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PREVAIL II: A Randomized Controlled Trial of ZMapp™ in Acute Ebola Virus Infection
Richard T. Davey; for the the Multi-National PREVAIL II Study Team,NIAID, NIH, Bethesda, MD, USA
Although there are currently no licensed treatments for Ebola virus disease (EVD), the triple monoclonal antibody cocktail ZMapp is one of the most promising immune-based approaches for treating EVD based upon non-human primate data. Given the changing patterns of morbidity and mortality for human EVD identified during the recent outbreak in West Africa, it was believed that the single most definitive means of determining the efficacy of such an intervention would be through performance of a randomized controlled trial (RCT) with a clinical endpoint.
In a collaboration sponsored by the U.S. Department of Health and Human Services and involving the Ministries of Health of Sierra Leone, Guinea and Liberia, Mapp Biopharmaceuticals, Inserm, and academic medical centers in the U.S., consenting patients of any age diagnosed with EVD by polymerase chain reaction (PCR) between March-November 2015 were enrolled in the affected countries. Patients were randomized 1:1 to receive either optimized standard of care (oSOC, defined minimally as intravenous (iv) fluid resuscitation plus electrolyte monitoring) or oSOC plus three iv infusions of 50 mg/kg ZMapp spread three days apart. Patients were stratified by baseline Cycle Threshold (CT) value (≤22 vs. > 22) on PCR and by treatment site (U.S. vs. Liberia/Sierra Leone vs. Guinea [where favipiravir was part of oSOC]). The primary endpoint was mortality 28 days following randomization. An independent Data and Safety Monitoring Board (DSMB) reviewed interim results.
As of January 5, 2016, 72 patients were enrolled in the U.S. (n=1), Liberia (n=5), Sierra Leone (n=54), or Guinea (n=12). 30/72 (42%) and 42/72 (58%) had CT values ≤22 and >22, respectively, with an overall mean CT value of 23.9 at enrollment. The mean age of the enrolled cohort was 26.1 years: 55.6% were female. Only 6.9% had prior occupational exposure to persons with known EVD. The mean #days since symptom onset was 4.2. Overall mortality at 28 days was 21/72 (29.2%).
In the only RCT of a putative therapeutic agent performed to date in the current crisis, 72 patients were randomized to receive either oSOC plus ZMapp versus oSOC alone over a 9 month period in the latter half of the 2014-15 EVD epidemic. Barring a resurgence of additional EVD cases and with DSMB concurrence, the study will be unblinded for safety and efficacy analyses on January 14, 2016, 42 days after the last confirmed EVD case in West Africa.