The US National Institutes of Health (NIH) announced yesterday that it will launch its first trials to test the safety and efficacy of treatments against long COVID. These trials will focus on therapies aimed at some of the most debilitating symptoms of the disease, including brain fog and disturbed sleep.

The announcement comes after two years of criticism from researchers and people with long COVID about the direction and productivity of the NIH’s nearly-US$1.2-billion RECOVER initiative. They say that the agency has moved too slowly to enrol people in studies and start testing potential treatments for the condition, which affects an estimated 65 million people around the world.

Responding to this criticism, Kanecia Zimmerman, a clinician at Duke University School of Medicine in Durham, North Carolina, who is helping to coordinate the RECOVER studies, said at a press briefing yesterday that there are many steps to launching a clinical trial, including drafting study protocols, consulting with specialists and people with the disease and getting approval from authorities.

Researchers who spoke to Nature say that launching treatment trials is a crucial step, but that it will take tangible progress in these trials to assure those affected that US health officials are taking their concerns seriously. “The fact there were no trials until this point has been highly discouraging,” says Eric Topol, executive vice-president at Scripps Research in La Jolla, California. “The community of people suffering are desperate and want to see the investment by NIH bear fruit.”

A constellation of symptoms

According to its announcement, the NIH has already launched one phase II trial and will launch another three in the coming months. These will test whether various treatments can reduce the amount of time that the SARS-CoV-2 coronavirus lingers in the body, relieve cognitive symptoms such as brain fog and memory loss, improve sleep quality and wakefulness, and reorient the autonomic nervous system, which regulates bodily functions such as heartbeat. In the trials, 100 to 300 people will receive each of the potential treatments.

The stakes are high: this is the world’s largest comprehensive study of long COVID, Walter Koroshetz, director of the National Institute of Neurological Disorders and Stroke, which is part of the NIH, said at the press briefing. Smaller trials have been launched around the world, but few are studying multiple treatments for the constellation of symptoms that define long COVID.

The first of the RECOVER treatment trials, which is already enrolling participants will evaluate Paxlovid, an antiviral made by New York City-based pharmaceticals firm Pfizer. A five-day regimen of Paxlovid pills is typically prescribed to people with acute COVID-19. Some research has found, though, that the virus can continue to cause symptoms and persist in the body for months after treatment¹. So the RECOVER trial aims to learn whether a longer, 15- or 25-day regimen can alleviate long-COVID symptoms.

The trial investigating brain fog, set to launch within weeks, will test two online training programmes and a home-based brain-stimulation device. “I’m encouraged by the comprehensiveness of the approach”, says Jim Jackson, a neuropsychologist at Vanderbilt University Medical Center in Nashville, Tennessee. If the therapies are proven safe and effective, they could be easily scaled and done at home, which would be a boon for accessibility, he adds.

Two more trials will launch within months, Zimmerman said. The one on sleep will evaluate the effects of wakefulness-promoting drugs solriamfetol and modafinil, as well as those of light therapy, supplementation with the sleep-inducing hormone melatonin and coaching on how to get good sleep. The trial aimed at the autonomic nervous system will test ivabradine, used to treat chronic heart failure, and an immune-boosting intravenous antibody therapy.

Officials have delayed a fifth trial focused on the fatigue that people with long COVID experience after exercise. The protocols for that trial have come under fierce scrutiny from those worried that putting some participants through exercise trials could cause harm. Zimmerman said that the NIH is “actively engaging” people with long COVID and specialists to determine how to move forward with this trial.

Slow going

It is great that the NIH has now launched some of these trials, says Ezekiel Emanuel, a bioethicist and oncologist at the University of Pennsylvania in Philadelphia, but he is watching whether they will meet their target enrolment. So far, the agency has recruited only 24,000 participants — well below its goal of 40,000 by the end of last year, he says. Topol says this might be because the agency has largely relied on conventional, rather than digital, protocols that require people with long COVID to join trials in person — a difficult proposition, given the debilitating nature of the condition.

Anna Nordvig, a cognitive neurologist at Weill Cornell Medicine in New York City, says she is grateful that the US government is following through on its commitment. “Although we all wished and hoped this would come faster, it’s important for this to be a highly coordinated approach,” she says.

When announcing the launch of the trials, officials also said that the US government is officially creating the Office of Long COVID Research and Practice, which will coordinate research efforts. The office, proposed a year ago, will be housed within the Department of Health and Human Services. To begin with, it will have only two full-time employees owing to limited funding, Michael Iademarco, deputy assistant secretary for science and medicine at the Office of the Assistant Secretary of Health, said at the briefing.

Funding for long COVID research could be hard to come by in future, too. The phase II RECOVER trials will be funded to completion, but the status of financing for future trials remains unknown, said Lawrence Tabak, acting NIH director, at the briefing. Since US President Joe Biden’s administration declared the end of the COVID-19 emergency in May, Congress has demonstrated little appetite for investing further in COVID-19.

The end of the pandemic emergency has led to “tremendous frustration” among people with long COVID and a feeling that they have been “completely abandoned”, Jackson says. But he adds that these trials have the potential to turn the tide: “There is no doubt this is what patients have been clamouring for.”