Canadian Hospitals to Start Enrolling Patients in Global COVID-19 Drug Trials

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Within the next week, more than a dozen Canadian hospitals will start enrolling patients as part of an unprecedented global collaboration to test four potential treatments for COVID-19, the disease caused by the pandemic coronavirus that currently has no vaccine or cure.

Dubbed SOLIDARITY, the multinational trial is being coordinated by the World Health Organization and aims to enroll thousands of patients from around the world. In the absence of a vaccine — something that is at least a year or more away — the goal is to quickly identify treatments that could mitigate the toll of COVID-19, which has already killed more than 20,000 people worldwide.

If successful, doctors will finally have some evidence-based research for deciding which drugs to use, or exclude, when treating patients with severe cases of COVID-19 — and the world will have a new playbook for conducting urgent clinical research in the middle of an international health emergency.

“This is a global, co-ordinated megatrial,” said Dr. Srinivas Murthy, an infectious disease and critical care specialist and associate professor with the University of British Columbia, who sits on the global steering committee for SOLIDARITY.

“With just a handful of patients, you can’t really prove anything ever. So we need lots and lots of patients from around the world to prove if (any of these drugs) are useful.

“This is completely unprecedented and if this gets pulled off, this is a new model for global collaboration.”

The Canadian arm of the global trial, dubbed CATCO (Canadian Treatments for COVID-19), is being funded by the Canadian Institutes of Health Research, which provided nearly $1 million as a part of the federal government’s $275-million commitment towards supporting medical research for COVID-19.

Murthy said at least 15 Canadian sites have signed on so far, including Sunnybrook Health Sciences Centre, the Canadian sponsor of the trial, and three other GTA hospitals.

Other participating countries include Argentina, Bahrain, France, Iran, Norway, South Africa, Switzerland, Thailand, and Spain. Three countries that are notably absent from the collaboration, however, are China, Italy and the United States — the nation's hardest hit by COVID-19 so far, collectively reporting more than 245,000 cases.

The decision over which drugs to include was the source of heated debate, according to Murthy, who has been consulting the WHO on COVID-19 since January. Eventually, the steering committee settled on four drug treatments that are already licensed for other diseases but show preliminary potential for treating COVID-19.

None of these are expected to be a “miracle cure,” Murthy cautioned, but may prove beneficial towards improving outcomes for certain patientsor allow doctors to rule out drugs that clearly don’t work.

In selecting these drugs, experts considered not only what was available and effective, but what could be quickly scaled up to reach populations around the world, Murthy said. Typically, the exercise of setting a research agenda is something that can take years; for SOLIDARITY, it all came together within weeks.

“The fact that we expedited it so quickly is probably a good thing,” he said. “But at the same time, when you expedite things, things can sometimes get lost, overlooked, or over-addressed. So did we make the right decisions? It’s unclear. But I think time will tell.”

The foundational work that allowed SOLIDARITY to assemble so rapidly was laid in the aftermath of the 2014 Ebola outbreak in West Africa, when the WHO came under fierce criticism for its slow and ineffective response. From that stemmed the creation of the WHO’s “R&D Blueprint,” a global strategy for ensuring that the world would be better prepared for future outbreaks.

The Blueprint created a plan for fast-tracking drugs and vaccines for a serious and sudden outbreak. It also identified a list of priority pathogens, including Ebola, SARS, MERS and “Disease X” — a placeholder name for a yet-unknown pathogen that experts knew would eventually emerge and explode into a pandemic. In other words, something like COVID-19.

In the absence of any treatments, desperate clinicians have started trying unproven drugs for COVID-19 and publishing small studies — reports that are often compelling but lack statistical significance and need to be replicated in much bigger studies before conclusions can be drawn.

Currently, more than 500 clinical trials are already registered with the WHO. This is impressive “but also concerning,” Murthy wrote in an editorial published Thursday with the Canadian Medical Association Journal.

“There’s been hundreds of small and likely not useful clinical trials testing a random number of different agents,” he told the Star. “When in fact what we need to do is coordinate all of these efforts at a global scale — and actually learn things that are useful.”

Small COVID-19 studies are already being harnessed in ways that are counterproductive or even harmful, Murthy said. For example, after French doctors published a tiny study about treating COVID-19 patients with a malarial drug called hydroxychloroquine and azithromycin, an antibiotic, the report caught the eye of U.S. President Donald Trump, who tweeted that it was a “game-changer” — even though scientists have criticized the study’s serious methodological deficiencies.

Nevertheless, the study has already had harmful ripple effects. Within days of its publication, there were reports of panic buying, drug shortages and even deaths after people tried self-medicating with chloroquine, a drug that is similar to hydroxychloroquine but more toxic.

These small studies “can be very influential when people feel like they are facing a condition like COVID … people are willing to latch onto data that is really very uncertain,” said Dr. Robert Fowler, a critical care physician at Sunnybrook who is heading his hospital’s involvement with SOLIDARITY.

“There’s a sense of urgency to be able to quickly evaluate what will or won’t work and the only way to do that with confidence and precision is to co-operate over (large) jurisdictions so you can gain information from many, many patients.”

Fowler expects to start enrolling COVID-19 patients by early next week and explains that those who consent to participate will be randomly selected for one of the drug treatments or randomized into a control group that receives the current standard of care — in the case of COVID-19, supportive treatment like ventilation.

Data about patients — for example, length of stay, outcome, any underlying health conditions — will then be collected and fed to the WHO in Geneva, where it will be consolidated with other international data and eventually interpreted.

Fowler said the study design is unique in that new drugs can always be added if promising new treatments come forward. As for how long it will take for SOLIDARITY to yield actionable data? That will depend on how effective the medicines are — if they are even effective at all — and the number of patients ultimately enrolled.

“Conceivably, if many, many, many countries are participating very quickly, over two to four months we might be able to get our first signals.”

The wait for a potential vaccine, however, will be much longer, even though there are already at least 44 vaccines in early-stage development, according to an editorial published in the journal Science on Thursday.

Experts caution that vaccines are much slower to create, test and roll out than drug treatments — for very good reasons.

“The distinction between therapeutics and vaccines is vitally important,” said Ross Upshur, head of clinical public health at the University of Toronto’s Dalla Lana School of Public Health.

“You give medications to people who are sick, and the first trials are in people who are very sick indeed. You give vaccines to people who are healthy” — a difference that significantly alters the risk-benefit analysis, Upshur says.

Upshur noted that in 1976, a vaccine was urgently rolled out in the U.S. amid concerns about an epidemic of swine flu, one that never materialized. The vaccine caused Guillain-Barré Syndrome in about one in 100,000 people, a rare disorder that causes nerve damage and sometimes paralysis. The debacle set back trust in vaccines for decades.

Unlike a COVID-19 drug treatment, which would be given to thousands of very sick patients in intensive care, a vaccine would be given to hundreds of millions or billions of healthy people worldwide, Upshur added. So in addition to being safe, any potential vaccine also has to be effective — worth a massive, worldwide rollout — and global supply chains must be able to manufacture huge amounts.

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