On Friday March 20, 2020, the World Health Organization (WHO) announced a large global trial, called SOLIDARITY, to find out whether any can treat infections with the new coronavirus for the dangerous respiratory disease. It’s an unprecedented effort—an all-out, coordinated push to collect robust scientific data rapidly during a pandemic. The study, which could include many thousands of patients in dozens of countries, has been designed to be as simple as possible so that even hospitals overwhelmed by an onslaught of COVID-19 patients can participate.
With about 15% of COVID-19 patients suffering from severe disease and hospitals being overwhelmed, treatments are desperately needed. So rather than coming up with compounds from scratch that may take years to develop and test, researchers and public health agencies are looking to repurpose drugs already approved for other diseases and known to be largely safe. They’re also looking at unapproved drugs that have performed well in animal studies with the other two deadly coronaviruses, which cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).
Study Details and Add-Ons
The design is not double-blind, the gold standard in medical research, so there could be placebo effects from patients knowing they received a candidate drug. But WHO says it had to balance scientific rigor against speed. The idea for SOLIDARITY came up less than 2 weeks ago, says Henao-Restrepo, and the agency hopes to have supporting documentation and data management centers set up next week. “We are doing this in record time,” she says.
On Sunday, INSERM, the French biomedical research agency, announced it will coordinate an add-on trial in Europe, named Discovery, that will follow WHO’s example and will include 3200 patients from at least seven countries, including 800 from France. That trial will test the same drugs, with the exception of chloroquine. Other countries or groups of hospitals could organize add-on studies as well, Heneo-Restrepo says. They are free to do additional measurements or observations, for instance on virology, blood gases, chemistry, and lung imaging. “While well-organized additional research studies of the natural history of the disease or of the effects of the trial treatments could well be valuable, they are not core requirements,” she says.
Treatments that SOLIDARITY will test:
Remdesivir: The new coronavirus is giving this compound a second chance to shine. Originally developed by Gilead to combat Ebola and related viruses, remdesivir shuts down viral replication by inhibiting a key viral enzyme, the RNA-dependent RNA polymerase. TrialSite News recently covered a story of a CA woman whose condition was improved with Remdesivir.
Chloroquine and hydroxychloroquine: The WHO scientific panel designing SOLIDARITY had originally decided to leave the duo out of the trial, but had a change of heart at a meeting in Geneva on 13 March, because the drugs “received significant attention” in many countries, according to the report of a WHO working group that looked into the drugs’ potential. The widespread interested prompted “the need to examine emerging evidence to inform a decision on its potential role.”
Ritonavir/lopinavir: This combination drug, sold under the brand name Kaletra, was approved in the US in 2000 to treat HIV infections. Abbott Laboratories developed lopinavir specifically to inhibit the protease of HIV, an important enzyme that cleaves a long protein chain into peptides during the assembly of new viruses. Because lopinavir is quickly broken down in the human body by our own proteases, it is given with low levels of ritonavir, another protease inhibitor, that lets lopinavir persist longer. The combination can inhibit the protease of other viruses as well, specifically coronaviruses. It has shown efficacy in marmosets infected with the MERS virus, and has also been tested in SARS and MERS patients, though results from those trials are ambiguous.
Thousands of patients
The design of the SOLIDARITY trial can change at any time. A global data safety monitoring board will look at interim results at regular intervals and decide whether any member of the quartet has a clear effect, or whether one can be dropped because it clearly does not. Several other drugs, including the influenza drug favipiravir, produced by Japan’s Toyama Chemical, may be added to the trial.
To get robust results from the study, several thousands of patients will likely have to be recruited, says Henao-Restrepo. Argentina, Iran, South Africa, and several other non-European countries have already signed up. WHO is also hoping to do a prevention trial to test drugs that might protect health care workers from infection, using the same basic protocol, Henao-Restrepo says.
The trial’s European counterpart, Discovery, will recruit patients from France, Spain, the United Kingdom, Germany, and the Benelux countries, according to an INSERM press release today. The trial will be led Florence Ader, an infectious diseases researcher at the University Hospital Center in Lyon.
Doing rigorous clinical research during an outbreak is always a challenge, Henao-Restrepo says, but it’s the best way to make headway against the virus: “It will be important to get answers quickly, to try to find out what works and what doesn’t work. We think that randomized evidence is the best way to do that.”
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