What Did We Learn From the Earliest COVID Trials?

It’s easy to forget how helpless clinicians around the world felt 5 years ago, when the World Health Organization declared COVID-19 a pandemic on March 11, 2020.

They were either bracing for or treating a flood of new patients coming to the hospital — and they had not a single clinical trial to guide treatment decisions.

There was, of course, no shortage of opinions on what to do, said Roy Gulick, MD, MPH, an infectious diseases physician at Weill Cornell Medicine in New York City, who was on the frontlines of the outbreak at the time.

“We turned to drugs that we already had, that seemed to have a rationale that they could perhaps help,” Gulick told MedPage Today. Those included hydroxychloroquine, ivermectin, and the HIV protease inhibitor lopinavir/ritonavir (Kaletra).

At the same time, there were “huge debates about whether we should be using corticosteroids or not,” Gulick said.

Across the pond, Martin Landray, MBChB, PhD, of the University of Oxford in England, and colleagues were working on launching the RECOVERY study, which gave the world some of the first and most important answers on how to effectively treat the sickest COVID patients.

The RECOVERY team faced resistance from all sides, Landray told MedPage Today.

“Many people said we shouldn’t use dexamethasone because it suppresses the immune system when you’re trying to fight an infection,” he said. “Some wrote to the regulators saying we shouldn’t allow the trial to happen.”

At the same time, others were writing to regulators about hydroxychloroquine, “saying this trial shouldn’t happen because everyone should have it,” Landray said.

“And it proved that there’s nothing quite like false certainty,” he said.

Five years later, clinicians know that dexamethasone is the standard of care for patients hospitalized with COVID, and that hydroxychloroquine has no role in their care.

“What really informs medicine is clinical trials,” Gulick said.

Rapidly Standing Up Trials

Four early clinical trial efforts — two in the U.K. and two in the U.S. — are regarded by infectious disease experts as the most important for delivering answers.

This includes the RECOVERY and PRINCIPLE trials in the U.K., and the ACTT and ACTIV series of trials in the U.S.

The first to launch was the ACTT-1 trial, though it didn’t have that name when it began at the University of Nebraska Medical Center in Omaha in late February 2020. Its aim was to evaluate the antiviral remdesivir (Veklury) in hospitalized COVID patients, as it had shown promise in animal models for treating other coronaviruses.

Also in late February, Landray was starting to talk with U.K. health leaders about standing up a clinical trial for hospitalized COVID patients.

Then, on a crowded bus ride in early March, Landray was comparing notes with then-head of the Wellcome Trust, Jeremy Farrar, MBBS, PhD, about information coming from colleagues in Italy, which was the first European country to face a large COVID outbreak.

“Their car parks were filling up with [ambulances], they were running out of drugs, they were taking people off ventilators,” Landray said. “Then he said to me, ‘London is going to be like this in 2 or 3 weeks.'”

“We agreed on that 10-minute bus ride that we needed a clinical trial and we had to get that trial up and running before the tsunami hit the U.K. because once it hit … processes would be established and you wouldn’t be able to disrupt them,” he said. “So the thing to do was get the randomization in early.”

Right after that bus ride, Landray started calling colleagues to help. In collaboration with Peter Horby, MBBS, PhD, also at Oxford, he wrote the protocol by March 10, and recruited the first patient on March 19.

The goal was to keep things simple in order to maximize enrollment, Landray said. “I went back to the early cardiovascular trials … from the mid-80s,” he said. “I remember the protocol from those early trials said that by far the most critical determinants of success will be the ease with which busy clinicians can enter their patients into the trial, and therefore additional workload must be absolutely minimal.”

Two additional milestones came on April 17, 2020: PRINCIPLE began enrolling patients to better understand outpatient treatment, and the NIH announced the launch of the ACTIV studies, though the latter didn’t get underway until the summer of 2020.

Stacey Adam, PhD, a vice president of science partnerships at the Foundation for the National Institutes of Health, which managed ACTIV, said the program came together with a weekend phone call in March from former NIH Director Francis Collins, MD, PhD, to the head of the foundation at the time, David Wholley.

“The advantage was years of experience working together on public-private partnerships,” Adam told MedPage Today. “They were leveraging years of earned trust and collaboration…. That allowed them to bring folks to the table for something that was going to be creatively brainstormed in the moment, because the folks coming to the table knew that they could do it.”

Earliest Answers

By late April 2020, science had its first answer for treating hospitalized COVID patients.

The ACTT-1 trial, reported in detail a month later in the New England Journal of Medicine (NEJM), showed that remdesivir shortened the time to recovery in adults hospitalized with COVID compared with placebo.

Another major finding came on June 5, 2020, when RECOVERY investigators reported that they stopped the hydroxychloroquine arm of the trial for futility — with no significant difference in the primary endpoint of 28-day mortality. “These data convincingly rule out any meaningful mortality benefit of hydroxychloroquine in patients hospitalized with COVID,” Landray and co-lead-investigator Horby said in a press statement at the time.

Just a few days before the June RECOVERY trial announcement, David Boulware, MD, MPH, of the University of Minnesota in Minneapolis, and colleagues reported in NEJM that in a multicenter, placebo-controlled trial, hydroxychloroquine didn’t work as post-exposure prophylaxis for COVID.

With the evidence stacking up against hydroxychloroquine, the FDA revoked its Emergency Use Authorization (EUA) — granted in March 2020 — for treating hospitalized patients on June 15, 2020.

Perhaps the most vaunted results of the pandemic came just a day later on June 16, 2020, when the RECOVERY investigators announced that dexamethasone reduced deaths by a third in patients on a ventilator, and by a fifth in those on supplemental oxygen. The final results were published in NEJM.

“When we announced the dexamethasone results, 3 hours later it was NHS [National Health Service] policy, and 3 weeks later it was global policy,” Landray told MedPage Today. “And it has saved hundreds of thousands of lives since.”

Findings continued to roll in. RECOVERY investigators showed that neither lopinavir/ritonavir nor the antibiotic azithromycin helped hospitalized patients recover from COVID.

On the other hand, the trial revealed positive effects for adding tocilizumab (Actemra) and, eventually, baricitinib (Olumiant), to dexamethasone for hospitalized patients.

Meanwhile, PRINCIPLE revealed several therapies that didn’t work as outpatient treatment, the first being the antibiotics azithromycin and doxycycline in January 2021.

“These drugs were being used at scale around the world and driving antibiotic resistance,” Chris Butler, MBChB, also of Oxford, told MedPage Today. “And azithromycin can have serious cardiac side effects.”

Butler noted that the findings “changed guidelines around the world,” and rapidly changed practice in the U.K. in particular. “Within days of these findings, every doctor [in the U.K.] got a clinical alert about these drugs,” he said.

PRINCIPLE also showed that ivermectin didn’t improve recovery times or prevent hospitalization and death compared with usual care — though these findings weren’t published until March 2024.

However, several other large studies had, in the interim, shown no benefits for ivermectin in the outpatient setting. This includes TOGETHER, COVID-OUT, and two different doses studied in the ACTIV-6 trial.

As for the rest of the ACTIV program, which evaluated a total of 37 different therapies, highlights included findings from ACTIV-1 about additional immunomodulators that could be added to dexamethasone. While the trial missed its primary endpoint of time to recovery, there did appear to be mortality benefits for infliximab (Remicade) and abatacept (Orencia), Adam said.

The ACTIV-4 studies also helped tease apart the best use of anticoagulation in both outpatient and hospital settings, with notable results in August 2021.

“Prophylactic anticoagulation was superior to therapeutic anticoagulation in the ICU. That was an important result,” Gulick said. “But in people who didn’t require intensive care, ACTIV showed that therapeutic was superior to prophylactic anticoagulation.”

ACTIV also provided answers on monoclonal antibodies as those treatments evolved, but Adam said — like with the RECOVERY and PRINCIPLE studies — its many negative findings were among its most important.

“We count among our successes the 25 agents that we definitively told people, ‘Please don’t take these, they’re not useful,'” Adam told MedPage Today.

Indeed, most of the 16 therapeutics evaluated in RECOVERY didn’t work in hospitalized patients.

“Negative results are less satisfactory but are as important as positive results,” Landray said. “They stop you from wasting resources and exposing patients to treatments that might cause side effects.”

James Lawler, MD, MPH, of the University of Nebraska Medical Center-Global Center for Health Security in Omaha, told MedPage Today that research “in the setting of outbreak and emergency response is often thought of as secondary, but in reality it should be one of the pillars of our response.”

“It’s the only way we can figure out how to improve the care we’re giving patients,” he said, “and figure out what works and what doesn’t.”

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