Rationale and Design of RECOVER-ENERGIZE: A Platform Clinical Trial of Interventions for Exercise Intolerance With and Without Post-exertional Malaise in Long COVID

Introduction

A prominent symptom of post-acute sequelae of SARS-CoV-2 infection (i.e., Long COVID) is exercise intolerance with or without post-exertional malaise (PEM). PEM is characterized by the worsening of both symptoms and function following even minor physical or mental exertion, with symptoms typically worsening 12 to 48 hours after activity and lasting for days or even weeks. Individualized, supervised cardiopulmonary rehabilitation is considered a safe and effective intervention for many cardiac and pulmonary conditions, and has been effective in gradually improving function in previously hospitalized and nonhospitalized patients with severe COVID-19. While traditional cardiopulmonary rehabilitation approaches appear helpful in some situations, the exercise intolerance symptoms experienced by many individuals with Long COVID may require a different approach, especially when attempts to increase physical activity result in PEM. No clear consensus exists on the optimal treatment of PEM, and no major studies have evaluated the efficacy in individuals with Long COVID of either carefully supervised, individualized cardiopulmonary rehabilitation programs for exercise intolerance without significant PEM or activity pacing interventions designed to treat or prevent PEM.

Methods and Analysis

The Researching COVID to Enhance Recovery Clinical Trials (RECOVER-CT) initiative funded by the National Institutes of Health (NIH) included a prospective, multicenter, randomized controlled platform trial (RECOVER-ENERGIZE) designed to assess two interventions in patients with Long COVID and exercise intolerance: (1) cardiopulmonary rehabilitation for patients without significant PEM and (2) structured activity pacing to prevent or reduce PEM in participants who experience the symptom. The intervention duration will be 12 weeks. The primary endpoints for the trial include the Endurance Shuttle Walk Test as a measure of endurance capacity for the cardiopulmonary rehabilitation intervention and a modified version of the DePaul Symptom Questionnaire–Post-Exertional Malaise for the pacing intervention. Assessments will be completed at baseline, middle of intervention, end of intervention, and 12 weeks after completion of the intervention, and include physical performance measures and patient-reported surveys.

Ethics and Dissemination

The RECOVER-ENERGIZE trial protocol has been approved by an institutional review board (Advarra), and written informed consent will be obtained from all participants prior to enrollment. The trial is registered on ClinicalTrials.gov ( NCT06404047 ). Formally assessing PEM and developing a structured activity pacing intervention delivered by local pacing coaches are novel features of this trial. Results will be disseminated through peer-reviewed publications, presentations at scientific conferences, and communication with participants, patient advocacy organizations, and the broader Long COVID community. De-identified participant data will be made available through the NIH RECOVER data repository in accordance with NIH data-sharing policies. If successful, this protocol will provide accessible tools that clinicians can use to address exercise intolerance and PEM in patients with Long COVID.

Trial registration

ClinicalTrials.gov – Platform: NCT06404047 ; Appendix A: NCT06404060 ; Appendix B: NCT06404073 . Registered on May 6, 2024.

Strengths and limitations of this study

• RECOVER-ENERGIZE is a large, multicenter, randomized controlled platform trial that stratifies participants by PEM status, separately evaluating cardiopulmonary rehabilitation in those without significant PEM and structured activity pacing in those with PEM, while mitigating the risk of exertional harm.

• The structured activity pacing intervention is novel and has not previously been tested in a randomized trial in Long COVID. Its coach-delivered, video-conference format is designed to be easily implemented and scalable across diverse clinical settings.

• Patient, caregiver, and community representatives were integrally involved throughout protocol development, shaping eligibility criteria, intervention design, and selection of outcome measures, which strengthens the relevance of the trial to the Long COVID community.

• The trial combines a performance-based measure of endurance capacity (the Endurance Shuttle Walk Test) with a modified, PEM-specific patient-reported instrument (mDSQ-PEM). However, the nature of the interventions precludes blinding of participants and providers, and several key outcomes rely on self-report, which may introduce bias.