US, WASHINGTON (ORDO NEWS) — On Friday, the World Health Organization (WHO) announced a global test called Solidarity to find a cure for a dangerous respiratory disease caused by the new coronavirus. This measure is truly unprecedented – a universal and coordinated attempt to quickly collect reliable scientific data against the backdrop of a pandemic.
The research method, which will cover many thousands of patients in dozens of countries, is so simple that even hospitals paralyzed by the influx of patients with COVID-19 can take part in it.
Approximately 15% of patients with COVID-19 have severe symptoms, and amid crowded hospitals, treatment is extremely urgent. Therefore, instead of coming up with drugs from scratch that take years to develop and test, researchers and public health authorities seek to reuse drugs that have already been approved for the treatment of other diseases and have proven themselves safe. Unapproved drugs are also considered, which have shown themselves well in the treatment of two other deadly coronaviruses in animals – severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS).
Drugs that suppress or destroy the new coronavirus, called SARS-CoV-2, not only save lives of seriously ill patients, but can also be used prophylactically to protect health workers and others at high risk of infection. In addition, the drug will reduce treatment time in intensive care units by releasing critical hospital beds.
Scientists offered dozens of existing drugs for testing, but WHO decided to focus on four of the most promising treatments: an experimental antiviral drug called remdesivir; malaria drugs chloroquine and hydroxychloroquine; combination drug against HIV lopinavir and ritonavir; and the same combination plus interferon beta (informational RNA of the immune system that will help neutralize viruses). Some evidence of their use in patients with COVID-19 is already available – for example, the combination of HIV drugs in a small study in China has failed – but WHO believes that a large-scale study with a wide variety of patients is justified.
Registering patients in Solidarity will be easy. When the patient with COVID-19 passes the selection, the doctor can enter the patient’s data directly on the WHO website, including an anamnesis that can change the course of the disease – for example, diabetes or HIV infection. The participant must sign a consent paper, which will be sent to WHO electronically. When the doctor tells you which drugs are available at his hospital, the site will link the patient to one of them.
“No measurements or other documentation will be required,” says Ana Maria Henao-Restrepo, a staff member at the WHO Department of Vaccines and Biologicals. Doctors will mark the day the patient leaves the hospital or dies, the length of the hospital stay and the need for oxygen or ventilation, she explains. “That’s all”.
The research methodology is not double blind – the gold standard in medical research – therefore, the placebo effect is possible, because patients will know that they are receiving a promising drug. According to WHO, a compromise had to be made between scientific rigor and speed. According to Enao-Restrepo, the concept of Solidarity appeared less than two weeks ago, and the agency hopes that supporting documentation and data management centers will be operational next week. “We fit in record time,” she says.
Bioethics from the Langone Medical Center at New York University Arthur Caplan likes the research method. “Nobody wants to burden doctors at the forefront of the epidemic, they are already overloaded and at great risk,” says Kaplan. Less busy hospitals will also be able to register data on the development of the disease, measuring the viral load in the body, Kaplan suggests. But for public hospitals, the simple results that WHO is asking are the only relevant data at the moment, said virologist Christian Drosten of the Charité University Hospital in Berlin: “We really don’t know much about this disease, and we can’t to say with confidence what, for example, means a decrease in the viral load in the throat.”
On Sunday, the French National Institute for Health and Medical Research (INSERM) announced that it will coordinate an additional study in Europe called Discovery (Discovery). It will be arranged following the example of WHO and will include 3,200 patients from at least seven countries, including 800 from France. The same drugs will be tested, with the exception of chloroquine. Other countries or hospitals may organize their additional research, says Henao-Restrepo. They will be able to conduct additional virological studies, a gas or chemical blood test and take pictures of the lungs. “Although well-organized additional studies on the medical history and its consequences of trial treatment methods may well be valuable, they are not among the basic requirements,” she says.
According to Henao-Restrepo, a list of drugs to be tested in the first place was compiled for WHO by a team of scientists evaluating evidence of future treatment. The group selected the drugs with the greatest chance of success, whose safety is confirmed by previous uses, and which, apparently, will be available in quantities sufficient to treat a significant number of patients – if the study yields positive results.
Here are the drugs that will be tested during Solidarity:
The new coronavirus will give this drug another chance to prove itself. Originally developed by Gilead to combat Ebola and related viruses, remdesivir stops the replication of the virus by inhibiting the key viral enzyme, RNA-dependent RNA polymerase (aka RNA replicase).
Researchers tested remdesivir last year during an Ebola outbreak in the Democratic Republic of the Congo along with three other drugs. He did not give any effect (unlike the other two). However, the enzyme it targets is similar to other viruses, and in 2017, researchers at the University of North Carolina at Chapel Hill, in vitro (in vitro) and in vivo (experimental animals) studies, showed that the drug suppresses coronaviruses. calling SARS and MERS.
The first case of COVID-19 in the United States – a young man from Snohomish County, Washington – received remdesivir when his condition worsened. The next day, it improved again, as appears from the medical history in the New England Medical Journal (NEJM). Remdesivir was also received by a patient from California, about whom doctors believed that he would not survive, and he recovered.
Individual cases do not yet prove that the drug is safe and effective. However, of all Solidarity drugs, remdesivir “has the best potential for use in clinics,” said Jiang Shibo of Fudan University in Shanghai, who has been working on anticoronavirus therapy for a long time. Jiang particularly likes the fact that it seems that you can prescribe high doses of the drug without causing toxicity.
Chloroquine and hydroxychloroquine
At a Friday press conference, President Donald Trump called chloroquine and hydroxychloroquine a “cardinal change”. “I have a good feeling about this,” Trump said. His comments have already led to a sharp increase in demand for antimalarial drugs, which have been around for several decades. (“It reminds me of the hype around toilet paper: everyone ran sharply to the store,” Kaplan comments.)
The WHO Scientific Group, which oversees Solidarity, initially decided to exclude these two drugs, but changed its mind at a meeting in Geneva on March 13, as in many countries these drugs were “closely monitored,” as is clear from the report of the WHO working group studying drug potential. Therefore, “the need to study emerging evidence to substantiate a decision on its potential role” led to widespread interest.
There is little data available. The drugs work by reducing the acidity in the endosomes – these intracellular organelles absorb the external material, and some viruses penetrate through them. But the main entrance for SARS-Cov-2 is different – it uses the so-called spike protein, attaching to the receptor on the surface of human cells. Cell culture studies have shown that chloroquines have some activity against SARS-CoV-2, but the required doses are usually high and can cause serious toxicity.
The encouraging results of cell studies with chloroquines against two other viral diseases, dengue and chikungunya, have not been confirmed in randomized clinical trials. The lower primates infected with chikungunya felt even worse when receiving chloroquine. “Researchers tried this drug on virus after virus, but it didn’t work in humans. The dose needed is too high, ”said Susanne Herold, an expert on pulmonary infections at the University of Giessen in Germany.
The results on patients with COVID-19 are still vague. Chinese researchers, reporting more than 100 patients with chloroquine treatment, talked about its benefits in an article in BioScience, but the data it relies on have never been published. In total, chloroquine or hydroxychloroquine was used in 20 Chinese studies of COVID-19, WHO notes, but their results are difficult to find. “WHO is working with its Chinese counterparts as part of a mission in Geneva and has received guarantees of improved collaboration. However, no data were available on chloroquine studies. ”
French researchers also published a study on the treatment of hydroxychloroquine in 20 patients with COVID-19. They concluded that the drug significantly reduces the viral load in nasal swabs. But this was not a randomized controlled trial, and no deaths were reported. In a guide published on Friday, the American Society of Resuscitators said that “there is no good reason to recommend chloroquine or hydroxychloroquine in the treatment of severe patients with COVID-19.”
The same hydroxychloroquine can do more harm than good. The drug has a number of side effects and in rare cases can lead to heart failure. Since heart patients are more at risk for severe COVID-19, this can’t help but worry, says David Smith, an infectious diseases specialist at the University of California, San Diego. “It’s a warning signal, but you still need to do the test,” he says. Finally, the rush to use an anti-COVID-19 drug may complicate the treatment of patients with rheumatoid arthritis or malaria.
Ritonavir / lopinavir
This combination drug, sold under the Kaletra brand name, was approved in the United States in 2000 for the treatment of HIV infections. Abbott Laboratories has developed lopinavir specifically to suppress HIV protease, an important enzyme that breaks down the long protein chain into peptides to assemble new viruses. Since lopinavir is rapidly cleaved in the human body by our own proteases, low doses of ritonavir, another protease inhibitor that prolongs its action, are prescribed with it.
The drug also inhibits the protease of other viruses, in particular coronaviruses. He performed well on monkeys infected with the MERS virus and was tested on patients with SARS and MERS, although the results of these tests are mixed.
The first test with COVD-19, however, did not add optimism. Doctors in Wuhan, China took 199 patients and divided them into two groups. One they gave two tablets of lopinavir / ritonavir twice a day in addition to standard treatment, while the other received only standard treatment. No significant difference was found between the groups, doctors said in the New England Medical Journal on March 15. But the authors warn that the patients were in serious condition – over a fifth of them died, and therefore treatment may have begun too late. Although the drug is generally safe, it can interact with drugs that are usually prescribed for severe patients, and doctors warn that this could result in significant liver damage.
Ritonavir / Lopinavir + Interferon Beta
The last unit of Solidarity will try a combination of a combination drug with interferon beta, a molecule that controls inflammation in the body. This combination also had an effect on monkeys infected with MERS. The combination of the three drugs is currently being tested in patients with MERS in Saudi Arabia, and this is the first randomized controlled trial for this disease.
But using interferon beta in patients with severe COVID-19 is risky, Herold says. “If given at a late stage of the disease, it may instead lead to serious tissue damage,” she warns.
Thousands of patients
The format of Solidarity may change at any time. The Global Data Security Monitoring Commission will monitor the interim results and decide whether a particular drug has a clear effect, and if not, excludes it. In addition, several more drugs may be added to the study – including the influenza drug favipiravine manufactured by the Japanese company Toyama Chemical.
Enao-Restrepo says that for the reliability of the results, several thousand patients will have to be recruited. Already registered Argentina, Iran, South Africa and several other non-European countries. WHO also hopes to conduct preventive testing based on the same basic protocol to protect healthcare workers from infection, says Henao-Restrepo.
According to a press release from the French National Institute for Health and Medical Research, the European trial Discovery will include patients from France, Spain, the UK, Germany and the Benelux countries. The trial will be led by Florence Ader, an infectious diseases researcher at the University Hospital Center in Lyon.
According to Enao-Restrepo, conducting thorough clinical trials during an outbreak is problematic, but this is the best way to succeed in combating the virus: “It’s important to quickly get answers and find out what works and what doesn’t. Therefore, we believe that the best way is a random selection method.”
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The article is written and prepared by our foreign editors from different countries around the world – material edited and published by Ordo News staff in our US newsroom press.