The names of these promising drugs to treat COVID-19 sufferers are starting to be known to the public: Remdesivir, Ritonavir, Lopinavir and of course the most talked about, Chloroquine. These four promising treatments will be the subject of a large global study by the World Health Organization (WHO). Another study on the same substances (excluding Chloroquine) has just been launched by Europe with Inserm as coordinator. These two mega studies are a first for their size, the nature of their deployment in the midst of an epidemic crisis and the cooperation they demonstrate between scientists from all countries.
Could any of these drugs save COVID-19 patients from serious harm or death? The World Health Organization (WHO) has announced a large global trial, called SOLIDARITY, to find out if any of them can treat infections with the new coronavirus for this dangerous respiratory disease. This is an unprecedented effort – a coordinated and total effort to quickly collect solid scientific data during a pandemic. The study, which could cover several thousand patients in dozens of countries, was designed to be as simple as possible so that even hospitals overwhelmed by an avalanche of COVID-19 patients could participate.
With approximately 15% of COVID-19 patients suffering from serious illnesses and overwhelmed hospitals, treatment is desperately needed. That is why, rather than creating compounds from scratch that could take years to develop and test, researchers and public health agencies are seeking to redirect drugs already approved for other diseases and which know they are largely safe. They are also examining unapproved drugs that have worked well in animal studies with the other two deadly coronaviruses, which cause severe acute respiratory syndrome (SARS) and Middle Eastern respiratory syndrome (MRS).
Drugs that slow or kill the new coronavirus, scientifically known as SARS-CoV-2, could save the lives of critically ill patients, but could also be used prophylactically, to protect healthcare workers and others. at high risk of infection. The treatments could also reduce the time spent by patients in intensive care units, freeing up critical hospital beds.
Tests conducted in record time
Scientists have proposed dozens of existing compounds to test, but WHO is focusing on the four most promising treatments: an experimental antiviral compound, remdesivir; the antimalarial drugs chloroquine and hydroxychloroquine; a combination of two HIV medicines, lopinavir and ritonavir; and that same combination plus interferon beta, an immune system messenger that can help paralyze viruses. Some data on their use in patients treated with COVID-19 have already been published – the HIV combination failed in a small study in China – but the WHO believes that a large trial with a wider variety of patients is warranted.
It will be easy to register subjects for SOLIDARITY. When a person with a confirmed case of COVID-19 is judged admissible, the doctor can enter the patient data on a dedicated WHO website, including any underlying condition which could modify the course of the disease. such as diabetes or HIV infection. The participant must sign an informed consent form which is scanned and sent to WHO electronically. Once the doctor has indicated which drugs are available in his hospital, the website randomly selects the patient for one of the drugs available or for local standard care for COVID-19.
” After that, no further action or documentation is required “Says Ana Maria Henao-Restrepo, a doctor in the WHO Department of Vaccines and Biologics. Doctors will note the day the patient left the hospital or died, the length of stay in the hospital, and whether the patient needed oxygen or ventilation, she said. ” That’s all“.
Find a balance between scientific rigor and speedThe design is not double-blind, the gold standard of medical research, so there could be placebo effects in patients knowing that they have received a candidate drug. But WHO says it had to strike a balance between scientific rigor and speed. The idea for SOLIDARITY emerged less than two weeks ago, says Dr Henao-Restrepo, and the agency hopes that documentation and data management centers will be set up next week. ” We do this in record time “, she says.
It will be important to get answers quickly, to try to find out what is working and what is not. We believe the best way to do this is through random evidence. Arthur Caplan, bioethicist at New York University’s Langone Medical Center, says he appreciates the design of the study. ” No one wants to penalize the overworked frontline caregiver who takes risks anyway “He said. Hospitals that are not overcrowded could record more data on the progression of the disease, for example by monitoring the level of virus in the body, suggests Caplan. But for public health, the simple outcomes that WHO is trying to measure are the only ones relevant at the moment, says virologist Christian Drosten of the Berlin Charity University Clinic: ” We do not know enough about this disease to know what it means when the viral load decreases in the throat, for example “
Joint European trial
Sunday, the National Institute of Medical Research (INSERM) announced that it will coordinate a complementary trial in Europe, called DISCOVERY, which will follow the example of the WHO and will include 3200 patients from at least 7 countries, including 800 of France. This trial will test the same drugs as the WHO. In its French section, the trial will include at least 800 patients with severe forms of the coronavirus. In total, some 3,200 European patients will be included in the study, which combines Belgium, the Netherlands, Luxembourg, the United Kingdom, Germany and Spain. The data obtained will be shared with WHO.
Other host countries or groups could also organize additional studies, according to Ana Maria Heneo Restrepo. They are free to make additional measurements or observations, for example on virology, blood gases, chemistry and lung imaging. ” Although well organized further studies on the natural history of the disease or on the effects of experimental treatments may be useful, they are not basic requirements “, she says.
The list of drugs to test first has been drawn up for WHO by a group of scientists who have been evaluating the evidence for candidate therapies since January, said Restrepo. The group selected the drugs which were most likely to be effective, which had the most safety data in their previous use and which were likely to be available in sufficient quantities to treat a large number of patients if the test showed that they were effective.
Remdesivir
The new coronavirus gives this compound a second chance to shine. Originally developed by Gilead to combat the Ebola virus and related viruses, remdesivir stops viral replication by inhibiting a key viral enzyme, RNA-dependent RNA polymerase.
Researchers tested remdesivir last year during the Ebola outbreak in the Democratic Republic of Congo, along with three other treatments. It has shown no effect. But the enzyme it targets is similar in other viruses, and in 2017, researchers from the University of North Carolina at Chapel Hill showed in test tubes and in animals that the drug can inhibit the coronaviruses that cause SARS and MERS.
The first COVID-19 patient diagnosed in the United States – a young man from Snohomish County, Washington State – received remdesivir when his condition worsened; it got better the next day, according to a case report published in the New England Journal of Medicine (NEJM). A Californian patient who had received remdesivir – and whose doctors thought he might not survive – also recovered.
Such evidence from individual cases does not prove that a drug is safe and effective. However, according to the SOLIDARITY trial drugs, ” remdesivir is most likely to be used clinically Said Jiang Shibo of Fudan University in Shanghai, China, who has long worked on treatments for coronaviruses. Jiang particularly appreciates the fact that large doses of the drug can be administered without causing toxicity.
However, it can be much more powerful if it is given at the start of an infection, like most other drugs, says Stanley Perlman, a coronavirus researcher at the University of Iowa. ” What you really want to do is give a drug like this to people with mild symptoms “He said. ” And you can’t do it because it’s a medicine [intraveineux], it’s expensive and 85 out of 100 people don’t need it “
Chloroquine and hydroxychloroquine
It’s the most talked about drug, even those who are not doctors. This was the case, at a press conference on Friday, of President Donald Trump who called chloroquine and hydroxychloroquine ” game changer“. ” I feel good with that“, He declared in his singular rhetoric. His remarks spurred decades of antimalarials.
The WHO science group that designed SOLIDARITY originally decided to leave the duo out of the trial, but changed their minds at a meeting in Geneva on March 13 because the drugs ” have received significant attention In many countries, according to a report from a WHO task force that looked at the potential of drugs. Widespread interest has aroused ” the need to examine emerging evidence to inform a decision about its potential role“.
The available data are scarce. Drugs work by lowering the acidity of endosomes, the compartments inside cells that they use to ingest external material and that some viruses can co-opt to enter a cell. But the main route of entry for SARS-Cov-2 is different, using its protein called “spike” to attach to a receptor on the surface of human cells. Cell culture studies have suggested that chloroquines have some activity against SARS-CoV-2, but the doses required are generally high and could cause serious toxicities.
Encouraging results from cellular studies of chloroquines against two other viral diseases, dengue and chikungunya, have not produced conclusive results in humans in randomized clinical trials. And non-human primates infected with chikungunya had even worse results when they received chloroquine. ” Researchers have tried this drug virus after virus, and it has never worked in humans. The dose required is simply too high “Says Susanne Herold, a pulmonary infection expert at the University of Giessen, Germany.
The results obtained in patients treated with COVID-19 are unclear. Chinese researchers claiming to have treated more than 100 patients with chloroquine touted its benefits in a letter published in BioScience, but the data underlying this claim has not been published. In total, more than 20 COVID-19 studies in China have used chloroquine or hydroxychloroquine, notes the WHO, but their results have been difficult to obtain. ” WHO has engaged with Chinese colleagues in the Geneva mission and has received assurances of better collaboration; however, no data were shared regarding the chloroquine studies “
The French team of the now famous Professor Didier Raoult has published a study in which doctors treated 20 COVID-19 patients with hydroxychloroquine. They concluded that the drug significantly reduced the viral load in the nasal swabs. But it was not a randomized controlled trial and it did not report clinical results such as death. In a guide published on Friday, the American Society of Critical Care Medicine stated that ” there is insufficient evidence to recommend the use of chloroquine or hydroxychloroquine in critically ill adults with COVID-19 “
These reservations did not prevent Professor Raoult from launching tests directly on patients at the IHU in Marseille, even before the publication of the results of the European clinical trial which started on Sunday.
Professor Philippe Parola, head of the infectious diseases department of the Marseille IHU justifies this decision: ” You do not have to wait for patients to get worse and come to intensive care to see what my fellow resuscitators are going through, that is to say a massive influx of patients who are often elderly and at a very advanced stage of the disease. “, He told France Info. Professor Parola also provided new data on chloroquine as part of a treatment for coronavirus. He said the tests should combine chloroquine “with an antibiotic called azithromycin.” ” On the first authorized trial that we had made, this combination of chloroquine and azithromycin meant that by six days the small number of patients who had received this treatment no longer had a detectable virus, that is to say that they did not were more contagious », Explains the doctor. In France, the only French manufacturer of chloroquine is currently working to be able to supply establishments carrying out tests.
However, there have been reports that hydroxychloroquine, in particular, may do more harm than good. This drug has many side effects and can, in rare cases, lead to heart problems. Since people with heart conditions are more exposed to serious COVID-19, this is cause for concern, said David Smith, a medical doctor specializing in infectious diseases at the University of California, San Diego. ” It’s an alarm signal, but we still have to try “He said.
Ritonavir / lopinavir
This combination of drugs, sold under the brand name Kaletra, was approved in the United States in 2000 to treat HIV infections. Abbott Laboratories have developed lopinavir specifically to inhibit the protease of HIV, an important enzyme that cuts a long chain of proteins into peptides when assembling new viruses. As lopinavir is quickly broken down in the human body by our own proteases, it is given with low levels of ritonavir, another protease inhibitor, which makes lopinavir last longer.
This combination can also inhibit the protease of other viruses, especially coronaviruses. It has been shown to be effective in marmosets infected with the MERS virus, and has also been tested in patients with SARS and MERS, although the results of these trials are ambiguous.
The first trial with COVD-19 was not encouraging, however. Doctors in Wuhan, China gave 199 patients two lopinavir / ritonavir pills twice a day in addition to usual care, or usual care alone. There was no significant difference between the groups, they reported in the March 15 NEJM. But the authors warn that the patients were very sick – more than a fifth of them died – and that the treatment may have been given too late to help them. Although the drug is generally safe, it can interact with drugs usually given to critically ill patients, and doctors have warned that it could cause serious liver damage.
Ritonavir / lopinavir + interferon beta
SOLIDARITY will also have a component that combines the two antivirals with interferon beta, a molecule involved in regulating inflammation in the body, which has also shown an effect in marmosets infected with MERS. A combination of these three drugs is currently being tested in patients with MERS in Saudi Arabia as part of the first randomized controlled trial for this disease.
But using beta interferon in patients with severe COVID-19 could be risky, warns Professor Susanne Herold. ” If given at an advanced stage of the disease, it could easily lead to more serious tissue damage rather than helping patients “, She warns.
Thousands of guinea pig patients
The design of the SOLIDARITY assay can be changed at any time. A global data security review board will review the interim results at regular intervals and decide whether one of the quartet members has a demonstrable effect or whether it can be abandoned because it clearly does not. Several other drugs, including the influenza drug favipiravir, produced by the Japanese company Toyama Chemical, may be added to the trial.
To get solid results from the study, several thousand patients will likely need to be recruited, says Henao-Restrepo. Argentina, Iran, South Africa and several other non-European countries have already signed. The WHO is also hoping to do a preventative trial to test drugs that can protect healthcare workers from infection, using the same basic protocol, says Henao-Restrepo.
The European test counterpart DISCOVERY will recruit patients from France, Spain, the United Kingdom, Germany and the Benelux countries, according to an INSERM press release issued today. The essay will be led by Florence Ader, a researcher in infectious diseases at the Center hospitalier universitaire de Lyon.
Doing rigorous clinical research during an epidemic is always a challenge, says Dr. Ana Maria Henao-Restrepo, but it is the best way to progress against the virus.
Source: Science
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