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

Official title

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

Overview

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

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 80% power, a bilateral alpha risk of 5%, and potentially 10% of loss to follow-up and/or missing data on the primary outcome, we need to randomize 96 patients to each group (N= 192, 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.

Interventions

• Other Neurocardiac rehabilitation program
  Patients receiving a neurocardiac rehabilitation program for 12 weeks.
• Other Standard of care
  No intervention during the neurocardiac rehabilitation program

Primary outcome measures

• Total score of the Pediatric Quality of Life Inventory (PedsQL) 4.0 questionnaire [Time frame: between Month 0 and Month 12]

Secondary outcome measures (12)

• Proxy-reported total score of the Pediatric Quality of Life Inventory (PedsQL) for paediatric patients [Time frame: 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) [Time frame: between Month 0 and Month 12]
• Behaviour Rating Inventory of Executive Function (BRIEF) scale scores [Time frame: between Month 0 and Month 12]
• Wisconsin Card Sorting Test scale score [Time frame: between Month 0 and Month 12]
• Wechsler Intelligence Scale scores [Time frame: between Month 0 and Month 12]
• NEPSY-II scale scores [Time frame: between Month 0 and Month 12]
• Wechsler Adult Memory Scale scores [Time frame: between Month 0 and Month 12]
• Vineland questionnaire [Time frame: between Month 0 and Month 12]
• Multiscore Depression Inventory for Children (MDI-C) scale score [Time frame: between Month 0 and Month 12]
• Beck's Depression Inventory (BDI) scale score [Time frame: between Month 0 and Month 12]
• Revised Child Manifest Anxiety Scale (R-CMAS) score [Time frame: between Month 0 and Month 12]
• State-Trait Anxiety Inventory (STAI) - Form Y score [Time frame: between Month 0 and Month 12]

Eligibility criteria

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 (mean gradient > 50 mmHg).
• 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) except in the case of repaired congenital heart disease with dilatation of the aorta inherent in the malformation and without significant risk of aortic dissection (tetralogy of Fallot, pulmonary atresia with VSD, transposition of the great arteries, truncus arteriosus, double outlet right ventricle, or single ventricle).
• Severe hypertrophic obstructive cardiomyopathy.
• 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 or suspected severe psychiatric disorder (major depression with or without suicidal ideation, psychotic diagnoses, severe anxiety /panic disorders) 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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Prevention

Study locations

France · 4 centers

• Hôpital Necker-Enfants malades (AP-HP) — Paris
• University Hospital of Montpellier - Arnaud de Villeneuve Hospital — Montpellier
• Saint-Pierre Institute — Palavas-les-Flots
• University Hospital of Bordeaux - Haut-Levêque Hospital — Pessac

Belgium · 1 center

• Saint-Luc University Hospital — Brussels

Germany · 1 center

• Deutsches Herzzentrum München — München

Publications

• Amedro P, Dorka R, Moniotte S, Guillaumont S, Fraisse A, Kreitmann B, Borm B, Bertet H, Barrea C, Ovaert C, Sluysmans T, De La Villeon G, Vincenti M, Voisin M, Auquier P, Picot MC. Quality of Life of Children with Congenital Heart Diseases: A Multicenter Controlled Cross-Sectional Study. Pediatr Cardiol. 2015 Dec;36(8):1588-601. doi: 10.1007/s00246-015-1201-x. Epub 2015 May 31. PMID 26024647
• Muller J, Christov F, Schreiber C, Hess J, Hager A. Exercise capacity, quality of life, and daily activity in the long-term follow-up of patients with univentricular heart and total cavopulmonary connection. Eur Heart J. 2009 Dec;30(23):2915-20. doi: 10.1093/eurheartj/ehp305. Epub 2009 Aug 18. PMID 19692392
• Amedro P, Picot MC, Moniotte S, Dorka R, Bertet H, Guillaumont S, Barrea C, Vincenti M, De La Villeon G, Bredy C, Soulatges C, Voisin M, Matecki S, Auquier P. Correlation between cardio-pulmonary exercise test variables and health-related quality of life among children with congenital heart diseases. Int J Cardiol. 2016 Jan 15;203:1052-60. doi: 10.1016/j.ijcard.2015.11.028. Epub 2015 Nov 10. PMID 26638054
• Amedro P, Gavotto A, Guillaumont S, Bertet H, Vincenti M, De La Villeon G, Bredy C, Acar P, Ovaert C, Picot MC, Matecki S. Cardiopulmonary fitness in children with congenital heart diseases versus healthy children. Heart. 2018 Jun;104(12):1026-1036. doi: 10.1136/heartjnl-2017-312339. Epub 2017 Nov 23. PMID 29170358
• Muller J, Bohm B, Semsch S, Oberhoffer R, Hess J, Hager A. Currently, children with congenital heart disease are not limited in their submaximal exercise performance. Eur J Cardiothorac Surg. 2013 Jun;43(6):1096-100. doi: 10.1093/ejcts/ezs712. Epub 2013 Jan 22. PMID 23345176
• Calderon J, Bellinger DC, Hartigan C, Lord A, Stopp C, Wypij D, Newburger JW. Improving neurodevelopmental outcomes in children with congenital heart disease: protocol for a randomised controlled trial of working memory training. BMJ Open. 2019 Feb 19;9(2):e023304. doi: 10.1136/bmjopen-2018-023304. PMID 30782877
• Calderon J, Angeard N, Moutier S, Plumet MH, Jambaque I, Bonnet D. Impact of prenatal diagnosis on neurocognitive outcomes in children with transposition of the great arteries. J Pediatr. 2012 Jul;161(1):94-8.e1. doi: 10.1016/j.jpeds.2011.12.036. Epub 2012 Jan 28. PMID 22284567
• Calderon J, Stopp C, Wypij D, DeMaso DR, Rivkin M, Newburger JW, Bellinger DC. Early-Term Birth in Single-Ventricle Congenital Heart Disease After the Fontan Procedure: Neurodevelopmental and Psychiatric Outcomes. J Pediatr. 2016 Dec;179:96-103. doi: 10.1016/j.jpeds.2016.08.084. Epub 2016 Sep 28. PMID 27692462

Identifiers

NCT: NCT05670132 · CHUBX 2021/66

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗