Pursuing Reduction in Fatigue After COVID-19 Via Exercise and Rehabilitation (PREFACER): A Randomized Feasibility Trial

Study Overview
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Brief Summary
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Long COVID or post-COVID-19 syndrome is a complex syndrome that affects people following SARS-CoV-2 infection. This currently affects 1.4 million Canadians, with the most common symptom being fatigue. This feasibility trial will compare a newly developed rehabilitation program (COVIDEx) for treating post-COVID-19 fatigue to standard of care. The experimental treatment group will receive an 8-week multi-modal rehabilitation program with two 50-minute sessions per week. Sixty participants will be recruited and randomly assigned to the COVIDEx program or standard of care and will be followed for 24 weeks.

Detailed Description
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The investigators propose a Zelen randomized, single-centre trial with two parallel groups (intervention vs standard of care). Zelen designs are recommended for evaluating real-world intervention effectiveness under conditions of incomplete adherence, thus are ideally suited to test rehabilitation interventions for PC19S. Participants will be identified and recruited from 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). As this is a Zelen trial, participants will be randomized prior to obtaining consent. Participants randomized to COVIDEx will be told they are part of an RCT comparing COVIDEx to standard of care (SoC) and that they were randomized to the COVIDEx group. They will be asked to participate and sign consent. The treatment period will be 8 weeks, with 2 COVIDEx sessions per week. Participants randomized to the SoC group will be asked to consent to participate in an observational study to follow the natural history of PC19S and costs associated with SoC for post-COVID-19 treatments. By blinding SoC patients to the presence of the experimental group, the 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, the control group 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. SoC patients will then be offered the COVIDEx intervention. The study team will not gather data from control group participants if they choose to participate in the COVIDEx intervention. Outcomes will be collected at baseline, 4-, 8-, 12- and 24- weeks follow-up during assessment sessions. Qualitative focus groups 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 focus groups.

Official Title
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Pursuing Reduction in Fatigue After COVID-19 Via Exercise and Rehabilitation (PREFACER): A Randomized Feasibility Trial

Conditions
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Long-COVID, Long Covid19, Post-COVID-19 Syndrome, Post-COVID Syndrome, Fatigue

Intervention / Treatment
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* Other: COVIDEx


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults of at least 18 years of age Able to provide informed consent 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 episode or persist from the initial illness. Fatigue symptoms may fluctuate or relapse over time. Exclusion Criteria: Active SARS-CoV-2 infection Unable to speak or understand English Pre-existing conditions that may cause cognitive impairment, or symptoms similar to those seen in post COVID-19 (e.g., major neurocognitive disorder, schizophrenia, chronic fatigue syndrome) Inability to follow study procedures Current alcohol or substance use disorder Physical, cognitive, or language impairments sufficient to adversely affect data derived from cognitive assessments Diagnosed reading disability or dyslexia History of clinically significant learning disorder Pregnant and/or breastfeeding Received investigational agents as part of a separate study within 30 days of the screening visit Active seizure disorder/epilepsy, not controlled by medication Presence of any unstable medical conditions

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: There are two parallel treatment arms: COVIDEx rehabilitation program and standard of care.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: COVIDEx<br>This arm will receive 2 50-minute rehabilitation sessions each week for 8 weeks. | Other: COVIDEx<br>* The program is delivered by physiotherapists and comprises of two 50-minute sessions each week for eight weeks. It is designed to be delivered by a physiotherapist either face-to-face or remotely in groups of 6 patients. The components of the program are: (i) warm-up (1 min), (ii) cardio training (5 min), (iii) rest (3 min), (iv) balance training (5 min), (v) breathing exercises (3 min), (vi) cognitive training (5 min), (vii) strengthening training (5 min), and (viii) stretching (10min).<br>|
| No Intervention: Standard of Care<br>This arm will receive standard of care (no intervention) for the 8-week intervention period. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recruitment | Number of screened patients who are eligible, the proportion of eligible patients who consent, number of patients enrolled per month, reasons for non-enrolment. | baseline | 
| Intervention fidelity | Proportion of participants who meet the acceptable level of intervention fidelity (>80%). A fidelity checklist will be used to assess feasibility that includes adherence (i.e., delivery of each key component of the intervention-absent/present), dosage (amount of intervention delivered, number of sessions completed, overall duration of sessions), quality of intervention delivery (i.e., mode of delivery of COVIDEx), and participant acceptability (extent to which participants in the intervention group found the intervention useful). | week 24 | 
| Retention | Proportion of missed assessments and incomplete outcome measures data, and proportion of participants who withdraw from the trial. | week 24 | 
| Zelen design acceptability | Proportion of patients in the standard of care group who provide consent to include their data in the RCT following the disclosure visit. | week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blinding success rate | Success rate of blinding of the outcome assessors will be evaluated with the James Blinding Index scale. The James Blinding Index (BI) is a continuous value such that 0 <= James BI <= 1. If the index is 1, all responses are incorrect, and complete blinding is inferred, albeit this may indicate unblinding in the opposite direction (e.g. opposite guessing). If the index is 0, all responses are correct, and complete unblinding is inferred. If the index is 0.5, then half of the guesses are correct and half of the guesses are incorrect, inferring random guessing. Unblinding may be claimed if the upper limit of the two-sided confidence interval is < 0.5. | week 24 | 
| Burden of outcome measures completeness | Proportion of missing visits, missing outcomes/data, and reasons for missingness. | week 24 | 
| Patient Perceptions | Upon completion of the study protocol, investigators will ask participants and treating physiotherapists to take part in a qualitative evaluation to understand their perceptions of acceptability of the intervention and their experiences with the Zelen design. To achieve this, the study team will conduct participant and treating physiotherapist focus groups led by experienced qualitative researchers using an interpretive description approach to focus on clinically meaningful findings that inform our understanding of the acceptability of the intervention, perceived benefits, barriers/facilitators to adherence and implementation challenges. Investigators will conduct between 2-3 focus groups with demographically and clinically diverse samples of 5-8 participants and 5-8 treating physiotherapists who participated in the trial. | week 24 | 
| Change in Fatigue | The PROMIS-Fatigue scale will be used to measure participants' fatigue levels on a 5-point Likert scale at baseline and at weeks 4, 8, 12, and 24. | baseline to week 8 | 
| Change in Pain | Pain levels will be measured by the Visual Analogue Scale (VAS-Pain) at baseline, weeks 4, 8, 12, and 24. | baseline to week 8 | 
| Change in Post COVID-19 Functional Status | Effect of COVID-19 on functional status is graded on a 5-point scale from 0 (no functional limitations) to 4 (severe functional limitations). | baseline to week 8 | 
| Change in Borg Scale of perceived physical exertion | Participants rate how difficult exercise/activity feels from 6 (no exertion at all) to 20 (maximal exertion). | baseline to week 8 | 
| Change in Global Rating of Change Scale | Participants will rate the change in their symptoms from -5 (much worse) to +5 (much better). | Baseline to week 8 | 
| Change in The DePaul Symptom Questionnaire | Physical symptoms are rated on a five-point scale for frequency (0=none of the time, to 4=all of the time) and severity (0=no symptoms, 4=very severe). | baseline to week 8 | 
| Change in Hospital Anxiety and Depression Scale | Statements are rated on a scale of 0 to 3 for how true they are for the participant. A higher score indicates a worse outcome. | baseline to week 8 | 
| Change in EuroQoL-5D | The EuroQol 5 Dimension 5 Level (EQ-5D-5L) is a self-report survey that measures quality of life across 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is scored on a 3-level severity ranking that ranges from no problems through extreme problems. | Baseline to 8 weeks | 
| Change in 30-second Sit-to-Stand test | Participants are timed for 30 seconds and the number of times they stand up and sit down in a chair in the 30-second period is recorded. More repetitions indicates higher functional ability. | baseline to week 8 |