This article was published with The Sick Times, a nonprofit newsroom covering long COVID.

Justin Lin’s daughter, Serena, developed long COVID in seventh grade. 

For more than three years, she has experienced postural orthostatic tachycardia syndrome — causing rapid heartbeat, dizziness, and cognitive dysfunction as well as post-exertional malaise (PEM). The latter causes debilitating crashes after minimal physical, cognitive, or emotional exertion, which forced her to switch to online school. With no approved pediatric treatments, Lin wonders whether Serena will be able to attend college.

As a community representative for the U.S. National Institutes of Health’s long COVID clinical trials initiative, called RECOVER-Treating long COVID (RECOVER-TLC), Lin is providing input for the largest pediatric long COVID trial to date. He hopes the trial will inspire more large-scale, well-designed studies for kids. “I think about long COVID and its impact on society,” Lin said. “Helping the kids could be one of the highest-leverage things you can do.” 

Pediatric research into long COVID is several years behind that of adults. Public health officials repeated the false claim that children could not spread the virus that causes COVID-19 early in the pandemic. Despite affecting an estimated 5.8 million U.S. kids as of 2023 — more than asthma — families face disbelief, referrals to psychological services, and even child welfare probes. 

“The first message out, and the one that gets repeated, sticks,” Megan Carmilani, founder and president of the advocacy group long Covid Families and also a representative for the RECOVER program, told The Sick Times. 

At the end of 2024, The Sick Times reported on the lack of pediatric drug trials for long COVID. The sparse trials, experts said, were a result of not understanding of the disease in children, cost, and age discrimination. Now there are at least three drug and supplement trials, one currently recruiting and two more in development. The trials are still few compared to the well over 100 for adults, many of which are active or soon to be recruiting, according to ClinicalTrials.gov. RECOVER-TLC’s testing will be the largest and best-funded long COVID trial in children so far. 

There’s still a ways to go before doctors and scientists fully understand pediatric long COVID, but the ongoing pressure from patient groups has led to new trials regardless.

Low-dose naltrexone for long COVID fatigue

RECOVER-TLC will recruit 1,300 children, teens, and young adults ages 6 to 25 for a randomized placebo-controlled trial of low-dose naltrexone (LDN) to treat a prevalent symptom of long COVID: fatigue.

Approved at 50 milligrams per day for adult opioid and alcohol use disorders, naltrexone acts as an opioid receptor blocker. It’s been used safely in much smaller doses (1 to 4.5 milligrams) off-label to treat fibromyalgia, myalgic encephalomyelitis (ME), and long COVID. Small randomized controlled trials suggest the drug may work for fibromyalgia, but the evidence for ME and long COVID is based on case reports and retrospective data looking at people who already took the drug. As a result, there’s still ambiguity over whether and how well it works. While some people report improvement, others report no difference.

LDN was one of the top choices for drugs to trial in kids because of its safety profile and anecdotal reports that it can help improve fatigue and other symptoms, said Carmilani.

Participants will be randomized to receive either a placebo or LDN for 16 weeks. The trial will require a six-month commitment as well as eight study visits, but only three will be on site, in order to make it more accessible for families. An NIH spokesperson confirmed that all of the 100 trial sites will take COVID-19 precautions, “including masking and separation of study participants and staff in rooms/areas during study visits.”

The primary outcome will assess whether the drug improves fatigue. Additionally, the study will stratify participants into three age groups to look for age-specific affects, and also measure quality of life, pain, function, and more. 

Nandini Raj, founder of the Children’s long COVID Network, a support group based in Canada, told The Sick Times the protocol is “largely rigorous, using validated pediatric patient-reported outcomes and strong safety oversight.” However, she said that it doesn’t use more objective measurements called biomarkers, or test PEM specifically.

The current study also doesn’t take into account how often children are able to attend school, an important issue for parents. These exclusions, she thinks, may “limit explanatory power, policy impact, and global generalizability.”

Outcomes reflecting school activity might better motivate families to try the treatment rather than fatigue reduction, if it succeeds in trials. An NIH spokesperson said the working group is discussing whether to incorporate these measures into the final protocol.

Researchers are also hoping to develop kid-friendly versions of the drug that could melt on the tongue, since some kids with long COVID aren’t able to easily swallow.

Larazotide to seal the gut

Kids infected with SARS-CoV-2, the virus that causes COVID-19, can also develop multisystem inflammatory syndrome in children (MIS-C). The rare condition causes persistent fever, extreme inflammation, gastrointestinal symptoms, and heart problems. Up to 25% of cases lead to long-term symptoms similar to long COVID.

Lael Yonker, a pediatrician at the University of Texas Southwestern Medical Center, found spike protein remnants in children with MIS-C. She hypothesized that the SARS-CoV-2 virus persists in the gut, boosting the levels of the protein zonulin, which widens gaps between gut cells and allows the virus’s spike protein to leak into the bloodstream, causing downstream symptoms. 

In a small clinical trial, Yonker and her former colleagues at Mass General Brigham found that larazotide, a zonulin blocker, safely treated MIS-C symptoms in kids with circulating spike protein. Now the Mass General and Boston Children’s Hospital team is recruiting for a 150-person randomized placebo-controlled trial, based in Boston, testing a 21-day course of larazotide in long COVID. Though the trial is open to anyone aged 7 to 50, Yonker is including a substantial number of kids and teens, she told The Sick Times. 

Precautions like masking and airborne filtration will be taken at the study sites. “And we accommodate any additional requests from participants,” Yonker said.

For this trial, the team dropped the spike protein requirement. The tests they had used in previous trials weren’t always available, delaying the trials, and in some individuals the spike protein levels varied over time, Yonker said. But she still thinks viral persistence is “an important component of pathogenesis,” she added. 
Outside of Yonker’s study in MIS-C, there is no published research assessing spike protein levels in pediatric long COVID and a lot of variation in this research for adult long COVID.

Though viral persistence may play a role in causing long COVID symptoms, scientists don’t know yet whether it represents a primary driver of the illness.

Yonker’s team will collect blood samples to assess the inflammatory responses. The study includes two on-site visits as well as two virtual visits, in total requiring an eight-week commitment from participants and their families. Like the LDN trial, it does not explicitly measure PEM. 

Set to finish in 2027, Yonker hopes the study will provide enough information to justify a pivotal phase 3 study that could lead to drug approval.

Taurine to counteract a possible deficiency

Meanwhile, in Canada, Calgary researchers are launching a trial of the amino acid taurine for long COVID that will include a pediatric arm. The rationale for the trial is based on a study linking lower taurine levels in the blood to worse long COVID symptoms and outcomes. Most participants in that study were over the age of 50.

The adult arm is a randomized placebo-controlled trial that will recruit 300 participants. The pediatric arm, which will include 30 participants, will be open-label, meaning everyone will receive taurine. Both trials will test if increasing participants’ taurine levels will improve fatigue levels and cognitive function after three months. Researchers are also collecting microbiome and blood samples along the way. 

The pediatric trial will be decentralized and open to participants across Canada. On-site visits will be required for blood draws at the start and end of the study. Lawrence Richer, one of the principal investigators on the trial, told The Sick Times that trial staff will inform families about the COVID-19 precautions that sites will take during the consent process at enrollment. 

The study will recruit pediatric participants regardless of their blood taurine levels at baseline, rather than selecting for those with lower levels. “It means we’re going to have a bit more of a mix of population in our study, but we’re going to characterize our population very well,” Richer said. 

Since it is open-label and small, the study won’t be able to prove efficacy. But they may see that raising the taurine levels alleviates symptoms in adults. They can then extrapolate that to the pediatric arm, and if they see children’s taurine levels increase, too, that would be a good clue that the treatment might work.

Designing kid-friendly trials

Scientists designing pediatric trials should keep families’ needs in mind.

Families need to take parking and traffic into consideration when visiting trial sites, and they’re often bringing siblings who they’re caring for, Carmilani said. Allowing for flexible scheduling on evenings and weekends and accommodating for last-minute changes in schedule due to severe symptoms and flare-ups can ensure the trial is accessible. Some recent long COVID trials for adults have even been decentralized, meaning people can participate from home.

Parents and patient advocates want to see that trial sites are taking COVID-19 precautions to avoid reinfection with the virus that put them in the trial in the first place, including high-quality masking and air filtration. 

“We are a family that has done every fucking thing we can [to avoid infection],” Cassidy Richey, a parent of a teen with long COVID, told The Sick Times. 

“Any kind of trial, anything that you would invite my family to, you have to do as much as we do.”