The National Institutes of Health (NIH) has launched a series of clinical trials aimed at investigating potential treatments for some of the most debilitating symptoms of long COVID, including sleep disturbances, exercise intolerance, post-exertional malaise (PEM), and autonomic nervous system dysfunction.
These mid-stage trials are part of NIH's Researching COVID to Enhance Recovery (RECOVER) Initiative and will join six other RECOVER studies currently enrolling participants across the United States. The trials represent a significant step forward in addressing the long-term health consequences of COVID-19 infection that continue to affect millions of Americans.
Sleep and Energy Trials Target Core Long COVID Symptoms
The RECOVER-SLEEP clinical trials will soon begin enrolling approximately 1,660 people across 50 study sites to investigate treatments for sleep disturbances, one of the most commonly reported long COVID symptoms.
One trial will test two FDA-approved medications—modafinil and solriamfetol—for treating hypersomnia, a condition where people have difficulty staying awake during the day. Participants will receive either the active drug or a placebo for 8-10 weeks.
A second sleep-focused trial will examine melatonin, an over-the-counter supplement commonly used for sleep disorders, and light therapy, which helps reset sleep cycles. Participants will be randomly assigned to receive either melatonin or placebo, along with either high-intensity (active) or low-intensity (placebo) light therapy for eight weeks.
"The group of symptoms these trials will try to alleviate are truly disruptive and devastating for so many people struggling with long COVID," said Walter J. Koroshetz, M.D., director of NIH's National Institute of Neurological Disorders and Stroke and co-lead of the RECOVER Initiative. "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."
The RECOVER-ENERGIZE trials will focus on exercise intolerance and post-exertional malaise, symptoms that severely limit physical activity in long COVID patients.
One trial will test personalized cardiopulmonary rehabilitation, combining exercise training, strength and flexibility training, education, and social support. This program is designed for those experiencing exercise intolerance with symptoms such as shortness of breath and fatigue. Importantly, participants who screen positive for post-exertional malaise will be excluded from this trial to prevent symptom exacerbation.
For those suffering from post-exertional malaise—the worsening of symptoms following physical or mental exertion—a separate trial will evaluate structured pacing. This approach helps participants identify, control, and minimize symptoms by regulating daily activities. Currently, structured pacing is the only intervention used to treat PEM.
"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," said Lucinda Bateman, M.D., an expert in PEM and founder of the Bateman Horne Center in Salt Lake City.
Autonomic Nervous System Dysfunction Trials
Two additional phase 2 clinical trials, collectively known as RECOVER-AUTONOMIC, have begun testing three treatments for adults with autonomic nervous system dysfunction resulting from long COVID. These trials specifically target postural orthostatic tachycardia syndrome (POTS), characterized by unexpected fast heart rate, dizziness, and fatigue when standing up.
"As a long COVID patient, I know firsthand how disruptive and frightening symptoms including rapid heart rate, dizziness and fatigue can be," said Heather Marti, co-chair of the RECOVER National Community Engagement Group. "These trials are giving me and others with long COVID hope that it will restore our health and get us back to the lives we so desire."
The RECOVER-AUTONOMIC trials will examine:
- Gamunex-C, a form of intravenous immunoglobulin (IVIG) containing antibodies to help the body protect itself against various diseases
- Ivabradine, an oral medication that reduces heart rate
- Coordinator-guided, non-drug care, including activities such as wearing a compression belt and eating a high-salt diet
"Patients who develop POTS after having COVID-19 are often severely limited by their symptoms, and there are no proven effective treatments," said Christopher Granger, M.D., of Duke University Medical Center, who is co-leading RECOVER-AUTONOMIC. "These interventions were selected because they have shown potential benefit in treating symptoms for POTS. The theory we're testing is that they might also help individuals with long COVID."
Researchers plan to enroll 380 participants at 50 sites across the United States for the autonomic dysfunction trials.
Community-Driven Research Approach
A distinguishing feature of the RECOVER Initiative is its emphasis on community involvement. All trials were developed with comprehensive feedback from patients, caregivers, community representatives, clinicians, and scientists.
"The trials were developed with input from people living with long COVID, caregivers, community representatives, clinicians and scientists all with unique expertise in the field," said Gary H. Gibbons, M.D., director of the National Heart, Lung, and Blood Institute at the NIH and co-chair of RECOVER. "We are grateful for their collective involvement which significantly shaped the trials and the choice of interventions."
Patient insights were especially important for the post-exertional malaise trial, which was developed to address concerns expressed by patient advocacy groups about safety.
Diversity and Inclusion Priorities
Diversity among trial participants is a high priority for the RECOVER Initiative. 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.
With the launch of these new trials, RECOVER is currently testing 13 treatments across eight clinical trials and continues to enroll participants. Those interested in learning more about RECOVER clinical trials can visit trials.recovercovid.org or search for the specific trial identifiers on ClinicalTrials.gov.
The RECOVER Initiative is part of the National Research Action Plan, a broader government-wide effort in response to the Presidential Memorandum directing the Department of Health and Human Services to mount a full and effective response to long COVID. The initiative aims to understand, diagnose, and treat the long-term effects of COVID-19, which continue to impact millions of Americans.
