.gov number, NCT02363322 .).

Figures

Figure 1
Figure 1. Randomization and Follow-up
One patient in the group assigned to the current standard of care alone was lost to follow-up after day 1, could not be evaluated, and was not included in the primary analysis.
Figure 2
Figure 2. Kaplan–Meier Plot of Survival, According to the Two Assigned Treatment Groups
There were no deaths in either group after day 8 of the trial.
Figure 3
Figure 3
Forest Plot of Absolute Difference between Groups in 28-Day Mortality, Overall and According to Subgroup.

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