Can drugs that inhibit other viruses also cause patients with COVID-19 to recover? UMC Utrecht is participating in international research to find out. "The starting point is that we quickly find out which of these drugs best reduces the serious symptoms," says researcher and physician-microbiologist dr. Miquel Ekkelenkamp. “This study is important because there is no vaccine and no medicine yet. The disease is serious and we are left empty-handed.”

The need is high. On Monday 30 March, nearly 3,500 patients with corona were (or have been) admitted to Dutch hospitals and there are currently more than 1,000 patients on an intensive care unit (ICU). And that admission to an ICU often takes several weeks. As a result, they ICU departments are getting fuller. That makes it more difficult to provide the necessary care anywhere, anytime. Haste is therefore urgent. The design of the international Discovery study - fast and flexible - is tailored to the acute demand for a drug that will make critically ill patients with corona recover faster.

Higher dose

“In most studies, you compare new agent A with existing agent B,” explains Miquel. “But we do things differently in this study. Five treatments are possible, one of which consists of optimally supported care and four of giving different pharmaceuticals. We also want to be able to adjust them gradually, so that patients can benefit from the medicines we are investigating during the study. If there are strong indications that a higher dose is better, for example, we want to be able to give it to the patient immediately. Normally this is not allowed, but in this case that approach is part of the study.”

Normalization of breathing

The study looks at the effectiveness and safety of four experimental treatments that may be effective against COVID-19. The aim is for 3,200 patients from various EU countries (in any case the Netherlands, Belgium, France and Luxembourg) and the United Kingdom to participate, of which 600 patients from the Netherlands. In the Netherlands, professor of medical microbiology Marc Bonten is the principal investigator and dr. Miquel Ekkelenkamp coordinates the study for the six participating hospitals. They expect more clarity about the value of the various regimens in the coming months. "We mainly look at whether a patient is recovering: whether he or she becomes fever-free, normalizes breathing and the lungs taking up oxygen from the environment again," says Ekkelenkamp. "That is really the most important thing."

Comparing results

"The premise of this study is that we quickly get an idea of which of the four experimental drugs best reduces the serious symptoms of COVID-19," he says. "If one drug shows that patients are recovering much better and faster than the others, you can stop the study and ensure that other patients get that drug immediately." This requires that we monitor carefully the effect of the drugs in all patients. Therefore, after every 100 patients out of a total of 3,200 who participate in the European part of the study, all known results so far are compared, allowing the researchers to see if all five treatment options of the study are being used, or whether one or more regimens stand out in a positive or negative manner.

Within 72 hours

The study may include patients over the age of 18 who are on a ventilator or have an oxygen saturation of 94 percent or less. "That's serious, because a healthy person has a saturation of at least 99 percent," says Miquel. "These people are very short of breath."

To properly compare study results, patients should have started enrollment in one of five treatment arms within a maximum of 72 hours of COVID-19 diagnosis. If possible, the patient himself is asked for permission. If this is not possible because he or she is ventilated and put to sleep, a legal representative will be asked for permission. The patient may then be able to provide or withdraw consent later. But because of the severity of the disease, Miquel expects that most patients with corona will happily participate.

Antiviral drug

Patients enrolled in the study are randomized to one of five treatment options. There is a control group that only receives standard treatment. Other patients will receive treatment with any of the following four agents: remdesivir, hydroxychloroquine, lopinavir/ritonavir or lopinavir/ritonavir plus interferon beta. What are these regimens? "Remdesivir is an antiviral drug that had an effect on SARS in cell cultures and also on viruses such as MERS and ebola in animal models," says Miquel. “In cell cultures, it is effective against the coronavirus. The question is whether it is also safe and effective for people.”

Hydroxychloroquine is on the market as an anti-malarial agent. It is not entirely clear how it affects viral infections. In the laboratory, it has an effect on various viruses in cell cultures, including SARS. The drug combination lopinavir/ritonavir (brand name: Kaletra) is on the market for people with HIV. It also seems to work against SARS in cell cultures and in animal models. It also inhibits the MERS virus in animal models. The combination of lopinavir/ritonavir plus interferon beta is the sum of this virus inhibitor with a body's own substance (interferon beta) that stimulates immune cells to clear viruses. "The coronavirus may shut down some of the body's defenses against viruses," says Miquel. "Interferon beta could counteract this by boosting the immune cells."

Antibodies

Treatment in the context of the study lasts one to two weeks. After the start, all European participants are followed for a month to see if the drugs are safe and effective. Doctors, researchers and nurses will collect a large set of data for this. In patients, blood pressure and oxygen saturation are measured repeatedly and blood samples are taken several times. This is necessary, among other things, to check how organs such as the liver and kidneys react, to see whether coronavirus is still present in the blood and whether a patient has developed antibodies against it.

It is possible that patients that participate in the study recover so well in the first or second week after admission that they can be discharged. In that case, the researchers will follow them up an outpatient basis until the month has passed and will call them for checks.

In principle, the European study ends when 3,200 patients participate. "It can also end sooner if there are hard conclusions to be drawn and we can immediately give patients better treatment on the basis of the study outcomes," says Miquel. It is also possible that the study will continue for longer because new treatment options are added or the regimens in the study are improved.

After completion of the European study, all research results will be shared with the World Health Organization (WHO). That organization has proposed the current protocol and supports several similar studies. This also makes it possible to draw conclusions worldwide. This is because research is also being conducted outside Europe into these regimens.

Emergency procedure

Permission from a Medical Ethics Review Committee (METC) is required to start the study in the Netherlands. It assesses whether the research design is satisfactory and whether it is responsible to conduct the study. For example, it must be clear which medication is given, who can participate and how it is determined who gets what. How do you ensure that an investigation is safe? And that you see in time which medicine is doing better or worse than others? The investigators have written this down in a research proposal. Since the coronavirus is not waiting, the METC has initiated an urgent procedure for its assessment. Most likely there will be permission soon and the study can start here in early April. France was the first to start on Saturday March 21. More than a hundred corona patients already have participated within five days.

There is still no drug that has been proven to benefit patients with corona. “The resources we investigate in this study are the only ones we have reason to believe could work in theory. But it is also possible that they are harmful. That is why we also check whether patients who do not receive the drugs, those in the control group, are not the best off, ”Miquel explains. “This is a hugely important study. So many people are ill now. Something has to happen."