A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection

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.)

Clinical Evaluation of Ebola Virus Disease Therapeutics

“…In February 2015, a randomized and controlled phase 1/2 clinical trial, the Partnership for Research on Ebola Virus in Liberia II (PREVAIL II), was initiated to evaluate the efficacy and effectiveness of ZMapp™ (ClinicalTrials.gov identifier: NCT02363322) [74]. The trial enrolled 72 patients (200 patients in the initial plan) from Liberia, Sierra Leone, Guinea, and the US, due to the substantial decline of EVD cases at the late stages of the outbreak [74].…”

“…The trial enrolled 72 patients (200 patients in the initial plan) from Liberia, Sierra Leone, Guinea, and the US, due to the substantial decline of EVD cases at the late stages of the outbreak [74]. The patients were randomized into either a control group receiving optimized standard of care only (oSOC, with aggressive fluid resuscitation, hemodynamic support, and other interventions available in an optimized care setting), or a treatment group receiving ZMapp™ plus oSOC (n=36 per group).…”

“…After assignment, patients received the first intravenous infusion of ZMapp™ (50 mg/kg of body weight) within 12–24 h, followed by two identical doses at every third day. The primary outcome was mortality at day 28 and data from 71 patients was included in the final analysis [74]. …”

“…The fatality rates were 37% (13 of 35) in the control group and 22% (8 of 36) in the ZMapp™ group, leading to a 91.2% posterior probability of superior protection from ZMapp™, which did not reach the preset threshold of ≥ 97.5% [74]. Therefore, ZMapp™ in combination with oSOC did not show a statistically significant decrease in fatality rate over oSOC, even though mortality was 40% lower in the ZMapp™ group relative to the control group.…”

“…In addition, the therapeutic benefit of ZMapp™ is likely underestimated, since seven of eight deaths in the ZMapp™ group occurred before the second dose of antibodies was received, suggesting that these patients may have been near, or at the terminal stage of EVD at the start of the treatment. The fatality rate (1/29) in the subgroup of patients who had finished all three doses of ZMapp™ was nearly eight times lower than among those who survived for > 3 days since admission into the control group [74]. This suggests that additional studies are clearly needed to properly evaluate the efficacy of ZMapp™.…”