Why are There Almost No Clinical Trials for Kids With Long COVID?

• The only ongoing pediatric trial in the U.S. is testing a drug, called larazotide, aimed at tightening the gaps between cells in the gut to prevent coronavirus spike protein from leaking into circulation.
   
• Because of cost and age discrimination, companies often develop drugs in adults before testing new treatments in kids.
   
• The RECOVER initiative is ramping up to start clinical trials in kids soon, but parents and kids want to see more urgency.
   
• Involving parents and children with long COVID throughout the clinical trial process is necessary to make trials more effective.

After an initial SARS-CoV-2 infection in January 2021, Laura’s then nine-year-old son Matthew* developed symptoms that never went away — fatigue, cognitive dysfunction, rashes, joint pain, and shortness of breath. 

His school recognizes he’s at extra risk if he attends in person when there are high levels of COVID-19, flu, or other transmissible diseases. For people with long COVID, reinfections can make symptoms worse, bring on new diagnoses, and further disable them.  So far during the 2024-2025 school year, he’s attended only three and a half days. 

“There’s always pretty much just pain,” Matthew, now 12, told The Sick Times. 

Matthew is on a baseball team but has to pace himself to avoid crashing. A treatment could make it easier for him to participate. “I wouldn’t have to save up all my energy just to do one thing,” he said. 

But as of October 16, there are only two registered drug trials for long COVID in kids — one in the U.S. and one in Pakistan. Why?

One reason is little acknowledgment of long COVID in children from policymakers or media outlets, according to Megan Carmilani, founder of the advocacy group Long Covid Families. “There was a lot of rhetoric and denial about the idea that COVID could affect kids so there’s just not a lot of research that has been conducted,” Carmilani said. 

The tide started to shift earlier this year in February. The National Institutes of Health’s RECOVER program, which includes studies tracking long COVID in children, published a review paper in Pediatrics estimating 5.8 million kids in the U.S. were living with long COVID, more than the 4.9 million children living with asthma. 

“Children are in the most high risk environment [for infection],” Carmilani added. Most daycares and schools have not upgraded their air filtration or implemented measures to prevent the spread of airborne infections. “Children cannot consent to infection at all, and they’re legally required to be in some of these environments where families are reporting they’re getting sicker.” Research suggests that kids represent one in every four people with long COVID.  

Carmilani tracked how often children were mentioned during the September meeting kicking off the RECOVER-Treating Long COVID initiative, which will support new clinical trials. “And in two and a half days, I think the total was 53 minutes,” Carmilani said. 

The initiative is a direct response from the National Institutes of Health (NIH) to criticism that the research program was moving too slowly to find treatments.

Experts who spoke with The Sick Times brought up many different reasons why developing new drugs for children with long COVID has moved at such a glacial pace. Many pharmaceutical companies might not see long COVID as profitable. And running trials in children is complex and expensive, as they can have different symptoms and underlying biological processes behind those symptoms from adults.

“I want more clinical trials focused on cures and effective treatments. We want treatments that are actually getting at the underlying causes and not just sticking a band aid on symptoms,” Katherine, a parent of a 16-year old with long COVID told The Sick Times.

*Editor’s note: Children with Long COVID and their parents who spoke to The Sick Times for this story are referred to by their first names to protect their privacy. 

Understanding the only U.S. pediatric drug trial

The only current American pediatric long COVID trial for larazotide is independent of the RECOVER program. Understanding how this clinical trial got going might help explain why there aren’t many more trials for kids with the disease.  

Early in the pandemic, kids infected with SARS-CoV-2 started to develop multisystem inflammatory syndrome in children (MIS-C), a rare illness that causes persistent fever, extreme inflammation, gastrointestinal symptoms, and heart problems. MIS-C usually develops within two months of the initial infection, and up to 25% of kids diagnosed with it develop long-term symptoms that can overlap with long COVID.

When kids with MIS-C came to Massachusetts General Hospital, Dr. Lael Yonker and her colleagues drew their blood to look for clues — profiling their immune cells, analyzing the levels of different antibodies, and checking for any remnants of SARS-CoV-2. Yonker saw elevated levels of spike protein in the blood. 

She hypothesized that the virus disrupted the equilibrium in the gut, increasing the levels of a protein called zonulin that is produced by gut cells. Zonulin made the spaces between cells in the gut bigger, allowing spike proteins from SARS-CoV-2 to leak into the bloodstream. 

Yonker and her colleagues developed a clinical trial to test larazotide, a drug which blocks the effects of zonulin, to treat MIS-C. Since larazotide was previously found to be relatively safe for adults with gut diseases, the team got the green light to try it with pediatric study participants.

Later, the clinic started seeing kids with long COVID, and found that they also had high levels of spike protein in their blood. Yonker set up a 48-person trial to test whether larazotide could ease long COVID symptoms. This clinical trial is distinct from the MIS-C trial, which was terminated early due to a lack of study participants.

The study involves screening children based on their symptoms and whether spike protein is present in the blood. Then, kids receive either the drug or a placebo for 21 days. Afterward, Yonker and her team collect blood, stool, and nasal swabs. The team follows up with participants one week and one month after their final doses. Data collection is planned to wrap up in March 2025 but it may take an additional year for researchers to publish their results.

“We can’t wait [to test treatments in kids],” Yonker told The Sick Times. “We don’t want kids to have to wait years, having their lives and their school impacted [by long COVID].”

Several parents whose kids had been screened or participated in the trial spoke positively of the experience. They said Yonker understood the seriousness and urgency to find treatments for the disease.

If this trial is successful, the next step would be running a larger, multi-center trial to test the drug in more children. Yonker noted these trials are expensive — a large trial can cost around 3.87 million. However, as Chemical & Engineering News reported recently, funding for long COVID treatments is drying up. 

To pharma companies, kids aren’t profitable

Even if drug companies were developing new treatments for long COVID, there is little financial incentive to focus on developing treatments in kids first. Running pediatric trials is more complex and expensive, as special rules and constraints need to be put into place to make sure kids are safe. 

For example, clinical visits need to be scheduled to accommodate parents and guardians. It takes more time for researchers to explain and obtain informed consent in pediatric trials, and medical procedures throughout the trial are more expensive. Pediatric trials are 60% more expensive than studies run in adults. 

As a result, many drug companies often avoid or delay pediatric trials.

In 2002 the Best Pharmaceuticals for Children Act was signed into law, giving drug companies some incentives to run pediatric trials. Shortly after in 2003, the Pediatric Research Equity Act started requiring drug companies to test new treatments in kids after they’re approved in adults. 

When a disease affects both children and adults, it tends to be studied in adults first because of economics and discrimination against children, “no matter what companies say about ethics,” said A.J. Allen. Allen, the chief medical officer at the Institute for Advanced Clinical Trials for Children (I-ACT4C), worked on pediatric drugs and trials for 10 years at the pharmaceutical company Eli Lilly. 

The I-ACT4C works to speed up drug development in kids by connecting researchers to networks of pediatric trial sites and experts that help with study design. “All that said, because the adult long Covid market is much larger than the pediatric long Covid market, I would expect companies to study adults first and only study kids when they are required to,” he said.

Do we know enough to start pediatric trials for long COVID?

Observational studies play an essential role in understanding pediatric long COVID, says neuroscientist Megan Fitzgerald, who works as part of the Patient-Led Research Collaborative and the Brain Inflammation Collaborative, studying how long COVID affects children. 

Fitzgerald is a patient representative working with RECOVER’s pediatric observational study. She was involved with one recent paper, which found that long COVID can look different across age groups. Part of the challenge of studying the condition in kids, Fitzgerald explained, is that there are so many developmental changes occurring throughout childhood and adolescence that might impact the course of the disease — and thus, require different ways of measuring how drugs work.

Virologist Ann Kwong knows about the challenges of bringing new drugs to market. In the 1990s Kwong worked at companies developing an antiviral drug, telaprevir [Incivek], to treat hepatitis C virus (HCV), which did not have a cure at the time. Eventually, telaprevir and several other antivirals hit the market, successfully treating the disease. Kwong recently joined a biotech startup, Persistence Bio, as the chief science officer to develop new antiviral treatments for long COVID.

Kwong doesn’t think we need perfect endpoints before testing drugs for long COVID. “The pharma industry has worked on many, many diseases that they don’t understand,” she said. “Look at the years of Alzheimer’s trials, one failed study after another that they stopped because we don’t really understand what’s going on.”

More funding and patient input needed

There are currently no public plans from the Food & Drug Administration (FDA) to facilitate the development of new long COVID treatments for kids. A spokesperson could not disclose to The Sick Times whether they were in talks with companies about running pediatric long COVID trials.

Fitzgerald thinks that researchers should pursue trials testing treatments that have shown to be safe in adults for kids with long COVID, as well as other infection-associated chronic diseases like Myalgic Encephalomyelitis (ME) and chronic Lyme disease. 

“I think a lot of researchers want to look in this population, [but] they don’t have the funding, and it’s just not there because it’s not mandated,” said Fitzgerald. Federal legislation could enable more trials in children, she added.

While the RECOVER initiative plans to run clinical trials in kids, the initiative is still in the planning stages. The FDA and NIH are also surveying patients, including children, with long COVID to get clues about drugs that might alleviate symptoms and find candidates for clinical trials. 

Some parents told The Sick Times that they felt let down by RECOVER and other long-term COVID-19 initiatives because of how long it took to start trials.

Kwong said that some antiviral medications, such as Paxlovid, are already approved for treating children, however running a trial to see if they’d help in long COVID would be expensive. “It’s really a matter of funding.”

Researchers and drugmakers should also be consulting parents and kids about how to design and study drugs for long COVID effectively.

“There are unique needs that families have that have to be considered,” Carmilani said. Many parents have long COVID themselves or left the workforce to become full-time caregivers for their kids. Quickly compensating parents for study visits, rather than having them wait several months, and providing accommodations like at-home participation and making clinical trial sites COVID-19 safe with masking and clean air would make trials easier to navigate. Several long COVID trials for adults have failed because they weren’t designed with patients in mind.

Clinical trials and new treatments could help kids like Matthew. His mother, Laura, said that a treatment for long COVID would give him his childhood back.

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