The Protective Potential of Exercise Training on the Cardiopulmonary Morbidity After COVID-19

Study Overview
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Brief Summary
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40 COVID-19 survivors that have been discharged from the hospital will be included in this investigator-blinded randomised study with a 12-week exercise intervention. Patients will be 1:1 block-randomised by sex to either a supervised high intensity interval-based exercise group or standard care (control group).

Detailed Description
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40 patients will be recruited and undergo baseline testing, including examination, biochemistry, ECG, DXA, OGTT, Pulmonary function, VO2max, RM, plasma volume, AX3, CGM, echocardiography, cardiac MRI. After baseline testing, participants will be randomly allocated into one group receiving standard of care (control group) or a group performing supervised high-intensity interval training three times a week over a period of 12 weeks. The randomization procedure involves a computer-generated block randomization schedule in a ratio of 1:1 stratified by sex by an independent person. Following the 12-week intervention period, both groups will complete a series of follow-up tests (as baseline testing). A 1-year follow-up experimental day is also planned in order to evaluate fitness, cardiac and pulmonary structure and function.

Official Title
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The Protective Potential of Exercise Training on the Cardiopulmonary Morbidity After COVID-19

Conditions
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COVID-19, SARS-CoV2

Intervention / Treatment
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* Behavioral: High intensity interval training
* Behavioral: Standard care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 40 years A laboratory-confirmed initial positive test followed by one negative tests of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ≤ 6 months after hospital discharge ≤10 L oxygen requirement during hospitalization Exclusion Criteria: Present atrial fibrillation Diagnosed with acute myocarditis Health conditions that prevent participating in the exercise intervention Patients who cannot undergo MR scans (e.g. kidney disease or metallic implants) Treatment with IL-6 receptor antagonists (tocilizumab, kevzara) within the last month due to drug interference with the cardiopulmonary exercise adaptations.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High intensity interval training<br>The experimental group will on top of standard care undergo a 12 weeks supervised exercise high intensity interval exercise training on an ergometer bike three times a week for 38 minutes. The specific intervals will be determined from our ongoing pilot study (NCT04549337) | Behavioral: High intensity interval training<br>* 12 weeks of high intensity interval training on exercise bike for 38 minutes 3 times a week<br>|
| Active Comparator: Control group<br>This group will be allocated to standard care and therefore no supervised exercise regimen. | Behavioral: Standard care<br>* standard care after discharge from hospital (control group)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in left ventricular mass | measured by MRI scan | Through study completion, an average of 12 months | 
| Change in right ventricular volume | measured by MRI scan | Through study completion, an average of 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stroke volume | Structural cardiac parameter: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| end-diastolic volume | Structural cardiac parameter: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| IVS thickness (intact ventricular septum) | Structural cardiac parameter: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| LVID (left ventricular internal dimensions) | Structural cardiac parameter: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| PWT (posterior wall thickness) | Structural cardiac parameter: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| LAVI (left atrial volume index) | Structural cardiac parameter: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| LVEF | Functional cardiac parameters: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| Global longitudinal strain | Functional cardiac parameters: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| E/A ratio | Functional cardiac parameters: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| E´ | Functional cardiac parameters: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| RV volumes | Functional cardiac parameters: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| RVEF | Functional cardiac parameters: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| TAPSE | Functional cardiac parameters: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| Change in maximal tricuspid regurgitation velocity and pressure gradient | Functional cardiac parameters: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| RV s´ | Functional cardiac parameters: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| Peak E velocity | Functional cardiac parameters: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| Peak A velocity | Functional cardiac parameters: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| Septal e´ | Functional cardiac parameters: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| Lateral e´ | Functional cardiac parameters: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| E/e´ septal | Functional cardiac parameters: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| E/e´ lateral | Functional cardiac parameters: measured by MRI scan and echocardiography | Through study completion, an average of 12 months | 
| Cardiac inflammation | measured with gadolinium and MRI scan | Through study completion, an average of 12 months | 
| Vascular dysfunction | measured with gadolinium and MRI scan | Through study completion, an average of 12 months | 
| Extracellular volume | measured with gadolinium and MRI scan | Through study completion, an average of 12 months | 
| Diffuse fibrotic changes | measured with gadolinium and MRI scan | Through study completion, an average of 12 months | 
| Blood and plasma volume | changes | Through study completion, an average of 12 months | 
| Body composition analysis measured with DXA | easuring Lean mass, Fat mass and BMD | Through study completion, an average of 12 months | 
| Cardiorespiratory fitness | Measured with an incremental VO2 protocol on exercise bike | Through study completion, an average of 12 months | 
| Dynamic spirometri | Pulmonary function testing | Through study completion, an average of 12 months | 
| Whole body plethymography | Pulmonary function testing | Through study completion, an average of 12 months | 
| Diffusion capacity | Pulmonary function testing | Through study completion, an average of 12 months | 
| Oral glucose tolerance test | 75g of glucose taken while fasting | 2 hours at baseline and same after intervention | 
| Continuous glucose monitoring | Three days of continuous glucose monitoring (CGM) is performed using enzyme-coated electrodes (iPro MMT- 7745WW; Medtronic, Northridge, CA, USA) placed subcutaneously in the abdominal wall. For calibration of the CGM system, finger-prick blood glucose measurements are performed by the participant four times daily. | 3 days at baseline and same after intervention | 
| Axial accelerometer-based physical activity monitors | Free-living physical activity is measured using axial accelerometer-based physical activity monitors (AX3; Axivity, Newcastle upon Tyne, UK) for a 4-day period | 4 days at baseline and same after intervention | 
| Blood samples analysed for markers related to low grade inflammation | Including high-sensitivity C-reactive protein, tumour necrosis factor-α, IL-1RA, interferon-γ and interleukins (IL-6, IL-10 and others) Following an overnight fast (10 hours), blood samples, are collected and processed by a trained laboratory technician and analysed according to standard procedures. Plasma is stored at - 80 °C prior to analysis. | Through study completion, an average of 12 months | 
| Blood samples analysed for markers related to cardiometabolic biomarkers. | Including total troponins, D-dimer, creatinine kinase, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, glycated haemoglobin, fasting insulin, fasting plasma glucose, pro-brain natriuretic peptide, haematology, electrolytes and liver and renal status. Following an overnight fast (10 hours), blood samples, are collected and processed by a trained laboratory technician and analysed according to standard procedures. Plasma is stored at - 80 °C prior to analysis. | Through study completion, an average of 12 months | 
| SF-36, King´s Brief Interstitial Lung Disease Questionnaire, Post-COVID-19 Functional Status | Questionnaires on quality of life will be filled in on baseline and after the intervention | Through study completion, an average of 12 months | 
| King´s Brief Interstitial Lung Disease Questionnaire | Questionnaires on quality of life will be filled in on baseline and after the intervention | Through study completion, an average of 12 months | 
| Post-COVID-19 Functional Status | Questionnaires on quality of life will be filled in on baseline and after the intervention | Through study completion, an average of 12 months |