Rehabilitation for Post-COVID-19 Syndrome Through a Supervised Exercise Intervention

Study Overview
=================
Brief Summary
-----------------
This is a randomized controlled trial of the efficacy of a tailored exercise program, based on multicomponent exercise training and/or inspiratory muscle training, compared to the WHO self-management leaflet commonly used in outpatient scenarios, on the recovery of persistent symptoms and functional limitations after COVID-19. . The primary objective of the study is to evaluate the clinical efficacy and safety of a tailored exercise-based treatment relative to the control arm in improving the subject clinical status in ambulatory patients.

Detailed Description
-----------------
A fraction  10% of the COVID-19 patients who undergo a variable acute symptomatic phase of the disease are coming forward with continuing effects of the disease over a month, with chronic complaints like mental fog, delayed latent periods in recalling events of recent past, tachycardia, extreme fatigue, inability to perform daily physical tasks and likely to develop stress, depression, irritability, insomnia, fear, confusion, anger and frustration. This condition is defined as post-COVID-19 syndrome and increasingly affecting a high number of people as the pandemic evolves. The post-COVID-19 syndrome has become a usual situation in the evolutionary course of the disease with its own entity. The National Health Service (NHS) of UK has recently published a clinical guide for long-term management of the effects of COVID-19 with a comprehensive plan for the assessment and care of patients who present or develop symptoms from the fourth week after diagnosis. The effective long-term management of the effects of COVID-19 is a challenge that requires awareness. The RECOVE project aims at determining the role of exercise in the treatment of post-COVID-19 syndrome ambulatory patients.

Official Title
-----------------
Rehabilitation for Post-COVID-19 Syndrome Through a Multicomponent, Educational and Supervised Exercise Intervention [RECOVE]

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

Intervention / Treatment
-----------------
* Behavioral: Exercise
* Behavioral: Inspiratory muscle training
* Behavioral: Controls


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: SARS-CoV-2 diagnosed using real-time reverse transcriptase polymerase chain reaction (PCR) tests or positive for SARS-CoV-2 virus antigen >90 days before randomization. Still present a chronic symptomatic phase lasting >90 days since debut of symptoms Have not been hospitalized There is no evidence on clinical records of pneumonia or any other organ failure related to SARS-CoV-2 Non-coincident participation in any intervention trial Capable and willing to provide an informed consent Exclusion Criteria: Refusal to participate expressed by patient or legally authorized representative if they are present Pregnancy or breast-feeding. Acute heart attack (recent 3-6 months) or unstable angina Uncontrolled atrial or ventricular arrhythmias Aortic dissecting aneurysm Severe aortic stenosis Acute endocarditis / pericarditis Uncontrolled high blood pressure (>180/100 mmHg) Acute thromboembolism Acute or severe heart failure Acute or severe respiratory failure Uncontrolled acute decompensated diabetes mellitus or low blood sugar A recent fracture in the last month. Conditions preventing cooperation

Ages Eligible for Study
-----------------
Minimum Age: 18 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exercise<br>Supervised exercise training | Behavioral: Exercise<br>* Participants from the experimental group will complete 8 weeks of a tailored, educational and supervised multicomponent exercise program adapted from the ACSM guidelines for Chronic Obstructive Pulmonary Disease and Cardiovascular Disease. Participants will complete a 3-days-a-week concurrent training routine: two days of resistance training (50% 1RM (one-repetition maximum), 3 sets, 8 repetitions, 4 exercises [squat, bench press, deadlift and bench pull]) combined with Moderate Intensity Variable Training (MIVT: 4-6 x 3-5 min at 70-80% Heart Rate Reserve (HRR) / 2-3 min at 55-65% HRR), and one day of Light Intensity Continuous Training (LICT: 30-60 min, 65-70% HRR). Progressions will be individualized and consistent with patient tolerance. Sessions will be supervised by certified strength and conditioning coaches, Graduated in Sports Sciences<br>|
| Experimental: Inspiratory muscle training<br>Non-supervised inspiratory muscle training protocol | Behavioral: Controls<br>* Controls will be advised (non-supervised) to follow the WHO guidelines: Support for Rehabilitation: Self-Management after COVID-19 Related Illness<br>|
| Active Comparator: Controls<br>Non-supervised WHO exercise guidelines | Behavioral: Inspiratory muscle training<br>* Participants enrolled in the inspiratory muscle training protocol will used the PowerBreath® Classic Heath Series mechanic threshold devices to perform 1 set of 30 repetitions, twice a day, every day of the week. This assumes a work intensity of approximately 62.5% ± 4.6% of the PIM (maximum inspiratory pressure). Increase in resistance will be made every two weeks by turning the load adjustment clockwise ¼ to 1 full turn, pending on participant tolerance to maintain a 12-15 RPE on modified Borg scale. The training will be preceded by a warm-up at 80% of the 30 RM load, with 2 min of rest between sets<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in subject clinical status | Post-COVID Functional Status (PCFS) on a 5-point ordinal scale (0 to 4 grades) and medical screening | Baseline to 8 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in cardiovascular fitness: Maximal oxygen consumption (VO2max) | VO2max estimated from standard algorithms using a submaximal multistage and individualized cardiopulmonary exercise test on cycloergometer. Heart rate (HR), rate of perceive effort (RPE) and load (W) will be combined to report VO2max in mml/kg/min. | Baseline to 8 Weeks | 
| Changes in neuromuscular performance during resistance exercise: Barbell Mean Propulsive Velocity (MPV) | Barbell displacement and velocity will be monitored in real time using a linear transductor during a progressive resistance training exercise tests. Displacement and velocity will be combined to report MPV | Baseline to 8 Weeks | 
| Changes in balance: center of pressure (COP) sway | COP sway during a balance test will be measured using a high resolution force plate | Baseline to 8 Weeks | 
| Changes in pulmonary function: Forced Vital Capacity (FVC) | The total amount of air exhaled (mL) during a forced expiratory volume test will be measured by spirometry. | Baseline to 8 Weeks | 
| Changes in pulmonary function: Forced expiratory volume (FEV) | The amount of air exhaled (mL) during the first (FEV1), second (FEV2), and third seconds (FEV3) of the forced breath will be measured by spirometry. | Baseline to 8 Weeks | 
| Changes in high sensitivity C-reactive protein (hsCPR) | hsCPR (mg/L) determined by blood-based biochemistry analysis | Baseline to 8 Weeks | 
| Changes in D-dimer | D-dimer (mg/L) determined by blood-based biochemistry analysis | Baseline to 8 Weeks | 
| Changes in Troponin | Troponin (ng/mL) determined by blood-based biochemistry analysis | Baseline to 8 Weeks | 
| Changes in glutamic-pyruvic transaminase (GPT) | GPT(IU/L) determined by blood-based biochemistry analysis | Baseline to 8 Weeks | 
| Changes in serum creatine kinase (CK) | CK (U/L) determined by blood-based biochemistry analysis lactate dehydrogenase (LDH) | Baseline to 8 Weeks | 
| Changes in lactate dehydrogenase (LDH) | LDH (U/L) determined by blood-based biochemistry analysis | Baseline to 8 Weeks | 
| Changes in physical activity levels | Metabolic Equivalents (METs) throughout a week, including activity for work, during transport and leisure time, using the self-reported general physical activity questionnaire (GPAQ) | Baseline to 8 Weeks | 
| Changes in tolerance to exercise: DePaul Symptom Questionnaire for Post-exertional malaise (DSQ-PEM) scores | DSQ-PEM will be administrate to obtain a score of tolerance to exercise (DSQ-PEM Scoring depends on the 10-item mixed questionnaire including scale and yes/no questions) | Baseline to 8 Weeks | 
| Changes in fatigue: Chalder Fatigue Scale scale (CFQ-11) | CFQ-11 will be administrate to obtain a score of fatigue (Each of the 11 items are answered on a 4-point scale ranging from the asymptomatic to maximum symptomology) | Baseline to 8 Weeks | 
| Changes in anxiety: Generalized Anxiety Disorder scale (GAD7) | GAD7 will be administrate to obtain a score of anxiety status (total score for the seven items ranges from 0 to 21) | Baseline to 8 Weeks | 
| Changes in depression: Patient Health Questionnaire (PHQ9) | PHQ9 will be administrate to obtain a score of depression status (total score for the nine items ranges from 0 to 27) | Baseline to 8 Weeks | 
| Changes in health related quality of life: 12-item Short Form Survey (SF12) | Two summary scores are reported from the SF-12 - a mental component score (MCS-12) and a physical component score (PCS-12). The scores will be reported as Z-scores (difference compared to the population average, measured in standard deviations). | Baseline to 8 Weeks |