New NIH-Funded Trial Tests Different Approaches to Long COVID Fatigue

In our recent article, Exercise and Autoimmune Disease: Evidence-Based, Low-Impact Approaches, experts emphasized that physical activity is not one-size-fits-all, particularly for people living with chronic illness. While movement can provide important benefits, some individuals experience symptom worsening after exertion and may require a more individualized approach. 

A new NIH-funded clinical trial is now exploring that question in Long COVID.

While Long COVID is not classified as an autoimmune disease, symptoms such as fatigue, exercise intolerance, and post-exertional symptom worsening are familiar challenges for many people living with autoimmune and other chronic illnesses.

The RECOVER-ENERGIZE platform trial will enroll approximately 660 participants with Long COVID-related exercise intolerance.

Researchers designed the study around an important distinction: some people experience post-exertional malaise (PEM), a worsening of symptoms after physical or mental activity, while others do not. 

To account for these differences, RECOVER-ENERGIZE consists of two parallel clinical trials. About 360 participants will be enrolled in a personalized cardiopulmonary rehabilitation study for people without significant PEM, while about 300 participants will participate in a structured pacing study designed for those who experience PEM. 

Participants without significant PEM will be assigned to a 12-week personalized cardiopulmonary rehabilitation program designed to improve endurance and physical function. Researchers emphasize that this is not traditional graded exercise therapy but an individualized program that adjusts activity levels based on symptoms and tolerance. 

Participants with PEM will instead take part in a structured pacing program that focuses on identifying symptom triggers, balancing activity and rest, and reducing symptom flare-ups.

According to the study authors, the pacing intervention has not previously been tested in a large randomized Long COVID trial.

To minimize the risk of symptom worsening, participants with PEM will not be assigned to exercise-based study activities. A notable feature of the study is the use of the modified DePaul Symptom Questionnaire to identify and monitor PEM throughout the trial. Participants who develop significant PEM during rehabilitation may be transitioned to the pacing pathway, helping researchers tailor interventions based on symptom profiles. 

The study was developed with input from Long COVID patients, caregivers, and community representatives, whose feedback helped shape eligibility criteria, outcome measures, and safety measures.

Patient advocates were particularly involved in ensuring that people with significant PEM were evaluated separately from those participating in rehabilitation-based interventions. 

While RECOVER-ENERGIZE is still underway, the trial may help researchers determine whether different rehabilitation strategies are needed for people with Long COVID depending on the presence of PEM and other symptoms, ultimately helping clinicians better match treatment approaches to individual patient needs.

Note: This study is a preprint and has not yet been peer reviewed by a scientific journal. The paper describes the design of an upcoming clinical trial rather than study results. Findings should be considered preliminary until they have undergone independent scientific review.

Citation

Friedly, J., Bateman, L., Berdan, L. G., Casaburi, R., Erdmann, N., Felker, G. M., Itchon-Ramos, N., Keteyian, S. J., MacIntyre, N., O’Brien, L., Reist, C., Rossiter, H. B., Silverstein, A., Taylor, E., Pike Welch, H., Yanez, N. D., Zimmerman, K. O., & Make, B. (2026). Rationale and Design of RECOVER-ENERGIZE: A Platform Clinical Trial of Interventions for Exercise Intolerance With and Without Post-exertional Malaise in Long COVID. medRxiv : the preprint server for health sciences, 2026.06.02.26354455. https://doi.org/10.64898/2026.06.02.26354455