Tuesday , January 31 2023

A pivotal step in the global response to Ebola: Clinical trial initiation


HEalth authorities are preparing to begin clinical trials to test whether the experimental ebola treatment improves the chances of survival in the Democratic Republic of Congo. This is an epoch-making moment of global effort to respond to this and future crises.

Randomized controlled trials compare three antiviral therapies to antiviral drugs rather than placebo. It is almost impossible for a trial to produce a clear outcome based on a single epidemic. It is expected to be across the country with multiple outbreaks – novel and challenging designs.

In the current outbreak, trials will become more complex due to the difficult security environment.


Dr. Jeremy Farrar, head of the Wellcome Trust, said he does not think the world is very grateful for the challenge of this environment. The Health Organization drafted a clinical trial plan.

Farrar said North Kivu's security environment is "people are being shot, sometimes not shooting." There are mortars and kidnappings. It is an intense environment that has undergone many conflicts over the years. "

The four experimental therapies to be tested were used for weeks on non-governmental organizations, the Doctors Without Borders (MSF) and the Ebola treatment devices operated by Alima. These treatments include Remedivir, the Gilead antiviral agent, ZMapp manufactured by Mapp Biopharmaceuticals, the three monoclonal antibody preparations, REGN 3470-3471-3479 from Regeneron, and mAb under development at the National Institute of Biomedical Research, DRC, 114. .

As of Friday, 139 patients received one of four.

So far, 329 Ebola cases and 205 death cases have occurred, and this Ebola occurrence, which started in July, is the third largest event in record.

Unlicensed drugs are rarely used in such quantities outside the context of clinical trials. In this case, the authorization was made through a kind of benign use protocol established by the WHO.

While the trial was being planned, the idea was that the protocol would be a bridge to allow use and be signed by a number of interested parties in the process. But the process took longer than many people expected, and frustration and concern about the continued use of experimental drugs to increase survival in animal experiments may not work well with people.

"We need to start randomization, we must have a harmonized way to create evidence and collect data." Dr. Annick Antierens, MSF's Medical and Strategy Advisor, took part in the negotiations.

Although there are some data collected from the cases handled so far, it is not clear how much data can be deduced without standardization. Antierens was compared to comparing apples with cherries, leeks and melons.

Mike Ryan, deputy chief of the WHO Emergency Response Center, asserted that these benevolent uses of the Ebola treatment center could help them become familiar with staff management when they reached the point where it worked. ZMapp is difficult to use. I inject three times over time. If a patient is treated with Remdesivir, liver function should be analyzed regularly.

"Ryan, who has spent the last few months in the onset, said NGOs and Congolese doctors and nurses all have clinical experience for weeks," he said. "This is a mechanical process and requires skill. And you become more relaxed by doing that muscle memory. "

He added, "Do not you just press the RCT button in this context?" He added, using the acronyms of randomized controlled trials.

The trial is expected to begin soon in November. Farrar will serve as a supporter of the trial of the National Institute of Biomedical Research in Congo.

However, the details remain to be resolved. The Ethics Committee advising the Congolese government is still reviewing the Protocol.

The Protocol was written in a way that allows countries some flexibility. The DRC says it will operate four weapons, meaning that all patients receive drugs at random. Other countries will have the option of adding a control device that can be compared to standard drugs.

Antierens said there was a problem with the idea. She said there is no standard for ebola therapy and that interventions used to treat Ebola patients are not actually proven to improve survival. It is not to say that they do not help, but that they have never done clinical trials.

How does Ebola cure compare to the four treatments without a control? One idea was to use ZMapp in West Africa as an "arm arm" to compare with other animals.

The ZMapp trial was more likely to survive patients who received antibody cocktails, but relapses did not start until late and did not register enough patients to give a definitive answer. Antierens said that not everyone is on board because of the idea of ​​using ZMapp as an anchor arm.

Marie-Pierre Preziosi said there is another possibility to compare three monoclonal antibody therapies to each other and to compare monoclonal antibodies with antiviral agents. Preziosi is one of the leading providers of WHO programs designed to promote the development of healthcare responses to disease threats that do not attract commercial pharmaceutical companies.

The data safety monitoring board will review the results at preset intervals. If a drug appears to be ineffective or is considered to be more effective than the other, Preziosi will decide whether to drop the drug or stop the trial at the end of the trial.

Ryan said that, given the difficulty of performing clinical trials at the time of Ebola, Ryan said that appropriate measures are needed, not to mention the occurrence of Ebola in a highly unstable situation.

"I think we need a solid operating and logistics plan for success in this area, and I hope that this will succeed," he added. "Everyone wants a good RCT to finally figure out what the value of this treatment is in ebola treatment. We have seen promising signs … but no one will know until we have done the appropriate RCT."

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