Restoring Energy With Sub-symptom Threshold Optimized Rehabilitation Exercise for Long COVID

Study Overview
=================
Brief Summary
-----------------
The overall goal of this study is to find out if rehabilitation exercise can help people who have long COVID. Participants will be randomized by chance to receive either aerobic exercise or breathing exercise (combined with stretches). Participants will be guided and supported in completing a tailored, 6-week home exercise program to be performed 5 - 6 days a week, prescribed and supervised by rehabilitation therapists. Participants will perform breathing exercises, which will be supervised by an occupational therapist. The focus of Aim 1 is to determine feasibility of implementing RESToRE in long COVID.

Detailed Description
-----------------
Long COVID, also known as post-acute coronavirus 2019 syndrome, is characterized by debilitating, multiorgan symptoms beyond 3 months from the onset of acute illness, consistent with autonomic nervous system dysfunction. Prevalence estimate of long COVID is 10 - 20% of survivors of COVID-19, representing about 10-20 million global long-term cases. Multiorgan, autonomic-related symptoms of long COVID, such as exhausting fatigue and post-exertional malaise, are remarkably like post-concussion syndrome and chronic fatigue syndrome. Post-exertional malaise, likely a cardinal symptom of long COVID, is an exacerbation of some or all of an individual's symptoms after physical or cognitive exertion, or orthostatic stress, significantly impacting functional ability and quality of life. This abnormal response to exertion is often described as flu-like and typically includes brain fog. Common long hauler symptoms reported in our cohort of patients with long COVID (n=30) were fatigue (>70%), symptoms of dysautonomia (80%, primarily orthostasis), brain fog (100%), and new or worse mood symptoms (90%), especially anxiety. Experience from Severe Acute Respiratory Syndrome (SARS-CoV-1) notably showed that survivors suffered chronic fatigue and mental illnesses 4 years after acute viral illness. Rehabilitation studies in coronavirus disease (Covid-19) have targeted sub-acute lung sequelae of Covid-19 rather than post-acute sequalae of long COVID. This study addresses the World Health Organization's urgent call for rehabilitation research for long COVID. The investigators identified blunted rise in heart rate (HR), called chronotropic intolerance, during maximal cardiopulmonary exercise testing (CPET) in 19 adults with long COVID. Chronotropic intolerance is defined as inability to meet 80% of age-derived heart rate, HR peak. Group HR peak mean (SD) was 69 (7.7) % predicted. This blunted rise in HR is associated with post-exertional malaise, similar to the pattern of symptoms in post-concussion syndrome and chronic fatigue syndrome, which share underlying autonomic nervous system (ANS) dysfunction and impaired cerebral blood flow regulation. The investigators identified a need for more comprehensive and precise measurement of post-exertional malaise in long COVID. In a randomized controlled trial (RCT), the investigators also tested a sub-symptom threshold aerobic exercise program, focused on treating persisting symptoms of post-concussion syndrome. The investigators found this aerobic exercise program reduced persistent symptoms of exercise intolerance, fatigue, and dysautonomia more quickly in subjects compared with a control group of stretching exercises (n=103). Informed by research in post-concussion syndrome, the investigators are proposing a two-arm randomized controlled trial (RCT) to study the feasibility of an exercise program called, Restoring Energy with Sub-symptom Threshold Aerobic Rehabilitation Exercise (RESToRE). The central hypothesis is that restoration of autonomic control through RESToRE will resolve persisting symptoms of long COVID faster compared with placebo-like stretching and breathing exercise (without rise in HR). RESToRE is an interdisciplinary, hybrid 8-week intervention consisting of three core components: (1) home-based aerobic exercise, of 20 minutes most days, with HR monitoring at 70-80% of the HR threshold at which symptoms increase, (2) phone-based motivational exercise coaching, 20 minutes weekly; and (3) supervised exercise with an exercise physiologist, twice-monthly in the clinic. Key to RESToRE's feasibility is its telehealth component, including Apple watch and app for HR fidelity monitoring, PhysiTrack's exercise library app, and LifeData dashboard for real-time post-exertional malaise and remote exercise monitoring. Our long-term goal is to establish an efficacious exercise program to speed recovery from long COVID.

Official Title
-----------------
RESToRE: Restoring Energy With Sub-symptom Threshold Optimized Rehabilitation Exercise for Long COVID

Conditions
-----------------
Long Covid19, Exercise Intolerance, Riboflavin-Responsive

Intervention / Treatment
-----------------
* Behavioral: Restoring Energy with Sub-symptom Threshold Aerobic Rehabilitation Exercise
* Behavioral: Light Stretching/Breathing Exercises


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: English speaking Age of 21 years or older Diagnosis of long COVID Score >0 on energy, daily activities, sleep, chest tightness, or breathlessness on COPD Assessment Test or self-reported brain fog Able to use a smartphone. Exclusion Criteria: >70years old due to risk of sarcopenia Frailty defined as gait speed <1 m/s on 4- Meter Gait Speed (4MGS) test due to falls risk Diagnosis of chronic cardiac or pulmonary disease, including atrial fibrillation, ME/CFS, post-concussion syndrome, chronic Lyme disease, lupus, or sarcopenia comorbidities (due to PEM and/or fatigue) Medical history of ICU stay for COVID-19 illness due to risk of post-ICU syndrome and increased rehabilitation needs Inability to ambulate independently and safely without a walking aide Diagnosis of dementia or neurodegenerative disease, multiple sclerosis, or rheumatoid arthritis with associated cognitive dysfunction or fatigue.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RESToRE<br>Participants will receive RESToRE, an interdisciplinary, hybrid 8- week intervention. | Behavioral: Restoring Energy with Sub-symptom Threshold Aerobic Rehabilitation Exercise<br>* 8 week exercise program. 20 minutes of home aerobic exercise most days, phone- based motivational exercise coaching and supervised exercise with our team exercise physiologist.<br>* Other names: RESToRE;|
| Active Comparator: Light Stretching Exercise<br>The control group will receive 8-week, attention-matched, stretching and breathing exercises, supervised by a rehabilitation clinician. | Behavioral: Light Stretching/Breathing Exercises<br>* The control group will receive 8-week, attention-matched, stretching and breathing exercises, supervised by a rehabilitation clinician (via 20-minute weekly video visits). Exercises performed 5 days a week will not increase HR significantly. Participants will record and track their HR with Apple watch and app; like RESToRE, fidelity of treatment will be objectively measured using HR data.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who enrolled | Feasibility of the RESToRE program will be determined by measuring the number of participants who enroll. | 10 weeks | 
| Number of participants who completed | Feasibility of the RESToRE program will be determined by measuring the number of participants who complete (participated through the end of the study). | 10 weeks | 
| Number of participants who adhered to session attendance | Feasibility of the RESToRE program will be determined by measuring the number of participants who achieve ≥80% exercise adherence and session attendance. | 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PROMIS-29 scale score | This toll/questionnaire is designed to measure participants quality of life. Score range is 1-5, with higher score correlating to worse outcomes. | baseline and post intervention at 8 weeks | 
| Rand 36-Item Health Survey (SF-36) score | This survey evaluates participants mental and physical health with 8 scales aggregated. Score range is 1-6, with the higher score correlating to worse overall health outcomes. | Baseline and Post Intervention at 8 weeks | 
| VO2 % predicted from Cardiopulmonary Exercise Testing (CPET) | VO2 % predicted (oxygen consumption) based on normative data. Participants' scores will be compared to norms for assessing exercise ability. Group means will be compared. | Baseline and post intervention at 8 weeks | 
| Number of participants with orthostatic hypocapnia. | The Nasa Lean Test: Participants will stand and lean against a wall with shoulder blades touching and heels 6 - 8 inches from the wall for 10 minutes. HR, BP, SpO2, ETCO2, and symptoms will be recorded in standing leaning posture every minute for 10 mins. Capnography will be used to identify orthostatic hypocapnia. | baseline and post intervention at 8 weeks | 
| EuroQol: Education Quotient-5D Visual Analogue Scale score | This is to measure quality of life. Score range is 0-100, with 100 being the best health you can imagine and 0 being the worst health. | baseline and post intervention at 8 weeks | 
| General Symptom Questionnaire (SGQ-30) score | This is to assess participants symptoms regarding pain/fatigue, psychiatric, neurological, and viral-like. Score range is 0 which is not at all to 4 which is very much. Higher score represents worst symptoms. | baseline and post intervention at 8 weeks | 
| PROMIS Cognitive Function score | This is an 8-item Short Form, measuring perceived difficulties in cognition (e.g., attention, concentration, executive functioning). Score range is 1-5. 1 is very often to 5 which is never. The higher score is better. | baseline and post intervention at 8 weeks | 
| Global Change Assessment (GCA) score | This is to measure patients change of symptoms in terms of physical function and fatigue throughout the study. Score range is -7 to 7. -7 is a very great deal worse and 7 is a great deal better. The higher the score the better. | baseline and post intervention at 8 weeks |