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 fatigue 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.