hrsEalth officials are preparing to launch a clinical trial designed to test whether experimental Ebola therapies improve patients' chances of survival at the outbreak in the Democratic Republic of Congo – a landmark in the world's efforts to respond to this and future crises.
The randomized controlled study will compare three different antibody treatments and one antiviral drug to each other, rather than involving a placebo. It is unlikely that the trial will give clear results based on a single epidemic; It is expected to cover several outbreaks and countries – a new and challenging design.
In the current outbreak, the attempt will be increasingly complicated by a difficult security environment.
"I do not think the world really appreciates the challenge of the environment where this happens," says Dr. Jeremy Farrar, Head of Wellcome Trust and Co-Chair of a Group Worked Worldwide Health Organization to draft the protocol.
"People are pushing on, and it's not just a single piece of shooting," says Farrar about the safety environment in northern Kivu. "There are mortgages, there are kidnappings – it is an intense fragile environment with much conflict that has been going on for years."
The four experimental therapies that will be tested have been used for weeks in Ebola treatment units operated by Doctors Without Borders (MSF) and Alima. These therapeutic agents are the Gilead antiviral drug Remdesivir and three monoclonal antibody preparations: ZMapp, made by Mapp Biopharmaceuticals, Regeneron REGN 3470-3471-3479 and mAb 114, developed by the National Institutes of Health and the DRC National Institute for Biomedical Research.
As of Friday, 139 patients had one of the four.
So far, there have been 329 confirmed and likely cases of Ebola and 205 deaths, making this Ebola eruption, which began in July, the third largest on record.
It is unusual for unlicensed drugs to be used in such quantities beyond the context of a clinical trial. In this case, the authorization came through a kind of compassionate usage protocol established by the WHO.
The idea was that the protocol would serve as a bridge to allow use while a clinical trial was designed and signed by the many parties that have a stake in the process. But that process has taken longer than many people, and there has been frustration and concern about the continued use of experimental drugs that have been shown to increase survival in animal studies, but may or may not work just as well for humans.
"We have to start randomizing. We have to start generating evidence and have a harmonized way of collecting data," says Dr. Annick Antierens, Pharmaceutical Council's Strategic Advisor, who has been involved in the negotiations.
Some data have been retrieved from the cases treated so far, but without any form of standardization it is not clear how much you can derive from it. The antier was similar to comparing "apples with cherry and leek and melons".
Dr Mike Ryan, Deputy Director of the WHO Emergency Response, insisted on this period of compassion has enabled Ebola treatment centers to come to the point where they work well and have 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 on a regular basis.
"Both NGOs and 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 it and you're getting more and more comfortable. "
"You do not just press the" RCT Button "in a context like this, you know?" He added, with an acronym for randomized controlled trials.
The trial is scheduled to start soon, probably in November, Farrar said – with the Congo National Institute of Biomedical Research as sponsor of the trial.
But there are tasks to be processed. An ethics committee advisory to the Congolese government is still reviewing the protocol.
The protocol is written in such a way that the countries get a little flexibility. While DRC has indicated it will drive four arms – meaning that all patients will be randomized to get one of the drugs – other countries will be able to add a control arm that allows the drugs to be compared to standard care.
Antierens said there is a problem with that thought. There is no care for Ebola, she said, and none of the measures used in the treatment of Ebola patients have been shown to actually improve survival. That's not to say they do not help, just that there have never been clinical attempts to show that they are doing.
In the case of Ebola Therapy, if there is no control arm, how do you compare four different therapies? One idea has been to use ZMapp – studied in the West African outbreak – as an "anchor arm", which compared the other drugs with it.
The ZMapp attempts appeared to generate a signal that patients infected with the antibody shock were more likely to survive, but the experiment was initiated late in the outbreak and failed to register enough patients to come to a decisive response. Not everyone is on board with the idea of using ZMapp as an anchor arm, "said Antierens.
Another possibility, says Dr. Marie-Pierre Preziosi, is to compare the three monoclonal antibody treatments with each other and to compare the monoclonals with the antiviral. Preziosi is part of a WHO program aimed at stimulating the development of medical countermeasures for disease threats that do not attract commercial drug manufacturers.
A data security monitoring card will review results at preset intervals. If one of the drugs does not appear to work – or vice versa seems to be much more efficient than the others – the board will advise the trial group whether to drop a drug or cancel the trial, Preziosi said.
Given the difficulty of conducting clinical trials during an Ebola eruption – even less an Ebola eruption in such a high volatile attitude – it must be done correctly, Ryan said.
"I think we need a period of solid operational and logistics planning in this area to make this a success. Everyone wants this to be a success," he added. "Everybody wants a good RCT to finally figure out what value each of these therapies has in the treatment of Ebola. We've seen promising characters … but nobody will ever know until we make a real RCT."