~A drug combo already used against HIV. A malaria treatment first tested during World War II. A new antiviral whose promise against Ebola fizzled last year.~
WASHINGTON--On Friday, 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 on Friday March 20.
According to an article published by Science magazine the trail is 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 per cent 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).
Drugs that slow or kill the novel coronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), could save the lives of severely ill patients, but might also be given prophylactically to protect health care workers and others at high risk of infection. Treatments may also reduce the time patients spend in intensive care units, freeing critical hospital beds.
Scientists have suggested dozens of existing compounds for testing, but WHO is focusing on what it says are the four most promising therapies: an experimental antiviral compound called remdesivir; the malaria medications chloroquine and hydroxychloroquine; a combination of two human immunodeficiency viruses (HIV) drugs, lopinavir and ritonavir; and that same combination plus interferon-beta, an immune system messenger that can help cripple viruses.
Some data on their use in COVID-19 patients have already emerged—the HIV combo failed in a small study in China—but WHO believes a large trial with a greater variety of patients is warranted, according to the magazine.
Enrolling subjects in SOLIDARITY will be easy. When a person with a confirmed case of COVID-19 is deemed eligible, the physician can enter the patient’s data into a WHO website, including any underlying condition that could change the course of the disease, such as diabetes or HIV infection. The participant has to sign an informed consent form that is scanned and sent to WHO electronically.
After the physician states which drugs are available at his or her hospital, the website will randomize the patient to one of the drugs available or to the local standard care for COVID-19.
“After that, no more measurements or documentation are required,” said Ana Maria Henao Restrepo, a medical officer at WHO’s Department of Immunization Vaccines and Biologicals. Physicians will record the day the patient left the hospital or died, the duration of the hospital stay, and whether the patient required oxygen or ventilation, she said. That’s all.”
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 two weeks ago, Henao Restrepo said, and the agency hopes to have supporting documentation and data management centers set up next week. “We are doing this in record time,” she said.
Arthur Caplan, a bioethicist at New York University Langone Medical Center, said he likes the study’s design. “No one wants to tax the frontline caregiver who’s overwhelmed and taking risks anyway,” Caplan says.
Hospitals that aren’t overburdened might be able to record more data on disease progression, for instance by following the level of virus in the body, Caplan suggests. But for public health, the simple outcomes WHO seeks to measure are the only relevant ones for now, said virologist Christian Drosten of the Charité University Hospital in Berlin, “We don’t really know enough about this disease to be sure what it means when the viral load decreases in the throat, for instance.”
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 3,200 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 said. 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 said.
The list of drugs to test was first put together for WHO by a panel of scientists who have been assessing the evidence for candidate therapies since January, Heneo-Restrepo said. The group of selected drugs that had the highest likelihood of working, had the most safety data from previous use, and are likely to be available in supplies sufficient to treat substantial numbers of patients if the trial shows they work.
According to the magazine, 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, Henao Restrepo said.
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 said.
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 on Sunday, March 22.
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 said, 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.”