Long COVID Clinical Trials May Offer Shortcut to New Treatments

Long COVID Clinical Trials May Offer Shortcut to New Treatments

Editor’s note: Find the latest long COVID news and guidance in Medscape’s Long COVID Resource Center.

With no proven treatments for long COVID, millions of Americans struggling with debilitating symptoms may be wondering whether it’s worth it to try something they’ve never considered before: a clinical trial. 

Dozens of clinical trials nationwide are already underway or starting soon, many of which are aided by $1.5 billion in funding from the National Institutes of Health to help identify new treatments for common symptoms like brain fog, fatigue, sleep disturbances, and a hard time breathing. But it may take years for these trials to prove which drugs, devices, and behavioral therapies are safe and effective. 

“We’re not in warp speed,” says Kanecia Zimmerman, MD, a principal investigator at the Duke Clinical Research Institute who is overseeing long COVID trials for the NIH. Operation Warp Speed — the 2020-2021  federal effort to get COVID vaccines designed, tested, authorized and distributed — benefited from existing scientific knowledge about other coronaviruses and about vaccines in general. But there’s no similar foundation of scientific knowledge about long COVID. 

“We are in a place of not really knowing anything,” Zimmerman says.

But some glimmers of hope are emerging. A Veterans Affairs study recently found the antiviral Paxlovid might help prevent long COVID. A small case study at Yale found the ADHD drug guanfacine may ease brain fog from long COVID. And preliminary results from an NIH-funded study suggest COVID vaccines might help children with a rare but serious inflammatory condition known as multisystem inflammatory syndrome (MIS-C). 

More results are expected very soon from the trial for kids with MIS-C, which can strike suddenly long after a COVID infection clears up. While the exact causes aren’t yet clear, MIS-C can cause dangerous inflammation in the heart, lungs, kidneys, brain, skin, eyes, or gastrointestinal system. 

Because the virus often triggered a delayed response of MIS-C in kids who had few if any symptoms of acute COVID-19, scientists wondered whether children infected with the virus might respond to a vaccine dose to prevent MIS-C from developing, Gary Gibbons, MD, director of the National Heart, Lung, and Blood Institute, said during a Dec. 9 presentation at the NIH.It’s not yet clear if vaccination helps, but it doesn’t harm the children, Gibbons said. 

“Indeed, the studies suggest with some relief that yes, these children could be vaccinated safely,” he said. 

Several new trials are also testing Paxlovid against long COVID, including one late-stage study that may have results in about a year. 

“We already know that Paxlovid reduces the risk of developing long COVID, but it would be a game changer if it can improve long COVID symptoms as well,” says Surendra Barshikar, MD, an associate professor and medical director of the COVID Recover program at the University of Texas Southwestern Medical Center in Dallas. 

In other studies, researchers are looking at a wide variety of previously approved and experimental drugs and devices. For example, scientists in New York are testing the mood stabilizer lithium to treat brain fog and fatigue. And researchers in Illinois are investigating efgartigimod, a drug approved for the rare muscle-weakening autoimmune disorder myasthenia gravis, to see if it helps ease a long COVID complication known as POTS that can cause a sudden rapid heart rate and chronic fatigue. 

“The good news is that enrollment will proceed quickly, given the vast number of patients,” says Kristin Englund, MD, director of the reCOVer Center of Excellence at the Cleveland Clinic in Ohio. 

This is all encouraging because roughly 1 in 5 American adults who have acute COVID infections develop persistent symptoms of long COVID, also known aspost-acute sequelae of SARS-CoV-2 (PASC). And many of these long COVID patients have complex, overlapping clusters of symptoms that make traditional treatment approaches largely ineffective against this new, formidable disease. 

But not every patient living with long COVID will qualify for trials or find it easy to take part even if they do. To decide if a trial makes sense, the best place to start is with the same person any patient should see for a diagnosis and treatment plan for suspected long COVID: a primary care provider. 

“Clinical trials are at the heart of medical advances, and they give us new ways to prevent, detect, and treat diseases,” says Tochi Iroku-Malize, MD, president of the American Academy of Family Physicians and chair and professor of family medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in Hempstead, NY. 

“However, they are just that — trials — and they come with risks and potential benefits,” Iroku-Malize notes. “It’s important to consult with your primary care physician, who knows your medical history, and to carefully weigh the pros and cons.”

Patients should consider how severe their symptoms are, the potential risks of any experimental treatments, and the many challenges they may have with getting to and from clinical trial sites that are largely concentrated around major cities and might be far from home. 

While this holds true for any type of trial, it’s essential for long COVID patients, who may have fatigue, muscle weakness, and other symptoms that make distance an impossible factor to ignore, says Aaron Friedberg, MD, clinical co-lead of the Post-COVID-19 Recovery Program at the Ohio State University Wexner Medical Center in Columbus. 

“I think it is a personal decision, since the fatigue and pain that patients with PASC can experience can make it very challenging to travel long distances,” Friedberg says. “I would recommend calling or messaging ahead to find out exactly what type of travel might be required because there may be steps that can be completed by email or video, which could make it easier to participate, and some trials may be entirely remote.”

Even when patients feel up to the travel, they still might not be a good fit for a clinical trial. Scientists often look for people who didn’t have pre-existing health problems before they got long COVID, Barshikar notes. Patients taking medications may also be unable to participate in drug trials, particularly for experimental treatments because of concerns about unknown side effects from drug interactions. 

When clinical trials do seem like a good option, patients may want to consider seeking treatment at an academic medical center that is already doing long COVID research, particularly if their symptoms are too complex or severe to manage only through their primary care provider, says Jonathan Whiteson, MD, who helped draft long COVID treatment guidelines for the American Academy of Physical Medicine and Rehabilitation. He also serves as co-director of the New York University Langone Health Post COVID Care Program.

Before joining a trial, patients should be reasonably sure they can stick with the study over several months or years, because it’s hard for researchers to get meaningful data if too many people drop out, Whiteson says. People also need to understand there’s a good chance, in any trial testing new treatments, that they might get a placebo pill or receive an intervention that doesn’t ultimately make them feel better. 

People also won’t know until trials are over whether they got a placebo treatment or a new therapy, Whiteson says. And, even if the experimental treatment works in the trial, they might not be able to get it right after the trial ends because it could still take many months, or even years, to win U.S. regulatory approval. 

“So long COVID clinical trial participants may not directly benefit from the trial they volunteer for, certainly in the short term,” Whiteson says. “Volunteering for a clinical trial is to some degree altruistic, helping science develop, clinicians learn and develop new treatments, and eliminate ineffective interventions.”

Still, many health care professionals on the front lines treating long COVID patients are optimistic that the sheer number of trials and the vast number of patients taking part should ultimately produce some better treatment options than people have right now. It’s just not going to happen overnight. 

“I suspect that while we will see some new treatments coming in the next 1 to 2 years, it may be several years before targets can be identified and full trials conducted to see results,” Friedberg says. “Getting good data takes time.”


U.S. National Library of Medicine: “Long COVID.”

National Institutes of Health: “NIH Launches New Initiative To Study Long COVID.”

Kanecia Zimmerman, MD, principal investigator, Duke Clinical Research Institute.

MedRxiv: “Nirmatrelvir and the Risk of Post-Acute Sequelae of COVID-19.”

Neuroimmunology Reports: “Clinical Experience with the α2A-Adrenoceptor Agonist, Guanfacine, and N-acetylcysteine for the Treatment of Cognitive Deficits in Long-COVID19.”

National Institutes of Health: “Advisory Committee to the Director – December 2022 (Day 2)”

COVID MUSIC Study: “The COVID MUSIC Study: Long-Term Outcomes After MIS-C.”

CDC: “For Parents: MIS-C Associated With COVID-19.”

Clinicaltrials.gov: “SARS CoV-2 Viral Persistence Study (PASC) – Study of Long COVID-19 (PASC).”

Surendra Barshikar, MD, medical director, COVID Recover program, University of Texas Southwestern Medical Center.

Clinicaltrials.gov: “Effect of Lithium Therapy on Long COVID Symptoms.”

Johns Hopkins Medicine: “COVID-19 and POTS: Is There a Link?”

Kristin Englund, MD, director, reCOVer Center of Excellence, Cleveland Clinic.

CDC: “Nearly One in Five American Adults Who Have Had COVID-19 Still Have ‘Long COVID.'”

Tochi Iroku-Malize, MD, chair, family medicine, Donald and Barbara Zucker School of Medicine, Hofstra/Northwell.

Aaron Friedberg, MD, clinical co-lead, Post-COVID-19 Recovery Program, Ohio State University Wexner Medical Center.

Jonathan Whiteson, MD, co-director, New York University Langone Health Post COVID Care Program.

American Academy of Physical Medicine and Rehabilitation: “AAPM&R Long COVID Consensus Guidance Statements Published  on Diagnosing and Treating Long COVID Symptoms of Breathing Discomfort and Cognitive Symptoms.”

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