Neuro-cardiac Rehabilitation in Youth With Congenital Heart Disease (QUALINEUROREHAB)

Study Overview
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Brief Summary
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Remarkable progress in paediatric cardiology and surgery have led to the substantial increase of congenital heart disease (CHD) survivors. Long-term outcomes in rare and complex CHD have become a critical priority as three major sources of morbidity have been identified in this population: neurodevelopmental sequelae, mental health issues and reduced exercise capacity. These challenges adversely affect their quality of life and constitute a major public health issue. We seek to evaluate the efficacy of the first integrative and holistic program in Neuro-Cardiac Health associating physical and psychological rehabilitation for children with rare CHD compared to the standard of care. Children randomly assigned to the intervention will undergo a 12-week neuro-cardiac intervention including home-based adaptive physical exercise, telehealth parent and child psycho-education and child computerized cognitive training, as well in-person individual sessions of intervention reinforcement. Parents will be actively involved and will receive personalized feedback and educational resources. Children assigned to the control group will receive the standard of care in congenital cardiology. Post-intervention effects will be measured after 12-months on several outcomes including health-related quality of life (HRQoL), trained and untrained cognitive skills, mental health outcomes and cardiovascular/physical variables.

Detailed Description
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Neurodevelopmental and mental health issues and reduced exercise capacity are the most frequent long-term morbidities in youth with CHD. These problems worsen with age and play a critical role in reducing the quality of life of patients and their families. The QUALI-NEUROREHAB CHD multicentre, randomized controlled trial seeks to test the efficacy of an innovative home-based neuro-cardiac intervention to improve physical and mental health of children, adolescents and young adults with rare CHD, as assessed by the patients themselves using patient-reported outcomes and standardized assessments. Outcomes relate to changes in scores for health-related quality of life (HRQoL, primary outcome measure), neurodevelopmental and mental health outcomes, and cardiopulmonary exercise test parameters, 12 months post-enrolment, in patients with rare CHD aged 8 to 25 years old. This is a two-arm parallel design study: intervention versus control. Intervention using the neuro-cardiac rehabilitation program will be the active arm. Standard of care will be used for the control group and involves normal cardiology consultations and follow-up without intervention programs on physical activity or neurocognitive training. The intervention group will include 12 weeks of neuro-cardiac training, comprised of at-home adaptive physical exercise, telehealth consultations and computerized neurocognitive training as well in-person individual sessions of intervention reinforcement. We hypothesize an increase in the overall HRQoL score of 6 ± 14 points (over 100). With a 90% power, a bilateral alpha risk of 5%, and potentially 20% of loss to follow-up and/or missing data on the primary outcome, we expect to include 138 patients in each group (N= 276, overall). Analysis will be performed using intent to treat (ITT) approach. We predict significant positive changes in quality of life, mental and physical health scores in patients who will be assigned to the neuro-cardiac intervention (active arm). If this intervention is effective, it can have critical public health implications for the organization and modalities of care for children with rare CHD in Europe. A neuro-cardiac rehabilitation programme tailored to the specific challenges of individuals with rare CHD would improve patient care pathways across major centers in Europe.

Official Title
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Impact of a Neuro-cardiac Rehabilitation Program on the Quality of Life of Children, Adolescents, and Young Adults With Congenital Heart Disease: the Multicentre Randomized Controlled QUALINEUROREHAB Trial

Conditions
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Congenital Heart Disease

Intervention / Treatment
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* Other: Neurocardiac rehabilitation program
* Other: Standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with a CHD of moderate to great complexity as defined in the 2019 AHA/ACC guidelines (Appendix 2)85. History of cardiac surgery and/or catheter-based cardiac intervention(s) during the first year of life. Age between 8 and 25 years at the time of enrolment. Parental or legal guardian's consent for minors (<18 years) and personal consent for adults. Social security affiliation (for France only) Exclusion Criteria: Unstable and/or severe heart failure: severe heart failure (class IV NYHA functional class), recent decompensated heart failure requiring hospitalisation and/or any significant change in medication (< 3 months before enrolment), systolic ventricle dysfunction (left ventricle or systemic ventricle ejection fraction < 50%)82. Severe hypoxaemia: pulse oxygen saturation (SpO2) at rest <85%, and/or SpO2 at exercise <80%, and/or patient requiring oxygen therapy. Pulmonary hypertension as defined by the 2020 ESC guidelines, whatever the aetiology83. Significant systolic right ventricle (sRV) hypertension (sRV pressure > 50% of systemic systolic pressure). Uncontrolled arrhythmia: symptomatic treated or untreated arrhythmia at rest and/or exercise, treated arrhythmia with sustained supraventricular or ventricular tachycardia on ECG monitoring or during exercise and/or CPET, occurrence or aggravation of any supraventricular or ventricular arrhythmia during exercise and/or CPET. Advanced atrioventricular block (degree 2 or 3), occurrence or aggravation of any conduction disorder during exercise and/or CPET. Uncontrolled arterial hypertension at rest (e.g. if the blood pressure at rest during the consultation >140/90 mmHg in adults, >95th percentile in children84). Acute or recent (< 3 months) myocarditis and pericarditis. Symptomatic aortic or sub-aortic stenosis. Non-corrected coarctation of the aorta (surgical or catheter-based repair) with a clinical systolic gradient > 20 mmHg. Dilatation of the aorta (aortic root > 40 mm in adults, > 2 Z-score in children85 (http://www.parameterz.com/sites/aortic-root). Severe hypertrophic obstructive cardiomyopathy diagnosed by non-echocardiography. Acute systemic illness. Recent (<3 months) intracardiac thrombus, embolism, or thrombophlebitis. Inability to follow instructions and/or complete the questionnaires, as determined by the investigator. Absolute contraindications for CPET: fever, uncontrolled asthma, respiratory failure, acute myocarditis or pericarditis, uncontrolled arrhythmias causing symptoms or haemodynamic compromise, uncontrolled heart failure, acute pulmonary embolus or pulmonary infarction, and patients with mental impairment leading to inability to cooperate. Inability to undergo the physical intervention: inability to physically exercise, any invasive medical intervention occurring within 6 months preceding the enrolment or scheduled during the 12-month study period (such as cardiac surgery, catheter-based intervention, orthopaedic surgery, chemotherapy for cancer, or any other significant medical treatment or intervention, as determined by the investigator). Patient with a previously diagnosed severe psychiatric disorder requiring hospitalization and/or continuous specialized care by a psychiatrist, as determined by the investigator. Patients who benefited from a cardiac rehabilitation within the 12 months preceding the enrolment. Patients who benefited from a computerized executive function or attention training such as Cogmed Working Memory Program within the 12 months preceding the enrolment. For female patients: pregnancy, pregnancy plan, or breastfeeding woman following questioning of the patient. Patients deprived of liberty due to an ongoing legal procedure, adult's patient under guardianship or curatorship or unable to personally express their consent. Any other clinical and/or pharmacological treatment that is believed to interfere with the study or the optimal clinical care. Initiation or total withdrawal of psychotropic medication (i.e., any psychotropic medication including methylphenidate, benzodiazepines, and mood stabilizers) within the 6 months preceding the enrolment. Patient participating or wishing to participate in any interventional clinical research (drug trial, medical device, non-drug trial).

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 25 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neurocardiac rehabilitation program<br>The home-based neuro-cardiac rehabilitation program will consist of weekly sessions of neuro-cardiac training during 12 weeks at home. The physical activity training consists of two 1-hour sessions of adapted physical activities per week supervised by an APA educator or equal. One weekly session is held in person, at home, and the second one in videoconference. All training sessions follow the same scheme with 30 minutes of bicycle training, adapted from high-intensity training (30-33), and 30 minutes of free adapted physical activities The neuropsychological component will consist of 2 home-based weekly 25-minute sessions of computerized cognitive training via the new platform of CogMed (standard format) for the patient and 1 weekly 30/45-min teleconsultation session of neuropsychological feedback on every-day life emotional regulation and executive functioning applied to school and family life for either the parent (for ages 17 and younger) or young adults with CHD. | Other: Neurocardiac rehabilitation program<br>* Patients receiving a neurocardiac rehabilitation program for 12 weeks.<br>|
| Active Comparator: Standard of care<br>The control group will follow European recommendations for cardiology care (standard of care) without introducing any additional interventions for research purposes at the exception of primary (HRQoL questionnaires) and secondary outcomes | Other: Standard of care<br>* No intervention during the neurocardiac rehabilitation program<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total score of the Pediatric Quality of Life Inventory (PedsQL) 4.0 questionnaire | Change in the self-reported total score of the PedsQL 4.0 questionnaire between baseline (Month 0) and the end of follow-up (Month 12) in both groups. | between Month 0 and Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proxy-reported total score of the Pediatric Quality of Life Inventory (PedsQL) for paediatric patients |  | between Month 0 and Month 12 | 
| Pediatric Quality of Life Inventory (PedsQL) 4.0 Health-related quality (HRQoL ) of life questionnaire score per dimension (self and proxy reports) |  | between Month 0 and Month 12 | 
| Behaviour Rating Inventory of Executive Function (BRIEF) scale scores | BRIEF (8-18 years) and BRIEF-A (older than 18 years) These scales make it possible to identify executive dysfunctions that have an impact on daily life. BRIEF assesses behaviours based on questions grouped into 8 scales: inhibition, flexibility, emotional control, initiation, material organization, working memory, planning/organization, and control. For the BRIEF-A (18 years and +), 9 scales are available and those yield the same indices and general composite score. | between Month 0 and Month 12 | 
| Wisconsin Card Sorting Test scale score | This test measures higher-order executive functioning including planning, anticipation, and cognitive flexibility. | between Month 0 and Month 12 | 
| Wechsler Intelligence Scale scores | Scores on the main indices of the Wechsler Intelligence Scale (WISC-V for children, WAIS-IV for adults): verbal comprehension, visual-spatial abilities, working memory, fluid reasoning and processing speed. | between Month 0 and Month 12 | 
| NEPSY-II scale scores | Score on tests of language (comprehension of instructions) and social cognition (understanding of facial emotions and theories of mind) from the NEPSY-II Child Neuropsychological Assessment battery | between Month 0 and Month 12 | 
| Wechsler Adult Memory Scale scores | verbal and visual memory tests | between Month 0 and Month 12 | 
| Vineland questionnaire | The Vineland-2 proxy-questionnaire of adaptive functioning: this is a parent- or other informant report on adaptive skills including social, communication, academic and daily-life independence of children. | between Month 0 and Month 12 | 
| Multiscore Depression Inventory for Children (MDI-C) scale score | Scale providing access to the child's emotional world and more specifically to depression through 8 dimensions: self-esteem, anxiety, sad mood, social introversion, pessimism, defiance, low energy, and feelings of powerlessness. | between Month 0 and Month 12 | 
| Beck's Depression Inventory (BDI) scale score | Self-report questionnaire (BDI-2) used to measure the characteristic attitudes and symptoms of depression | between Month 0 and Month 12 | 
| Revised Child Manifest Anxiety Scale (R-CMAS) score | Self-administered questionnaire providing a more specific assessment of anxiety in its multiple expressions: worry/hypersensitivity, physiological anxiety, and social concern/concentration, based on a global measure of the child's or adolescent's anxiety level. | between Month 0 and Month 12 | 
| State-Trait Anxiety Inventory (STAI) - Form Y score |  | between Month 0 and Month 12 | 
| Resilience Scale score | Resilience Scale for Children (RS10) score and Resilience Scale for Adults: self-administered questionnaire relating to the ability to cope and respond to life events. | between Month 0 and Month 12 | 
| Cardiopulmonary exercise test (CPET) |  | between Month 0 and Month 12 | 
| Muscular strength | Muscular strength measured using a handgrip dynamometer . This parameter represents the strength of the upper extremities and correlates with inspiratory muscle function and Vital Capacity (FVC) of the lungs. It is measured three times on both hands while sitting with the elbows in a rectangular position. The highest value of the better arm will be used. | between Month 0 and Month 12 | 
| Metabolic equivalent of task (MET) | Physical activity intensity and energy expenditure measured by an actimeter | between Month 0 and Month 12 | 
| Following physical activity questionnaires | Self-administrated questionnaire : International Physical Activity Questionnaire(IPAQ) for patients ≥15 years | between Month 0 and Month 12 | 
| Following physical activity questionnaires | Self-administrated questionnaire : Physical Activity Questionnaire for Children (PAQ-C) for 8 to 14-year-old children | between Month 0 and Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuro-cardiac rehabilitation program, Quality of life