Several coronavirus clinical trials, same key questions: ‘Is it safe?’ ‘Does it work?’

Anschutz Medical Campus researchers are studying safety and efficacy of antivirals, immunosuppressants, convalescent plasma, and more.
May 6th, 2020
University of colorado hospital where coronavirus clinical trials are available and researched.
UCHealth University of Colorado Hospital (UCH) on the Anschutz Medical Campus has been fueling medical advances for more than a century. Photo by UCHealth.

The tight relationship between University of Colorado School of Medicine faculty researchers and UCHealth University of Colorado Hospital (UCH) on the Anschutz Medical Campus has been fueling medical advances for more than a century. Now these institutions are working together to bring experimental therapies to patients and, they hope, beat back the coronavirus in a matter of weeks or months.

Coronavirus clinical trials

As of this writing, four coronavirus clinical trials are already happening at UCH, with more on tap. (Clinical trials, as opposed to laboratory research, involve actual patients.) If that doesn’t sound like many, consider that Colorado’s first COVID-19 case was reported to the state on March 5 – just two months ago – and that clinical trials typically take three or more months to initiate before the first patient is enrolled.

The Anschutz Medical Campus’s $500-million-a-year research enterprise has mobilized to take on the coronavirus at an unprecedented pace. That has meant compressing the timelines of study design, regulatory considerations and approvals, and many other factors – all while ensuring patient safety and maximizing the medical knowledge reaped from a study.

“I know that the research and administrative teams have stayed very, very late into the night and addressed things in days which would normally take weeks,” said Dr. Thomas Flaig, vice chancellor of research on the Anschutz Medical Campus.

Dr. Thomas Flaig talking about coronavirus clinical trials.
Dr. Thomas Flaig

These thorough checks are necessary for many reasons. Drugs tested in a clinical trial can be new to medicine or, as is the case with the therapies being rushed to coronavirus patients, they can be existing drugs such as the antiviral remdesivir and the antimalarial hydroxychloroquine.

In either case, Flaig says, responsible medical science demands that clinical trials proceed in structured ways that produce solid data which can help answer three questions: “Is it safe?” “Does it work?” and “If it works, what’s the right dose?”

Even amid a global pandemic starved for medical breakthroughs, there’s only so much one can rush this process. You might ask why, given the enormous human and economic costs of the coronavirus, we don’t just throw bowl after bowl of proverbial spaghetti at the wall and just see what sticks?

Because we wouldn’t know what actually sticks and what doesn’t. The vast majority of clinical trials fail (86% of them, by one count), either because the drugs aren’t safe or they’re not effective. Without a clinical trial, and drugs that do no good – or, worse, outright harm – would continue to endanger patients as surely as did charms and bloodletting back before empirical medicine.

“We have to balance between going fast and still having high-quality data that’s going to answer a question for us,” Flaig said. “I see researchers balancing that very, very well in a way that we really haven’t had to do before.”

Promising antiviral

Flaig and other CU School of Medicine research leaders have established a committee to quickly review and prioritize COVID-19-related clinical-trial proposals.

“The tricky part is deciding which ones we can open and should open,” he said. “We want to make sure there’s not so many trials that we sort of trip over each other.”

Dr. Thomas Campbell talks about coronavirus clinical trials
Dr. Thomas Campbell

The group has reviewed perhaps three dozen proposals; as of this writing, four are underway, with more coming soon.

Dr. Thomas Campbell, a University of Colorado School of Medicine and UCHealth infectious-disease specialist, is leading three of these studies on the Anschutz Medical Campus. Two involve Gilead Sciences’ antiviral drug remdesivir, a drug originally developed for – and found to less effective than other medicines for – Ebola. But lab studies showed remdesivir to impede replication of the SARS-CoV-2 coronavirus, so two trials, each involving dozens of medical centers, quickly ramped up.

One considered hospitalized patients with severe cases of COVID-19; the other hospitalized patients with moderate (still very sick, but not on a ventilator) disease. Campbell says 40 UCH patients have been on one or the other of these clinical trials, and that both trials are now in what’s called the extension phase. That means the randomized arms are gone, and every patient is getting the drug. That’s because of preliminary results of another trial involving the severe patients. The study shows that the hundreds of patients at 68 sites who received remdesivir infusions and ultimately recovered did so in 11 days; those who received the placebo recovered in 15 days.

The results from the remdesivir trial involving moderately-ill patients have yet to be posted, Campbell says.

Campbell, a virologist, and his CU School of Medicine laboratory focused on clinical trials of HIV antivirals for 15 years before he pivoted the team to studying the coronavirus two months ago.

“I realized we were going to be hit with a tidal wave,” he said.

His research group was poised to ride it. Remdesivir’s mechanism – it’s a nucleotide analog that inhibits viral RNA replication and, by extension, viral replication – is similar to that of HIV antivirals. But there were marked differences, too: HIV-drug trials usually happen with outpatients who are still reasonably healthy; COVID-19 trials involve hospitalized, very sick patients.

“So it’s not like you could evaluate them on Monday and start them in the trial in the next week or two weeks later,” Campbell said. “If they’re evaluated on Monday, we try to get them treated on Monday. So it’s a much faster pace of research.”

Campbell believes remdesivir will turn out to be a good first step in developing COVID-19 treatments.

“It’s probably not the last step, and maybe it’s not going to turn out to be the best. But it’s the first, so it gives us a foothold against the virus, and it will allow us to design and build better treatments in the future,” he said.

The pace of research, he says, has been remarkable. It took four years from the discovery of the AIDS virus to the first AIDS antiviral, AZT. Remdesivir was approved within about four months of the SARS-CoV-2 coronavirus being described.

Quelling the storm

The third study Campbell is leading at UCHealth is part of a 63-center clinical trial of sarilumab, a drug developed by Regeneron Pharmaceuticals and Sanofi. Sarilumab blocks a cell receptor (IL-6) involved in the immune system’s inflammatory response to infection. Many COVID-19 deaths have been caused not by the virus alone, but by collateral damage wrought by an overzealous immune response that attacks cells in the lungs and other organs. Sarilumab shows promise in quelling this “cytokine storm” and reducing the damage of this friendly-fire assault. Roughly equal numbers of patients have been enrolled in the sarilumab and  remdesivir trials at UCHealth, Campbell says.

machine that takes Julies plasma at work
A nurse from Poudre Valley Hospital who has recovered from COVID-19 gives convalescent plasma at Garth England Blood Donation Center in Fort Collins recently. Photo: Kati Blocker, UCHealth.

The fourth clinical trial, led by Dr. David Beckham, a CU School of Medicine virologist and infectious-disease specialist, is underway at multiple sites in UCHealth. That trial is testing the effects of infusing blood plasma from someone who has recovered from the coronavirus into a current coronavirus patient. The hope is that the healed patient’s antibodies will help the patient still fighting the virus. Convalescent plasma has shown to have an effect with Ebola and MERS patients, and a small Chinese study showed promise vis-a-vis coronavirus. At least one critically ill patient who received convalescent plasma has recovered – anecdotal evidence, but good news nonetheless.

Hydroxychloroquine is also a potential COVID-19 treatment, Campbell says. Apparent success with the antimalarial drug in a small COVID-19 trial in France elevated the drug to political darling; subsequent studies have cast doubt on its effectiveness and raised alarm about possible heart issues associated with its use in coronavirus patients. However, hydroxychloroquine has shown to slow coronavirus replication in the laboratory, and given the urgent need to find working COVID-19 therapies, the drug remains a research focus.

Dr. Marc Moss, a critical-care and lung specialist, is leading the UCH arm of the 43-center ORCHID trial. The trial will monitor the drug’s antiviral potency and its effects on the heart of hospitalized coronavirus patients. Dr. Adit Ginde, emergency medicine and critical care physician, is leading the UCH arm of a multicenter trial designed to test hydroxychloroquine on patients who aren’t sick enough to be hospitalized. The ORCHID trial will start enrolling the week of May 11; Ginde’s trial will soon follow..

These efforts are among many laboratory- and observational-research efforts racing ahead on the Anschutz Medical Campus. They involve understanding the disease’s progression in the lungs (particularly with ARDS, an area of particular expertise), COVID-19’s role in triggering dangerous blood clotting, its effect on the lungs, its impact on the heart (cardiologist Dr. Michael Bristow is leading a major effort here), its role in disrupting immune-system function, and more.

Ambitious faculty physicians and their teams are at the heart of all these efforts, but the proximity UCH and Children’s Hospital Colorado to the CU School of Medicine’s research labs plays a role, too, Flaig says.

“It’s that back-and-forth, both intellectually and physically, that allows us to accelerate discoveries at an even faster rate,” he said.

 

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About the author

Since 2008, Todd Neff has written hundreds of stories for University of Colorado Hospital and UCHealth. He covered science and the environment for the Daily Camera in Boulder, Colorado, and has taught narrative nonfiction at the University of Colorado. He was a 2007-2008 Ted Scripps Fellowship recipient in Environmental Journalism at CU.

His latest book, "The Laser That’s Changing the World," tells the story of the inventors and innovators who saw, and ultimately realized, the potential of lidar to help solve problems ranging from smokestack-pollution detection, ice-sheet mapping, disaster recovery, and, ultimately, autonomous-vehicle guidance, among many other uses. His first book, "From Jars to the Stars," recounts how Ball Aerospace evolved from an Indiana jar company - and a group of students in a University of Colorado basement - to an organization that managed to blast a sizable crater in the comet 9P/Tempel 1. "Jars" won the Colorado Book Award for History in 2012.

Todd graduated with a business degree from the University of Michigan, where he played soccer, and with a master’s degree from the Fletcher School of Law and Diplomacy at Tufts University. Before becoming a journalist at the turn of the millennium, he was an IT and strategy consultant. He once spoke fluent Japanese and still speaks fluent German.

When not writing, he spends time with teenage daughters and wife Carol, plays soccer, and allows himself to be bullied by a puggle he outweighs by a factor of seven.