Long COVID is a complex condition that affects approximately 1.4 million Canadians following SARS-CoV-2 infection. Fatigue is the most common symptom of Long COVID. This feasibility trial will evaluate a new rehabilitation program called COVIDEx for treating fatigue after COVID-19, and compare its effectiveness to the standard treatment currently used. The experimental treatment group will receive an 8-week multi-modal rehabilitation program with two 50-minute sessions per week. 60 participants will be recruited, randomly assigned to the COVIDEx program or standard of care (SoC) and followed for 24 weeks.

The investigators propose a modified Zelen, randomized, single-centre, feasibility trial with two parallel groups (intervention vs standard of care). Zelen designs are recommended for evaluating interventions - specifically, to estimate effectiveness rather than efficacy - under real-world conditions of incomplete adherence. Thus, the proposed design is particularly well suited to examine rehabilitation interventions for Long COVID. Participants will be identified and recruited from the community and St. Joseph's Post-Acute COVID-19 outpatient program at Parkwood Institute. Once the clinician and research personnel have determined eligibility, they will log into the web-based computer-generated randomization system. The randomization scheme will be constructed using varying, permuted blocks, stratified by sex and hospitalized status (1 = hospitalized, 0 = otherwise). In alignment with the modified Zelen design's unique approach, all participants will be randomized before obtaining their informed consent. However, immediately after randomization, all participants, irrespective of their group, will be informed and asked to consent to the following:

All participants will be informed that they are part of an observational study designed to follow the natural progression of Long COVID and to evaluate the costs associated with standard post-COVID-19 treatments. This includes both the COVIDEx and SoC groups. The objective is to ensure comprehensive data collection on health outcomes and healthcare utilization across the spectrum of post-COVID care. By blinding patients to the presence of the experimental group, the modified Zelen design will mitigate the effects of feeling disappointed, frustrated, or discouraged about being assigned SoC, which is important given the primary outcome is a subjective, patient reported outcome measure (detection bias). This approach will also reduce the likelihood that patients in the SoC group begin self-motivated programs trying to mimic the intervention (performance bias) since there is no standard of care for this population. Upon completion of the study, both groups will attend a disclosure interview where the randomized nature of the study will be revealed, the rationale for this deception/treatment delay will be provided and full informed consent to use their data for the RCT will be sought. The deception disclosure interview for participants will occur over the phone. A member of the Parkwood research team (research coordinator or research assistant) will telephone each control group participant upon completion of the participant's study procedures and disclose the deception to participants. While on the phone, a copy of the debriefing letter of information/consent (LOI/C) will be emailed to the participant, for the participant to read. The research coordinator or assistant will answer any questions that the participant has and give the participant as much time is needed to sign the consent form. SoC patients will then be offered the COVIDEx intervention. The treatment period will be 8 weeks, with 2 COVIDEx sessions per week.

Outcomes will be collected at baseline, 4-, 8-, 12- and 24- weeks follow-up during assessment sessions. Outcomes include feasibility measures and clinical outcomes, including a transcranial magnetic stimulation (TMS) brain function test. Qualitative one-on-one interviews will explore the acceptability of the intervention and barriers/facilitators to intervention adherence and study retention. Only participants randomized to the COVIDEx group will be asked to participate in the interviews. The study team will not gather data from control group participants if they choose to participate in the COVIDEx intervention.

Measurement of post-exertional malaise (PEM): Some participants may indicate that they experience PEM on the demographic questionnaire. PEM is defined as the worsening of symptoms (such as difficulty thinking, problems sleeping, sore throat, headaches, feeling dizzy, or severe tiredness) after a physical or mental activity that would not have caused a problem before COVID-19 infection and subsequent post-COVID-19 fatigue. We will address this in the trial by: (1) Pacing the COVIDEx session to prevent over-exertion. A pacing strategy and protocol may reduce exacerbation of PEM for those with Long COVID. Pacing will entail frequently gathering subjective measurements of intensity from participants, as well as ensuring that all components of the session (i.e., cardio, strength training) have adequate rest and recovery in between periods of more intense activity. Participants will inform the physiotherapist or exercise instructor of their resting heart rate and blood oxygen levels before each session and after each component of the session, which will help determine exercise intensity and pacing. (2) Monitoring blood lactate levels in participants. All COVIDEx participants, throughout the COVIDEx sessions, will use an Apple Watch to monitor surrogate measures for their blood lactate levels (specifically, heart rate, blood oxygen, steps activity, and sleep). This device is required to be worn by participants as often as possible over the 24-week study period, but especially during each COVIDEx session. Monitoring surrogate measures for blood lactate enables examination of metabolic responses (i.e., mitochondrial dysfunction, reduced tissue oxygenation) in individuals with Long COVID, which could help prevent the onset of PEM by ensuring participants do not exceed a threshold that could induce PEM. Specifically, our objective of monitoring surrogate measures for blood lactate is for safety purposes to prevent overreaching in participants with Long COVID. Participants will be asked to inform the physiotherapist or exercise professional of their blood oxygen levels and heart rate at various time points throughout the COVIDEx intervention, so the instructor can gauge intensity and modify exercise intensity as needed. The instructor will have a lactate range table on hand to ensure participants are within the Safe and Functional Overreaching zones (stated within the research plan) and will approximate this based on participant's blood oxygen levels. The Apple Watches will be provided to participants at no cost to them. Participants have the choice to use their own Apple Watch or can be provided one from the study team. Participants may be required to input basic profile information on the wearable device, such as email, age, height, weight, and/or gender to personalize the tracking features.

To also assist in assessing PEM and fatigue, an ecological momentary assessment (EMA) design will be used to ask participants how they're feeling at random time-points after participating in the COVIDEx sessions (up to the 24-week follow-up). For comparison, participants in the control group will also be administered the EMA questions. These questions are based off the DePaul Symptom Questionnaire-SF. Participants will be asked to download the ExpiWell app, which will be the way of administering the questions at random time-points. Collecting EMA data will assist the researchers in identifying potential cases of PEM and/or any other adverse or serious adverse events. EMA data will be collected for 24 weeks once the participant signs the LOI and agrees to participate in the study.

Inclusion Criteria:

• Adults of at least 18 years of age
• Able to provide informed consent
• Can speak and understand English
• Documented history of SARS-CoV-2 infection (positive PCR/antigen test during acute illness or clinical diagnosis by physician during or after the acute illness)
• Fatigue symptoms within 3 months of COVID-19 infection, lasting at least 2 months
• Fatigue symptoms cannot be explained by an alternative diagnosis
• Fatigue symptoms may be new onset following initial recovery from an acute COVID-19 infection or persist from the initial illness
• Fatigue symptoms may have an episodic nature, fluctuate or relapse over time
• Minimal functional capability: able to walk 10-15 minutes and be recovered within 30-60 minutes or without significant post-exertional malaise (PEM)
• Has applicable technology to access Microsoft Teams and Webex (i.e., computer, laptop, tablet)

Exclusion Criteria:

• Active SARS-CoV-2 infection
• Pre-existing physical, cognitive, and/or mental health conditions that make exercise contraindicated, consent unattainable, or that cause symptoms similar to those seen in post COVID-19 (e.g., major neurocognitive disorder, schizophrenia, chronic fatigue syndrome) that could affect data
• Inability to follow study procedures
• Pregnant and/or breastfeeding
• Received investigational agents as part of a separate study within 30 days of the screening visit
• Has any type of metal bodily implant in head or heart (i.e., pins, plates, pacemakers)
• Current participation in other studies related to COVID-19, exercise, and/or fatigue interventions OR participation within 30 days of the screening visit

Outcome Assessors (physiotherapists) will be blinded to group allocation.