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Experimental Ebola drugs face tough test in war zone

Health workers take a man's temperature at an Ebola-vaccination centre in the Democratic Republic of the Congo. Credit: Olivia Acland/Reuters

Health workers fighting the ongoing Ebola outbreak in the Democratic Republic of the Congo (DRC) have given nearly 20 people experimental drugs to treat the virus since mid-August. But because the drugs have been dispensed on a case-by-case, ‘compassionate use’ basis, it is hard to know whether any are effective. Now, desperate to determine which therapy works best, researchers from the DRC and US governments, the World Health Organization and other groups are meeting this week to plan a clinical trial that will compare multiple drugs as the outbreak continues.

For ethical reasons, the trial scientists say they do not intend to give any study participants a placebo. Instead, they hope to compare the two experimental medicines now in use to ZMapp, an antibody therapy that showed promise in limited tests three years ago during a major Ebola epidemic in West Africa1. Patients in the coming trial would receive one of these three drugs at random. The study design draws on a flexible clinical-trial framework that the WHO expects to unveil early next week. The framework is intended for use in multiple Ebola outbreaks, to produce data that can be pooled over time.

The scientists working on the DRC trial hope to launch the effort in the coming weeks. “A clinical trial will give us the scientific evidence we need,” says Jean-Jacques Muyembe-Tamfum, director-general of the National Institute for Biomedical Research in Kinshasa, which will lead the study.

But planning for the trial is complicated by the realities of working in a conflict zone: the DRC’s North Kivu and Ituri provinces, where fighting has killed more than 5 million people over the past two decades. Instability in the region could prevent clinicians from giving patients repeated infusions of drugs and collecting the biochemical data that a trial would require. “We can’t control what happens around a treatment centre,” Muyembe-Tamfum says. “Armed groups can do what they want.”

Moving quickly

The current outbreak began on 1 August, and has grown to include 115 confirmed and probable cases of Ebola — including 77 people who have died, the DRC health ministry said on 28 August. Public-health workers have vaccinated 4,645 people, and doctors have given 3 people the antiviral drug remdesivir, made by Gilead Sciences of Foster City, California. Another 13 patients have received mAb114, an experimental treatment derived from antibodies found in the blood of a person who contracted Ebola in 1995 and survived.

That swift response is a major shift from the handling of the Ebola epidemic that struck West Africa in 2014. Experimental drugs were not used widely in West Africa then because there was no proof of their safety or efficacy — clinical trials did not begun until the outbreak was near its end. That delay helped to drive the death rate among Africans infected with Ebola to 63%. But several Westerners infected with Ebola received the nascent therapies in top hospitals; the fatality rate for this group of patients was just 18%2. The controversy over this disparity eventually prompted the WHO to develop guidelines aimed at ensuring wider access to experimental treatments during future Ebola outbreaks.

But the only way to determine how well a drug works — and to rule out confounding factors, such as overall quality of medical care — is through a randomized, controlled clinical trial. Thus far, researchers have not managed to complete a trial of any experimental Ebola drug, because outbreaks of the disease have ended before enough patients enrolled in the studies. So the WHO has been working with international experts to create a basic trial design that can be adapted as data accumulate and logistical challenges change.

Practical challenges

Muyembe-Tamfum says that the trial being planned now for the DRC will make use of that framework. It is likely to test three drugs: mAb114, remdesivir and ZMapp, made by Mapp Biopharmaceutical in San Diego, California.

Although there are fewer data on mAb114 than on the other two drugs, it has attracted researchers because it is relatively simple to administer. Patients require just one dose, and the medicine is stable when refrigerated — an advantage in hot countries such as the DRC that lack steady electricity supplies.

But the inclusion of ZMapp complicates the trial plan, because the drug must be kept frozen and is given as multiple hours-long infusions, delivered under the watchful eyes of clinicians . “If you have 50 patients, this would require a huge number of doctors,” says Augustin Augier, the secretary-general of Paris-based ALIMA, one of the main medical organizations treating patients in the latest Ebola outbreak. “But if ZMapp turns out to be two times more superior to the other drugs, you will want to use it anyways.”

Stationing a large number of medical professionals in an Ebola unit is particularly fraught during the latest outbreak, because those people could become targets for the more than 100 militias roving the eastern DRC. If armed groups show up at a treatment centre, health workers might leave rather than risk their lives — and any clinical trial could come to a halt. “We are far better off than we were in West Africa, but this outbreak has tough challenges with security,” says Anthony Fauci, head of the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland.

But Ana Maria Henao Restrepo, who helps to lead the WHO’s Ebola Research and Development team, is unfazed. “Every trial has its own challenges,” she says. “That’s why we are coming out with an approach that’s flexible.”

Nature 561, 14 (2018)



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