EXercise InTervention in Heart Failure

Study Overview
=================
Brief Summary
-----------------
This is a pragmatic, non-inferiority clinical trial, enrolling heart failure patients who will be randomized to a 12-week exercise training program either centre-based or home-based with telemonitoring. The impact of this intervention will be assessed on established surrogate markers in HF such as maximal exercise capacity, plasma biomarkers and quality of life. The cost-effectiveness and overall satisfaction with the treatment will also be studied. In addition to measure the clinical and economic impact of this innovative way of delivering exercise, it is intended to unravel new molecular pathways and assess a pool of biomarkers that provide a wide mechanistic picture underlying the clinical effects of exercise.

Official Title
-----------------
EXercise InTervention in Heart Failure (EXIT-HF): a Randomized Controlled Trial

Conditions
-----------------
Heart Failure

Intervention / Treatment
-----------------
* Other: Exercise Training Program


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of HFrEF and HFpEF according to criteria of the European Society of Cardiology (2016) Clinical stability for ≥ 6 weeks Optimal medical treatment for ≥ 6 weeks Patients that are able to understand and follow the exercise prescription Written informed consent Exclusion Criteria: Patients who have undertaken cardiac rehabilitation within the past 12 months Patients who have received an intracardiac defibrillator (ICD), Cardiac 3. Resynchronisation therapy (CRT) or combined CRT/ICD device implanted in the last 6 weeks Inability to exercise or conditions that may interfere with exercise intervention Signs of ischemia during cardiopulmonary exercise test Comorbidity that may influence one-year prognosis Symptomatic and/or exercise induced cardiac arrhythmia or conduction disturbances Currently pregnant or intend to become pregnant in the next year Expectation of receiving a cardiac transplant in the next 6 months Participation in another clinical trial Patients who are unable to understand the study information or unable to complete the outcome questionnaires

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: Home-based exercise training<br>The 12-week exercise-training program will include two sessions of combined exercise training per week, performed at home | Other: Exercise Training Program<br>* The 12-week exercise-training program will include two sessions of combined exercise training per week, performed at the hospital or at home.<br>|
| Active Comparator: Clinical-based exercise training<br>The 12-week exercise-training program will include two sessions of combined exercise training per week, performed at the hospital | Other: Exercise Training Program<br>* The 12-week exercise-training program will include two sessions of combined exercise training per week, performed at the hospital or at home.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak oxygen uptake (ml/kg/min) | Patients will be submitted to cardiopulmonary treadmill exercise tests at baseline and after 3 moths | Change from baseline in peak oxygen uptake (ml/kg/min) at 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-min walk test (6MWT) distance | Changes in distance from the 6MWT. | Change from baseline to 3 months, and to 12 months. | 
| Health status (EQ-5D-5L) | Health status will be evaluated by the 5-level EQ-5D version (EQ-5D-5L) questionnaire. The questionnaire comprises five dimensions, each describing a different aspect of health (mobility, self-care, usual activities, pain/discomfort and anxiety/depression). Each dimension has five response levels of severity which range from 0 (no problems) to 5 (extreme problems/ unable to do). In addition, there is a score of overall health range from 0 to 100%. | Change from baseline to 3 months, and to 12 months. | 
| Health-related quality of life (MLHFQ) | Health-related quality of life will be evaluated by the Minnesota Living with Heart Failure Questionnaire (MLHFQ). The MLHFQ is composed of 21 questions rated on a scale from 0 (no effect) to 5 (very much). The questionnaire is scored by summation of all 21 responses, where higher scores indicate worse quality of life. | Change from baseline to 3 months, and to 12 months. | 
| Anxiety and Depression (HADS) | Anxiety and Depression will be evaluated by the Hospital Anxiety and Depression Scale (HADS). The questionnaire is composed of 14 questions on a four-point (0-3) scale. The possible scores ranged from 0 to 21 for anxiety and 0 to 21 for depression. A score of 0 to 7 for either subscale will be regarded as being in the normal range, a score of 11 or higher indicating probable presence of the mood disorder and a score of 8 to 10 being just suggestive of the presence of the respective state. | Change from baseline to 3 months, and to 12 months. | 
| Disutility | Individual disutility (inconvenience) perceived by patients and respective quality of life gains. Longevity to offset the exercise program disutility will be expressed in days. | Evaluate at 3th month | 
| Physical activity (steps/day) | Physical activity will be assessed by a POLAR-M200 device with the numbers of daily steps. | Change from baseline to 3 months, and to 12 months. | 
| Daily physical activity levels (min/day) | Daily physical activity levels it will be measure with a POLAR-M200 device. Measures will be described as time spend in light physical activity, moderate and vigorous physical activity, and spend sitting or lying (minutes per day). | Change from baseline to 3 months, and to 12 months. | 
| Dyspnea | Dyspnea will be evaluated by the Dyspnea-12 (D-12) questionnaire. The D-12 consists of 12 descriptor items on a scale of none (0), mild (1), moderate (2), or severe (3). It provides an overall score for breathlessness severity that incorporates seven physical items and five affective items. Total scores from the D-12 range from 0 to 36, with higher scores corresponding to greater severity. | Change from baseline to 3 months, and to 12 months. | 
| Mediterranean diet | Adherence to Mediterranean diet will be evaluated by the 14-Item Mediterranean Diet Assessment Tool (MEDAS-14). The answer to each of the 14 items is scored with 1 in the case of meeting the criteria defined as typical of this type of food (range of possible variation 0-14 points). A total score ≥10 as represent a good adherence to the Mediterranean diet. | Change from baseline to 3 months, and to 12 months. | 
| Hand grip strength | Hand grip strength will be assessed by Jamar dynamometer (kg) | Change from baseline to to 3 and to 12 months. | 
| Circulating number of endothelial progenitor cells, circulating endothelial cells, nitric oxide and endothelial Nitric Oxide Synthase | These markers will inform endothelial function, damage and repair | Change from baseline to 3 months | 
| Biomarkers (pg/ml) | NTproBNP and ST2 (pg/ml) | Change from baseline to 3 months | 
| Biomarkers (mg/L) | hsCRP and Troponin (mg/L) | Change from baseline to 3 months | 
| Concentration of plasma exosomes | Plasma exosomes will be isolated using microbead-based sorting techniques and characterized by nanoparticle tracking analysis, Western blot, and quantitative real-time polymerase chain reaction assessments | Change from baseline to 3 months | 
| Percentage of protein aggregates | Protein aggregates (%) will be analysed using a diagonal two-dimensional (D2D) SDS-PAGE assay with mass spectrometry to identify and characterize detergent-resistant protein aggregates in plasma pre-cleared from albumin and immunoglobulin. | Change from baseline to 3 months | 
| Cost-effectiveness of home-based exercise Vs. clinical-base exercise | Compare cost effectiveness analysis of home-based exercise Vs. clinical-base exercise. The main outcome measure for this study will be cost per quality adjusted life year (QALY) | At 12th month | 
| Physical fitness levels evaluation | Physical fitness levels will be evaluated by the Senior Fitness test | Change from baseline to 3 and to 12 months. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Heart failure, Home-based exercise, Maximal oxygen consumption, Cost-effectiveness