A health worker gets ready to perform medical checks inside an Ebola treatment center in the Democratic Republic of the Congo.

Health officials are preparing to launch a clinical trial designed to test whether experimental Ebola therapies improve patients’ chances of survival in the outbreak in the Democratic Republic of the Congo — a landmark moment in the world’s efforts to respond to this and future crises.

The randomized controlled trial will compare three different antibody treatments and an antiviral drug to each other, rather than involving a placebo. It is unlikely that the trial will produce clear results based on a single epidemic; it is expected to span several outbreaks and countries — a novel and challenging design.

In the current outbreak, the trial will be made all the more complicated by a difficult security environment.

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“I don’t think the world quite appreciates the challenge of the environment in which this is happening,” said Dr. Jeremy Farrar, head of the Wellcome Trust and co-chair of a group that has been working under the auspices of the World Health Organization to draft the trial protocol.

“People are being shot at, and it’s not just the occasional bit of gunfire,” Farrar said of the security environment in North Kivu. “There’s mortars, there’s kidnappings — it is an intensely fragile environment with a lot of conflict that’s been going on for years.”

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The four experimental therapies that will be tested have been used for weeks in Ebola treatment units being operated by nongovernmental organizations Doctors Without Borders (MSF) and Alima. Those therapeutics are the Gilead antiviral drug Remdesivir and three monoclonal antibody preparations: ZMapp, made by Mapp Biopharmaceuticals, Regeneron’s REGN 3470-3471-3479, and mAb 114, which is being developed by the National Institutes of Health and DRC’s National Institute of Biomedical Research.

As of Friday, 139 patients had received one of the four.

To date, there have been 329 confirmed and probable cases of Ebola and 205 deaths, making this Ebola outbreak, which began in July, the third largest on record.

It is unusual for unlicensed drugs to be used in such quantities outside of the context of a clinical trial. In this case, the authorization came through a sort of compassionate use protocol established by the WHO.

The idea was that the protocol would serve as a bridge to allow use while a clinical trial was being designed and signed off on by the numerous parties that have a stake in the process. But that process has taken longer than many people anticipated, and there has been frustration and concern about continued use of experimental drugs that have been shown to increase survival in animal studies, but may or may not work as well in people.

“We need to start randomizing. We need to start generating evidence and having a harmonized way of collecting data,” said Dr. Annick Antierens, MSF’s medical department strategic adviser, who has been involved in the negotiations.

There have been some data gathered from the cases treated to date, but without any kind of standardization, it’s not clear how much can be deduced from it. Antierens likened it to comparing “apples with cherries and leeks and melons.”

Dr. Mike Ryan, deputy head of the WHO’s emergency response operation, insisted this period of compassionate use has allowed the Ebola treatment centers to get to the point where they are functioning well, and has given their staff time to become familiar with how to administer the drugs. ZMapp is difficult to use; it takes three infusions, given over hours. If patients are treated with Remdesivir, their liver function must be analyzed regularly.

“Both NGOs and the Congolese doctors and nurses have had this clinical experience over the weeks,” said Ryan, who spent the last month in the outbreak zone. “It’s a mechanical process and it requires a skill. And you get that muscle memory from doing that and you become more and more comfortable.”

“You don’t just push the ‘RCT button’ in a context like this, you know?” he added, using an acronym for randomized controlled trials.

The trial is expected to start soon, likely in November, Farrar said — with Congo’s National Institute of Biomedical Research serving as the sponsor for the trial.

But there remain details to be worked out. An ethics committee advising the Congolese government is still reviewing the protocol.

The protocol is written in such a way as to allow countries a little flexibility. While DRC has indicated it will run four arms — meaning all patients will be randomized to receive one of the drugs — other countries will have the option to add a control arm that would allow the drugs to be compared to standard care.

Antierens said there’s a problem with that idea. There is no one standard of care for Ebola, she said, and none of the interventions used in the treatment of Ebola patients has been proved to actually improve survival. That’s not to say they don’t help, only that there have never been clinical trials to show they do.

In the case of the Ebola therapeutics, if there is no control arm, how do you compare four different therapies? One idea has been to use ZMapp — which was studied in the West African outbreak — as an “anchor arm,” comparing the other drugs to it.

The ZMapp trial appeared to generate a signal that patients who were infused with the antibody cocktail were more likely to survive, but the trial was started late in the outbreak and did not manage to enroll enough patients to come to a conclusive answer. Not everyone is on board with the notion of using ZMapp as an anchor arm, Antierens said.

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Another possibility, said Dr. Marie-Pierre Preziosi, is to compare the three monoclonal antibody treatments to each other, and to compare the monoclonals to the antiviral. Preziosi is one of the leads of a WHO program designed to spur development of medical countermeasures for disease threats that don’t attract commercial pharmaceutical manufacturers.

A data safety monitoring board will review results at preset intervals. If any of the drugs don’t appear to be working — or conversely appear to be much more effective than the others — the board will advise the trial team on whether to drop a drug or discontinue the trial, Preziosi said.

Given the difficulty of conducting clinical trials during an Ebola outbreak — let alone an Ebola outbreak in such a highly volatile setting — this needs to be done right, Ryan said.

“I do think we need a period of solid operational and logistics planning in the field to make this a success. Everyone wants this to be a success,” he added. “Everyone wants a good RCT to finally work out what value each of these therapies has in the treatment of of Ebola. We’ve seen promising signs … but no one will ever know until we do a proper RCT.”