Advocates ask the US biomedical agency to rethink the design of its RECOVER initiative, citing possible harm and funding waste.
Patients and patient advocates are calling on the US National Institutes of Health (NIH) to reconsider its decision to include exercise trials in its RECOVER initiative, which aims to study and find treatments for long COVID. They argue that a large proportion of people with long COVID have reported experiencing post-exertional malaise (PEM) — a worsening of symptoms such as fatigue, difficulty regulating body temperature and cognitive dysfunction, after even light exercise — and worry that putting certain RECOVER participants through exercise trials could cause them harm. In a petition and multiple letters, the advocates request that the NIH and affiliated physicians explain their rationale for this testing and share the trial protocols.
“In a world where there’s hundreds of things to trial, why are we choosing this one thing that we know has the potential to cause harm to a substantial portion of patients?” asks Lisa McCorkell, a co-founder of the Patient-Led Research Collaborative for long COVID, a research and advocacy group based in Washington DC.
The RECOVER Clinical Trials Data Coordinating Center at the Duke Clinical Research Institute in Durham, North Carolina, sent Nature a statement on behalf of the NIH saying that the trials being planned for RECOVER — which stands for Researching COVID to Enhance Recovery — have not yet launched and that the agency is working with patient representatives in shaping the exercise trial protocol. The statement also says that the study’s investigators are meeting with those representatives to discuss the concerns expressed in the letters and petition. The NIH did not make the representatives available to Nature for an interview by the time this story was published and said that the full protocols for the trial would be released publicly only after they have been reviewed by an institutional review board.
Hitting a wall
Long COVID isn’t the first disease for which people have reported experiencing PEM. People who have myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS), have long reported exacerbation of symptoms after overexertion that make their day-to-day functioning difficult. Similar to long COVID, ME/CFS often develops after a viral illness; its symptoms include PEM, cognitive impairment and joint and muscle pain.
Although it seems counter-intuitive that exercise — normally considered an ingredient of good health — can cause harm, researchers have confirmed some of the physical effects of PEM through controlled studies. Scientists have measured people’s heart rate and oxygen intake during 2 maximal-exertion exercise tests spaced 24 hours apart. They found that those with PEM perform noticeably worse on the second day1. Meanwhile, for those without PEM — a group that included athletes, sedentary people and people with conditions such as heart failure and cystic fibrosis — results were similar, if not identical, on both days. Studies have also shown unusual patterns in gene expression2, metabolism3 and cognitive functioning4 after exertion for those with PEM.
As researchers find out more about long COVID, it has become clear that many people with the condition meet the criteria for ME/CFS. In a study published online late last year5, researchers reported that of the 465 people with long COVID surveyed, 58% could be categorized as having ME/CFS.
And in a 2021 study, researchers at the Patient-Led Research Collaborative, including McCorkell, surveyed 3,762 people with long COVID and found that, over a 7-month period, one of the most frequent symptoms reported was PEM6. Around 89% of participants reported experiencing PEM at some point during the course of their illness, with 72% of them still reporting it at month 7.
All of this has advocates concerned about the inclusion of exercise trials in the RECOVER initiative. According to the NIH, RECOVER is the most expansive long-COVID study yet, with the trials expected to last four years, and to enrol more than 15,000 adults and 6,000 children.
The statement from the NIH to Nature said that the exercise trial would use “inclusion and exclusion criteria to make sure that people who could be harmed by exercise will not be included in that platform trial”. But patient advocates still worry that the trials are a waste of time and money.