November 27, 2018
An international research team has begun patient enrollment in a clinical trial testing multiple investigational Ebola therapies in the Democratic Republic of the Congo (DRC). The randomized, controlled trial is enrolling patients of any age with confirmed Ebola virus disease (EVD) at a treatment unit in the city of Beni operated by The Alliance for International Medical Action (ALIMA), a medical humanitarian organization.
The trial, which will expand to additional DRC districts, is organized through an international research consortium coordinated by the World Health Organization (WHO). It is led and funded by the National Institute for Biomedical Research (INRB), part of the DRC Ministry of Health, and the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health, and also involves several additional international partners.
“Combatting Ebola requires a comprehensive response that draws on the strengths of all areas of public health. Biomedical research can lead to critical new tools, such as potentially life-saving therapies,” said NIAID Director Anthony S. Fauci., M.D. “Through scientifically and ethically sound clinical trials, we hope to efficiently and definitively establish the safety and efficacy of these investigational Ebola treatments, offering new ways to save lives.”
On August 1, 2018, the DRC Ministry of Health declared the country’s 10th outbreak of EVD. As of November 25, 2018, 240 deaths out of 419 confirmed and probable cases of EVD have been reported in the northeastern provinces of North Kivu and Ituri. Under the leadership of the DRC Ministry of Health, the WHO has coordinated the outbreak response with several international partners. NIAID, along with the U.S. Centers for Disease Control and Prevention, the U.S. Agency for International Development (USAID), and other U.S. government partners, have provided guidance and support to the multi-sectoral outbreak response.
“We urgently need a safe and effective treatment for this deadly disease,” said DRC Minister of Health Oly Ilunga Kalenga, M.D., Ph.D. “As we face a 10th outbreak of Ebola, we hope this clinical trial will give us more information about how best to treat patients.”
The trial aims to compare mortality among patients who receive one of three investigational Ebola drugs with a control group of patients who receive the investigational monoclonal antibody cocktail treatment ZMapp, developed by Mapp Biopharmaceutical, Inc. The therapies being tested include: mAb114, a single monoclonal antibody developed by NIAID, with early support from the INRB; and remdesivir (also known as GS-5734), an antiviral drug developed by Gilead Sciences, Inc. The trial has been approved to begin enrolling patients in these three groups, and plans are underway to amend the trial to include REGN-EB3 (also known as REGN3470-3471-3479), a monoclonal antibody cocktail developed by Regeneron Pharmaceuticals, Inc.
The participating Ebola treatment units will continue to provide all participants with supportive care for EVD. Ebola care includes supportive oral and/or intravenous fluids, electrolyte replacement, maintaining oxygen status and blood pressure, and pain management.
The investigational treatments have varying levels of data to support their use from testing in the laboratory, animals, and humans. However, none has been approved for treating EVD. ZMapp is the only investigational treatment previously tested in a randomized, controlled efficacy trial. Results from that study, conducted in the U.S. and West Africa during the 2014 to 2016 outbreak, suggested that ZMapp appeared to be beneficial, but as the outbreak waned, the trial ultimately could not enroll enough participants to definitively establish the drug’s efficacy.
The investigational treatments also have been administered to most of the Ebola patients in the current outbreak in the DRC under an ethical framework developed by the WHO called Monitored Emergency Use of Unregistered and Investigational Interventions (MEURI). However, this emergency-use mechanism cannot yield generalizable evidence on how well the treatments work.
“A randomized, controlled clinical trial is necessary to obtain reliable data about the safety and efficacy of investigational Ebola treatments,” said H. Clifford Lane, M.D., director of NIAID’s Division of Clinical Research. “It is possible to conduct rigorous clinical research in an outbreak setting, and we anticipate this trial will provide useful data.”
Professor Jean-Jacques Muyembe-Tamfum, M.D., Ph.D., director-general of the INRB, and Richard T. Davey, Jr., M.D., deputy director of NIAID’s Division of Clinical Research, are co-principal investigators for the study.
Trial participants will be randomly assigned to receive one of the investigational treatments by intravenous infusion. Site clinicians will monitor patients’ symptoms and take blood samples for laboratory tests. Patients will remain in the Ebola treatment unit until they fully recover from the disease. They will be asked to return to the clinic approximately two months after receiving treatment for a check-up and to provide additional blood samples for laboratory tests.
Plans are underway to expand the trial beyond the ALIMA site in Beni to additional Ebola treatment units operated by medical humanitarian organizations, including International Medical Corps. The trial also may be adapted to continue across more than one outbreak and in several countries. The number of participants enrolled in the trial ultimately will depend on the evolution of Ebola outbreaks. The study is designed to enroll 112 patients per arm, potentially over multiple outbreaks.
“This clinical trial marks a significant and important step forward for the DRC and our international partners,” said Dr. Muyembe. “We are eager to learn more about each of these investigational treatments as we continue to work tirelessly to identify new cases, trace contacts and control the spread of disease.”
An independent data and safety monitoring board will regularly review the study data. For more information, visit ClinicalTrials.gov and search identifier NCT03719586.
Randomized, Controlled Clinical Trial of Investigational Treatments for Patients with Ebola Virus Disease
It is a randomized controlled Phase 2/3 clinical trial to test the safety and efficacy of four investigational Ebola treatments in patients with Ebola virus disease (EVD) in the Democratic Republic of the Congo (DRC) in Africa. The study will compare mortality among patients who receive one of three investigational Ebola drugs with a control group of patients who receive the investigational monoclonal antibody cocktail ZMapp.
The study will begin at a treatment unit in the city of Beni in North Kivu Province. The treatment unit is operated by ALIMA, a medical humanitarian organization, but the study is expected to expand to other Ebola treatment units in the affected area operated by the medical humanitarian group International Medical Corps. The study protocol is designed to enroll across Ebola outbreaks, so the study could potentially expand to other countries.
The DRC has been experiencing its 10th outbreak of Ebola virus disease in the northeastern provinces of North Kivu and Ituri since August 1, 2018. As of November 25, 2018, the World Health Organization (WHO) and the DRC Ministry of Health have reported 240 deaths from 419 confirmed and probable cases of EVD, making it the largest Ebola outbreak ever reported in the DRC.
The study is being carried out by an international research consortium and coordinated by the WHO in connection with Ebola outbreak response activities. The clinical trial is co-led and funded by the National Institute for Biomedical Research (INRB), part of the DRC Ministry of Health, and the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health, and involves multiple international partners.
Professor Jean-Jacques Muyembe-Tamfum, M.D., Ph.D., director-general of the INRB, and Richard T. Davey, Jr., M.D., deputy director of NIAID’s Division of Clinical Research, are co-principal investigators for the trial.
The study will initially compare mortality rates after 28 days among patients who receive either of the following three investigational Ebola drugs: ZMapp, developed by Mapp Biopharmaceutical, Inc., based in San Diego; mAb114, a single monoclonal antibody developed by NIAID (with early support from the INRB); and remdesivir (also known as GS-5734), an antiviral drug developed by Gilead Sciences, Inc., based in Foster City, California. The protocol is in the process of being amended to include a fourth investigational treatment, REGN-EB3 (also known as REGN3470-3471-3479), an investigational monoclonal antibody cocktail developed by Regeneron Pharmaceuticals, Inc., based in Tarrytown, New York. ZMapp serves as the control arm for the study. All the investigational agents will be administered intravenously.
Each of the investigational treatments has varying levels of supportive data from testing in the laboratory, animal studies and early-phase human studies, but none has been licensed for treating EVD. The investigational treatments have been administered to some Ebola patients on an emergency, compassionate use basis in the current outbreak in the DRC through an ethical framework developed by the WHO called the Monitored Emergency Use of Unregistered and Investigational Interventions, or MEURI.
ZMapp is the only investigational Ebola treatment previously tested in a randomized, controlled efficacy trial. Results from that study conducted in the United States and West Africa during the 2014-16 Ebola outbreak, indicated that ZMapp appeared to be beneficial, but the clinical trial ultimately did not enroll enough participants to definitively establish the drug’s efficacy because the Ebola outbreak at that time ended. Despite the lack of definitive evidence of efficacy, the investigators believe ZMapp is a more appropriate control than a placebo in this setting.
The number of study participants will depend upon the progression of the DRC Ebola outbreak and potential future. However, initial estimates are that 112 men, women and children with symptoms of Ebola virus disease and a positive lab test for Ebola virus will need to be enrolled in each arm of the study, for a total of 448 participants. Participants will be required to provide informed consent personally or through a legally acceptable representative if the patient is too sick or too young to do so. Although pregnant women are eligible to enroll, men and women participants who are of childbearing age must agree to use effective methods of contraception from time of enrollment until day 58 of the study.
Although some study treatment sites may have resource constraints, the participating Ebola treatment units will also attempt to provide all participants with supportive medical treatment for Ebola virus disease. This includes supportive oral or intravenous fluids, electrolyte replacement, maintaining oxygen status and blood pressure, and pain reduction.
Patients will remain in the Ebola treatment unit until they fully recover from the disease or die. Study staff will examine participants 28 days and 58 days after they receive treatment and obtain additional blood samples from them at that time for laboratory testing. Adult male participants will be asked to provide a semen sample to look for the persistence of genetic material from the Ebola virus.
The well-being and safety of study participants is always our top priority. An independent data and safety monitoring board of global physicians, biostatisticians, health care professionals and ethicists will regularly review the study data and, if warranted, will make recommendations about dropping or replacing poorly performing study arms or closing the study early. Additionally, ethical review boards at the DRC’s University of Kinshasa School of Public Health and the NIH will be overseeing the study data to monitor for adverse events and other developments. The study has also undergone review by the U.S. Food and Drug Administration.
EVD is frequently fatal, and there are no existing, approved treatments that have been scientifically proven to work. Although the investigational treatments being tested in this clinical trial have been administered to some Ebola patients on an emergency basis during the current outbreak, there is no way to conclusively determine based on that use how well the different treatments work and whether any of them is a more effective treatment than the others. A randomized, controlled clinical trial is the most scientifically rigorous way to determine the safety and efficacy of these investigational Ebola treatments. It allows for the most rapid determination of relative safety and efficacy and, thus, is the quickest way to provide the most effective treatment to the greatest number of patients.
The projected end date for the clinical trial is 2023; however, that time frame could be shorter or longer depending on the pace and size of the current and any subsequent Ebola outbreaks.