Monrovia, October 13, 2016 – Results from the PREVAIL II clinical trial of ZMapp, an experimental treatment for Ebola virus disease (EVD), have been published by an international research team in the October 13th issue of the The New England Journal of Medicine. Overall, ZMapp was safe and well-tolerated, and when delivered along with the best available standard of care, may have benefitted patients more than optimized standard of care alone. However, the rapid decline in new cases of EVD in the affected countries prevented the trial from enrolling enough patients to prove this point definitively.
ZMapp (made by Mapp Biopharmaceutical Inc. of San Diego, CA, USA) is a mixture of three monoclonal antibodies that target a protein on the surface of the Ebola virus, thereby blocking its ability to infect human cells.
The U.S. co-leader of the trial, Richard T. Davey, Jr., MD, noted, “This was the first randomized controlled trial in humans of what many experts had regarded as the most promising candidate Ebola treatment prior to the West African outbreak. Our findings, while not definitive, provide valuable insights into ZMapp’s prospects of possible benefit, which appear large. Moreover, we demonstrated that rigorous treatment research can be successfully conducted even during an infectious disease outbreak in a setting of limited resources.” Dr. Davey is Deputy Clinical Director in the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health (NIH).
The study opened in March 2015. The first of 72 participants, a health care worker evacuated from Sierra Leone, was enrolled at the NIH Clinical Center in the United States. All other patients were enrolled in West Africa: 5 in Liberia, 12 in Guinea, and 54 in Sierra Leone. Patients of all ages with documented Ebola infections were eligible. The average age of the participants was 24 years, and slightly more than half were women. Although the team planned to enroll up to 200 patients, the study closed in late January 2016 once it became clear that public health efforts had succeeded in curtailing new Ebola cases in West Africa.
Designed as a randomized controlled trial, each patient was assigned by chance at entry to one of two study groups. One group received the best available standard of care at their treatment sites, which included giving intravenous fluids; balancing electrolytes and minerals needed to regulate body functions; maintaining healthy oxygen and blood pressure levels; and treating other infections if they occurred. The second group received optimized standard of care plus three infusions of ZMapp over the course of one week. The researchers often gave patients antihistamines and fever-reducing agents before the ZMapp infusions to reduce possible side effects.
The percentage of patients who experienced serious adverse events (SAEs) was similar in the two groups: 37 percent among those patients receiving optimized standard of care alone versus 31 percent among the patients who also received ZMapp. Only one SAE (high blood pressure) was judged related to the ZMapp infusion.
Nearly one-third of the patients (21 patients) died during the study. To assess whether ZMapp was effective, the team compared the number of deaths in each study group after 28 days. The group of 36 who received ZMapp plus optimized standard of care had 8 deaths (22 percent) compared with 13 deaths among the 35 patients (37 percent) who received optimized standard of care alone. (One patient left the study early and was not included in the analysis.) Although this translates to a 40 percent lower risk of death among those who received ZMapp, the difference did not reach statistical significance.
Mapp Biopharmaceutical has received funding from the U.S. Biomedical Advanced Research and Development Authority to offer ZMapp to future patients with confirmed EVD in the four countries where the trial occurred, under an expanded access protocol (EAP). Expanded access is a U.S. regulatory mechanism that enables an investigational drug to be made available to treat a serious or life-threatening disease for which no comparable or satisfactory alternative therapy is available. The EAP was reviewed and considered safe to proceed in the United States by the U.S. Food and Drug Administration. The company will make appropriate regulatory applications in the three West African countries that participated in PREVAIL II as well.
Moses B.F. Massaquoi, MD, MPH, FLCP, the Liberian co-leader of the study, said, “This clinical study was the first to involve a Sub-Regional Consortium of researchers from Liberia, Sierra Leone, and Guinea, a collaboration forged during the Ebola outbreak. Our consortium is committed to expanding the capacity and expertise in West Africa to carry out high-quality clinical research to improve the health of people living in our countries and beyond.” Dr. Massaquoi is Chair of the Sub-Regional Consortium on EVD Vaccine & Therapeutic Trials, and National Chair of Case Management at the Incident Management System of Liberia’s Ministry of Health.
Brigadier General Foday Sahr, MD, who led the trial in Sierra Leone where most patients were enrolled, added, “Experiences gained from this multicenter sub-regional collaboration will be useful in setting up future clinical trials in this area of West Africa.” Brig. Gen. Dr. Sahr was recently named the First Surgeon General of the Republic of Sierra Leone Armed Forces (RSLAF).
According to Denis Malvy, MD, PhD, co-leader of the study in Guinea, “The results of the ZMapp study are a significant step forward in the medical care of patients with Ebola. I am very glad to see the benefits of this partnership between our institutions and the Guinea authorities, and I have no doubt that our sub-regional research collaboration will contribute much more in the months ahead.” Dr. Malvy is Head of the Tropical Medicine Division at the University Hospital of Bordeaux, and Permanent Senior Researcher at INSERM, the French national institute of health and medical research.
Financial or logistic support for the trial was provided by NIAID/NIH; INSERM; RSLAF; the Ministries of Health and U.S. Embassy staff in Liberia, Sierra Leone, and Guinea; the U.S. Centers for Disease Control and Prevention (CDC) and the CDC Foundation; the U.S. Biomedical Advanced Research and Development Authority; and the U.S. Defense Threat Reduction Agency. The trial was conducted in partnership with other academic, governmental and non-governmental agencies providing research support within the West African region. Study collaborators from the United States and Canada included experts from the University of Minnesota; Leidos Biomedical Research Inc.; Emory University Hospital; the University of Nebraska Medical Center; Boston Medical Center; and Toronto General Hospital.
Reference: The PREVAIL II Writing Group (R Davey et al.), for the Multi-National PREVAIL II Study Team. A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection. The New England Journal of Medicine DOI: 10.1056/NEJMoa1604330 (2016).