In partnership with the Liberian government, the National Institute of Allergy and Infectious Diseases (NIAID) today 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.
The University of Nebraska Medical Center expects to receive approval of the study in a few weeks. The study is currently being reviewed by the Institutional Review Board, which also monitors biomedical research involving humans. Other sites expected to receive approval are Walter Reed National Military Medical Center in Bethesda, Md. and Emory University Hospital in Atlanta.
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.
“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.
“Our Biocontainment Unit research team has been actively involved in the development of this research protocol and looks forward to participating in the implementation of the research here in Nebraska,” said Christopher Kratochvil, M.D., UNMC associate vice chancellor for clinical research and vice president for research, Nebraska Medicine. “The invitation to participate in this research project once again recognizes the world-class facilities at Nebraska Medicine as well as the expertise of the researchers and staff of the Nebraska Biocontainment Unit.”
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 Ebola virus. 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.
Andre Kalil, M.D., professor in the UNMC Department of Internal Medicine and infectious diseases physician at Nebraska Medicine, said that the “adaptive” clinical trial will provide answers about the safety and effectiveness of ZMapp and other potential treatments in patients with Ebola virus disease.
“This is really a very important study with an innovative approach,” said Dr. Kalil, who has been involved in the design of the study with Dr. Kratochvil. “We must scientifically and rigorously evaluate the experimental treatments that have been given to date to determine what is safe and effective to our patients. We will find out what is working and what is not while the clinical trial is ongoing and adapt the study based on patients’ clinical response.”
“The idea is to discover and offer the safest and best therapies in the shortest period of time,” Dr. Kalil said. “We look forward to working with our national and international research partners.”
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. Participants will provide informed consent prior to enrollment.
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, Japan;
- 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, N.C.;
- AVI-7537 from Sarepta, based in Cambridge, Mass.
NIH is collaborating with experts from UNMC and Nebraska Medicine, the University of Minnesota; Leidos Biomedical Research Inc.; Emory University Hospital; 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 also will be given to other sites in the outbreak region that express interest.
Jeffrey P. Gold, M.D., UNMC chancellor and board chairman, Nebraska Medicine, said the medical center is thrilled to be part of the promising research. “It is an honor for us to continue our important leadership in this research area that could offer a treatment for this devastating disease which has taken the lives of so many. The research will be complete when it changes some human life — when it prevents a disease, treats a disease or improves a human condition. That’s what we are after in conducting truly relevant research.”
NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website at http://www.niaid.nih.gov.
NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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