In partnership with the Liberian government, the National Institute of Allergy and Infectious Diseases (NIAID) on Friday launched a clinical trial to obtain safety and efficacy data on the investigational drug ZMapp as a treatment for Ebola virus disease. The study, which will be conducted in Liberia and the United States, is a randomized controlled trial enrolling adults and children with known Ebola virus infection.
“Although ZMapp has been used to treat several Ebola-infected patients in recent months, we cannot determine if the drug actually benefitted those patients because it was not administered within the context of a clinical trial,” said Anthony S. Fauci, M.D., director of the NIAID, at the National Institutes of Health (NIH). “This clinical trial will help us determine if ZMapp and other treatments are safe and effective for use in the current devastating outbreak in West Africa as well as in future outbreaks.”
ZMapp, developed by Mapp Biopharmaceutical Inc., based in San Diego, is composed of three different proteins called monoclonal antibodies. ZMapp is designed to prevent the progression of Ebola virus disease within the body by targeting the main surface protein of the Ebola virus. The antibodies comprising ZMapp are produced in tobacco plants specially bioengineered to produce large quantities of these proteins. Studies in nonhuman primates demonstrated that ZMapp has strong antiviral activity and rescued the animals from death as late as five days after infection with Zaire ebolavirus. The drug has not yet been tested in human clinical trials, but was administered under emergency use authorization to nine infected patients in Africa, the United States, and Western Europe.
The trial will be led by co-principal investigators Richard T. Davey, Jr., M.D., deputy clinical director of NIAID’s Division of Intramural Research, and Moses Massaquoi, M.D., National Chair for Case Management at the Ebola Incident Management System in Monrovia. The trial will enroll adults and children of any age who have been admitted to Ebola treatment units in Liberia, health care workers who were infected with Ebola virus in West Africa and have returned to the United States for treatment, and adults and children who may have acquired Ebola infection in the United States through secondary transmission. All participants will provide informed consent prior to enrollment. Treatment centers in Monrovia, Liberia, will include the ELWA 2 Ebola treatment unit and the Monrovia Medical Unit – staffed by the Commissioned Corps of the U.S. Public Health Service. The NIH Clinical Center in Bethesda, Maryland will serve as a treatment center in the U.S. Additional trial sites under consideration in the U.S. include the Walter Reed National Military Medical Center in Bethesda, Maryland, Emory University Hospital in Atlanta, and the University of Nebraska Medical Center in Omaha, Nebraska.
All participants will receive the optimized standard of care for treating Ebola infection, which includes providing intravenous fluids, balancing electrolytes, maintaining oxygen status and blood pressure and treating other infections if they occur. Participants will then be assigned randomly to one of two groups: the first group, which will act as the control, will continue to receive the current optimized standard of care. The second group will receive the optimized standard of care plus three separate intravenous infusions of ZMapp administered three days apart. The total dose of ZMapp at each infusion will depend on the weight of the participant. Study participants will be monitored up to 30 days following discharge from the hospital and may return for outpatient visits for additional follow up.
Researchers designed the study protocol to include a series of two-arm comparisons (the first being ZMapp compared to the current standard of care) to establish a framework to evaluate multiple potential Ebola treatments in the future. If one investigational treatment proves to be statistically more effective, it will then become the basis of the new standard of care against which additional investigational Ebola interventions could be tested and compared. Each experimental therapy will be examined in up to 100 participants per arm. If scientists are unable to establish a significant difference after enrolling 100 participants per arm, then that particular treatment will be declared ineffective and scientists will begin testing the next therapy. These additional treatments may also include the following:
- Tekmira siRNA from Tekmira Pharmaceuticals Corp., based in Burnaby, British Columbia
- Favipiravir from Toyama Chemical Co. LTD, based in Tokyo
- Convalescent or post-immunization plasma collected from recent Ebola infection survivors. It is possible that this category could potentially be expanded to include plasma donors who have participated in Phase 1 Ebola vaccine clinical trials and whose plasma shows high neutralizing activity against the virus.
- BCX4430 from BioCryst, based in Durham, North Carolina
- AVI-7537 from Sarepta, based in Cambridge, Massachusetts
NIH is collaborating with experts from the University of Minnesota, Minneapolis; Leidos Biomedical Research Inc.; Emory University Hospital, Atlanta; the University of Nebraska Medical Center, Omaha; the Centers for Disease Control and Prevention; the Uniformed Services University of the Health Sciences; and the Walter Reed National Military Medical Center to conduct this trial. The Biomedical Advanced Research and Development Authority, within the Office of the Assistant Secretary for Preparedness and Response at the U.S. Department of Health and Human Services, is funding the production of ZMapp. The trial is expected to conclude in December 2016. Given the current decline in the number of new Ebola cases in Liberia, study investigators anticipate the need for flexibility in the conduct and design of the trial to address the changing nature of the outbreak in West Africa. Consideration will also be given to other sites in the outbreak region that express interest.