The trials will investigate potential treatments for long COVID-related sleep disturbances, exercise intolerance, and post-exertional malaise.

RT’s Three Key Takeaways:

  1. The NIH’s RECOVER Initiative is launching mid-stage clinical trials to investigate potential treatments for long COVID symptoms, including sleep disturbances, exercise intolerance, and post-exertional malaise, enrolling 1,660 participants across 50 sites.
  2. The RECOVER-SLEEP trials will test melatonin, light therapy, and two FDA-approved drugs (modafinil and solriamfetol) to treat long COVID-related sleep disturbances like hypersomnia and complex sleep disturbances.
  3. The RECOVER-ENERGIZE trials will explore personalized cardiopulmonary rehabilitation and structured pacing programs to alleviate exercise intolerance and post-exertional malaise in long COVID patients.

The National Institutes of Health (NIH) will launch clinical trials to investigate potential treatments for long-term symptoms after COVID-19 infection, including sleep disturbances, exercise intolerance, and the worsening of symptoms following physical or mental exertion known as post-exertional malaise. 

The mid-stage trials, part of NIH’s Researching COVID to Enhance Recovery (RECOVER) Initiative, will join six other RECOVER studies currently enrolling participants across the United States testing treatments to address viral persistence, neurological symptoms, including cognitive dysfunction (like brain fog) and autonomic nervous system dysfunction. 

The new trials will enroll approximately 1,660 people across 50 study sites to investigate potential treatments for some of the most frequent and burdensome symptoms reported by people experiencing long COVID.

“The group of symptoms these trials will try to alleviate are truly disruptive and devastating for so many people struggling with long COVID,” says Walter J. Koroshetz, MD, director of NIH’s National Institute of Neurological Disorders and Stroke, and co-lead of the RECOVER Initiative, in a release. “When people can’t get reliable sleep, can’t exert themselves, and feel sick following tasks that used to be simple, the physical and mental anguish can lead to feelings of utter helplessness. We urgently need to come up with answers to help those struggling with long COVID feel whole again.”

Sleep Trials

RECOVER-SLEEP clinical trials will soon begin enrolling participants and include:

  • A trial to test two drugs (modafinil and solriamfetol) approved by the Food and Drug Administration to treat people with hypersomnia. These medications are well-known but have not been studied widely in people with long COVID. Participants will be randomly assigned to receive either the active study drug or a placebo control for eight to 10 weeks, depending on the assigned study drug.
  • A trial to test potential treatments for complex sleep disturbances due to long COVID, including melatonin, an over-the-counter supplement commonly used to treat people with sleep disorders and general insomnia; and light therapy, which is used to help people reset their sleep cycles. Participants will be randomly assigned to receive either melatonin or a placebo control, and either high-intensity (active) light therapy or low-intensity (placebo) light therapy for eight weeks. 

Energize Trials

RECOVER-ENERGIZE clinical trials will soon begin enrolling participants and include:

  • A trial to test a program that combines exercise training, strength and flexibility training,  education, and social support, collectively known as personalized cardiopulmonary rehabilitation. The program is designed to help people who experience exercise intolerance with symptoms such as shortness of breath and fatigue during exercise after having COVID-19.  All participants in RECOVER-ENERGIZE trials will be screened for post-exertional malaise. Participants who are identified as having post-exertional malaise, via a validated post-exertional malaise questionnaire, will not be included in this trial. Participants will be randomly assigned to receive either personalized cardiopulmonary rehabilitation or basic exercise education for three months.
  • A trial to test a program known as structured pacing, which is designed to help participants with post-exertional malaise identify, control, and minimize symptoms that developed after having COVID-19 by regulating or pacing their daily activities. Currently, structured pacing is the only intervention used to treat post-exertional malaise. The trial will not include any exercise training or physical movement to protect participants from developing worsened symptoms of post-exertional malaise. Participants will be randomly assigned to receive either structured pacing with a trained coach or basic post-exertional malaise education for three months.

Community-Driven Trials

All four trials were developed using comprehensive feedback from the community and in close partnership with patient representatives, whose insights were especially important for the post-exertional malaise trial. The post-exertional malaise trial was developed to address concerns expressed by patient advocacy groups about patient safety and to better understand how this study program may help improve post-exertional malaise symptoms.

“Structured pacing is currently the only intervention used to prevent post-exertional malaise, so we hope to test its effectiveness and determine how to best guide patients regarding activity management,” says Lucinda Bateman, MD, an expert in post-exertional malaise and founder of the Bateman Horne Center, in a release.

Representation Across Study Sites

Diversity among trial participants is a high priority for the RECOVER Initiative, according to a release from the NIH. To support diverse and inclusive representation, study sites are chosen based on geographic location, their connection to communities, and track record for enrolling diverse research participants. Teams at the selected study sites will recruit participants from their health systems and surrounding communities.

Sites currently activated for each trial can be found on ClinicalTrials.gov (RECOVER-SLEEP NCT06404086, NCT06404099, NCT06404112 and RECOVER-ENERGIZE NCT06404047, NCT06404060, NCT06404073). New sites will be added to clinicaltrials.gov as they begin enrolling participants.

With the launch of these four studies, RECOVER is currently testing 13 treatments across eight clinical trials and continues to enroll participants.