Trial Shows Rigorous Clinical Research Feasible During a Public Health Emergency
October 12, 2016
A clinical trial to evaluate the experimental Ebola treatment ZMapp found it to be safe and well-tolerated; however, because of the waning Ebola epidemic, the study enrolled too few people to determine definitively whether it is a better treatment for Ebola virus disease (EVD) than the best available standard of care alone. The findings from the randomized, controlled trial known as PREVAIL II appear in the October 13th issue of The New England Journal of Medicine. Initial trial findings were reported in February 2016, at the Conference on Retroviruses and Opportunistic Infections in Boston.
“Although we do not have definitive evidence that ZMapp is superior to the optimized standard of care, the results of the PREVAIL II trial are promising and provide valuable scientific data,” said Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). “Importantly, the study establishes that it is feasible to conduct a randomized, controlled trial during a major public health emergency in a scientifically and ethically sound manner.”
ZMapp, developed by Mapp Biopharmaceutical, Inc., based in San Diego, is composed of three different laboratory-made proteins called monoclonal antibodies. The treatment is designed to prevent the progression of EVD within the body by targeting the main surface protein of the Ebola virus. Earlier studies in nonhuman primates demonstrated that ZMapp had strong antiviral activity and prevented death when administered as late as five days after experimental infection with Zaire ebolavirus.
The study launched through a collaboration between the Liberian Ministry of Health and NIAID, known as the Partnership for Research on Ebola Virus in Liberia (PREVAIL). It later expanded to include research partners within the countries of Sierra Leone and Guinea and the French medical research organization INSERM.
The study team was led by co-principal investigators Richard T. Davey, Jr., M.D., deputy clinical director of NIAID's Division of Intramural Research; Moses Massaquoi, M.D., National Chair for Case Management at the Ebola Incident Management System in Monrovia; Foday Sahr, M.D., Brigadier General and First Surgeon General of the Republic of Sierra Leone Armed Forces; and Denis Malvy, M.D., Ph.D., head of the tropical medicine division at the University Hospital of Bordeaux and permanent senior researcher at INSERM.
The trial enrolled 72 participants of any age with confirmed Ebola virus infection from March 2015 through November 2015. The participants came from Sierra Leone (54 patients), Guinea (12 patients), Liberia (five patients) and the United States (one patient, a health care worker evacuated from Sierra Leone).
The average age of the participants was 24 years, and slightly more than half were women. Investigators closed the study in January 2016 because they could not enroll additional patients, up to the targeted 200, because of the decline in the number of new Ebola cases as the outbreak diminished.
The study sought to determine if the experimental drug ZMapp plus the optimized standard of care for treating EVD—providing intravenous fluids, balancing electrolytes needed to maintain bodily functions, and maintaining healthy oxygen and blood pressure levels—was superior to the optimized standard of care alone in reducing deaths caused by EVD. All participants received the optimized standard of care, and half were randomly assigned to also receive three intravenous infusions of ZMapp administered three days apart.
Investigators compared the number of deaths in each group at 28 days after enrollment. Thirteen deaths (37 percent mortality) were reported in the group of 35 patients who received the optimized standard of care only, while eight deaths (22 percent mortality) occurred in the ZMapp group of 36 patients. One patient left treatment early and was not included in the analysis. Although the difference between the two groups translates to a 40 percent lower risk of death for those who received ZMapp, the difference did not reach statistical significance.
Should new cases of Ebola arise, Mapp Biopharmaceutical has taken steps to offer ZMapp to 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 is awaiting approval of its similar regulatory applications in the three West African countries.
Financial and logistic support for the trial was provided by NIAID; INSERM; the Republic of Sierra Leone Armed Forces; 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); 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: R Davey et al. A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection. The New England Journal of Medicine DOI: 10.1056/NEJMoa1604330 (2016).