Fontan, Heart Failure, Dapagliflozin, Cardiovascular Diseases, Sodium-GLucose coTransporter-2 Inhibitors
Conditions
Keywords
fontan, heart failure, dapagliflozin, Sodium-glucose cotransporter 2 (SGLT2) inhibitor, Congenital heart disease
Brief summary
While the Fontan operation improves survival for patients with a functional single ventricle, complications like heart failure remain prevalent during follow-up, causing frequent hospitalizations and reduced quality of life. Currently, there are no evidence-based heart failure therapies or guidelines for patients with Fontan palliation. There is growing interest in using sodium-glucose cotransporter 2 inhibitors (SGLT2i) to optimize cardiac conditions in this group. SGLT2i's observed benefits relate to protective effects on cardiac energy metabolism, renal function, sympathetic activation, inflammation, oxidative stress, erythropoiesis, and vascular function. Therefore, SGLT2i may represent a new therapeutic agent to improve exercise capacity and ventricular function in patients with Fontan circulation. This prospective, open-label, single-arm clinical trial investigates the FDA-approved drug dapagliflozin. An open-label design is utilized due to the relatively small cohort of patients with complex underlying hearts. The trial will be conducted at Hong Kong Children's Hospital (the sole pediatric cardiology center in Hong Kong) and Queen Mary Hospital (the largest tertiary referral center for adult congenital heart patients). The total study duration is 2 years. Subjects will participate for 3 months, receiving oral dapagliflozin 10mg once daily. The primary endpoint is VO2 max (maximum rate of oxygen consumption) during cardiopulmonary exercise testing at 3 months. Secondary assessments include questionnaires, history taking, physical examinations, 12-lead electrocardiogram, blood tests, echocardiography, bioelectrical impedance analysis, and urine pregnancy tests. If the hypothesis holds true, clinical translation of this project will: i) Improve long-term outcomes and quality-of-life for Fontan patients, reducing the healthcare burden from repeated heart failure hospitalizations; ii) Revolutionize the management of Fontan-associated heart failure by introducing SGLT2i as a novel, evidence-based therapy locally and globally; iii) Pave the way for multicenter international trials evaluating SGLT2i in the Fontan population and broader congenital heart diseases.
Detailed description
Eligible patients with Fontan circulation who meet all predefined inclusion and exclusion criteria will be recruited from Queen Mary Hospital and Hong Kong Children's Hospital in Hong Kong. Prospective candidates will undergo a screening interview conducted by the research staff. During this interview, the objectives of the clinical trial, the required procedures, and any potential risks will be comprehensively explained. Prior to formal enrollment and the initiation of any study-specific procedures, written informed consent will be legally obtained from the patient or their designated legal guardian. The study protocol involves a series of scheduled clinical assessments, beginning with a baseline evaluation at Visit 1. During this initial visit, patients will undergo a comprehensive medical history review and a physical examination. Baseline vital signs, including blood pressure, pulse rate, and resting oxygen saturation via pulse oximetry, will be recorded. Routine cardiovascular evaluations will include standard 12-lead electrocardiography. Unless performed within the preceding three months, a comprehensive laboratory panel will be drawn; this includes a complete blood count, renal and liver function tests, calcium and phosphate levels, N-terminal pro b-type natriuretic peptide (NT-proBNP), hemoglobin A1c, fasting glucose, and a lipid profile. Additionally, a urine pregnancy test will be administered to all women of childbearing potential. To establish baseline patient-reported outcomes, participants will complete either the Kansas City Cardiomyopathy Questionnaire (KCCQ) or the Paediatric Quality of Life Inventory (PedsQL). Specialized cardiovascular diagnostics and subsequent follow-up evaluations will be conducted at Visit 1 (Week 4 ± 1) and Visit 3 (Week 12 ± 1). At the Week 12 follow-up visit, patients will complete a re-administration of the KCCQ or PedsQL questionnaires. During both specified visits, patients will undergo cardiopulmonary exercise testing (CPX) under the direct supervision of a cardiologist. This testing is designed to evaluate critical functional parameters, including peak oxygen consumption (VO₂), total functional capacity measured in metabolic equivalents (METs), oxygen pulse as a surrogate for stroke volume, the anaerobic threshold (VO₂ AT), and ventilatory efficiency (VE/VO₂). In conjunction with the exercise testing, comprehensive echocardiography will be performed by an independent echocardiographer at Visit 1 and Visit 3, though the baseline scan may be waived if a comprehensive assessment is available from the preceding three years. The echocardiographic analysis will utilize color Doppler flow imaging for the semi-quantitative assessment of systemic atrioventricular (AV) valve regurgitation severity. Conventional pulsed-wave Doppler will be employed to measure early and late diastolic AV valve inflow velocities, allowing for the calculation of the AV systolic-to-diastolic ratio based on the regurgitant jet, which serves as a clinical correlate for ventricular end-diastolic pressure. Furthermore, pulsed-wave tissue Doppler imaging (TDI) will be conducted in the apical four-chamber view. By positioning the sample volume at the lateral AV annulus, researchers will record systolic, early diastolic, and late diastolic velocities to calculate the TDI-based myocardial performance index (MPI). Finally, speckle-tracking echocardiography (STE) will be applied to accurately quantify the systolic and diastolic myocardial deformation, or strain, of the single ventricle.
Interventions
Subjects in SGLT2 inhibitor Group will take dapagliflozin 5-10mg once daily orally from Visit 1 (Week 1) to Visit 3 (Week 12 ± 1)
Sponsors
The University of Hong Kong
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with a functional single ventricle and who have undergone Fontan procedure * Adolescents aged ≥ 12 years with body weight ≥30kg and adults
Exclusion criteria
* Planned cardiac and/or non-cardiac surgery in 3 months * Arrhythmias requiring change in therapy in recent 6 months * Intervention procedure within 6 months prior to enrollment * Documented structural abnormalities of the Fontan circulation * Chronic kidney disease stages 4 to 5 * Inability to perform cardiopulmonary test * Recent use of SGLT2 inhibitors within 6 months * Known hypersensitivity to SGLT2 inhibitors * History of diabetic ketoacidosis * Recent symptomatic hypoglycaemia within 6 months * Insulin dependent diabetes mellitus * History of perineum infection * Recent urinary tract infection within 6 months * Recent genital infection within 6 months * Other known contraindications to SGLT2 inhibitor * Pregnancy or breast feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximal oxygen uptake (VO2 max) on cardiopulmonary exercise (CPX) at 3 months | At Visit 3 (3 months) | Efficacy of SGLT2 inhibitors for improving cardiopulmonary function as assessed the maximal oxygen uptake (VO2 max) on cardiopulmonary exercise testing in Fontan patients at 3 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Metabolic equivalents (METs) on cardiopulmonary test (CPX) | At Visit 3 (3 months) | Metabolic equivalents (METs) assessed during CPX for effect of of SGLT2 inhibitors in Fontan patients |
| Oxygen pulse on cardiopulmonary exercise (CPX) at 3 months | At Visit 3 (3 months) | Oxygen pulse assessed during CPX for effect of of SGLT2 inhibitors in Fontan patients |
| Anaerobic threshold (VO2 AT) on cardiopulmonary exercise (CPX) at 3 months | At Visit 3 (3 months) | Anaerobic threshold (VO2 AT) assessed during CPX for effect of of SGLT2 inhibitors in Fontan patients |
| Ventilatory equivalent for oxygen (VE/VO2) on cardiopulmonary exercise (CPX) at 3 months | At Visit 3 (3 months) | Ventilatory equivalent for oxygen (VE/VO2) on cardiopulmonary exercise (CPX) assessed during CPX for effect of of SGLT2 inhibitors in Fontan patients |
| Cardiac biomarkers level | At Visit 3 (3 months) | Cardiac biomarkers level, including NT-proBNP in Fontan patients at 3 months as assessed via blood tests for effect of SGLT2 inhibitors |
| Systemic ventricular function | At Visit 3 (3 months) | Effect of SGLT2 inhibitors on systemic ventricular function in Fontan patients as assessed by performing echocardiography at 3 months |
| Systemic ventricle dimension | At Visit 3 (3 months) | Effect of SGLT2 inhibitors on systemic ventricle dimension in Fontan patients as assessed by performing echocardiography at 3 months |
| Atrioventricular valve regurgitation | At Visit 3 (3 months) | Effect of SGLT2 inhibitors on atrioventricular valve regurgitation severity as assessed by echocardiography at 3 months |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) score | At Visit 3 (3 months) | Kansa City Cardiomyopathy Questionnaire (KCCQ) score as completed with Fontan patients for effect of SGLT2 inhibitors. The KCCQ Overall Summary Score ranges from a minimum of 0 to a maximum of 100. Higher scores indicate a better outcome, reflecting fewer symptoms, less physical limitation, and better quality of life. |
| Paediatric Quality of Life (PedsQL) | At Visit 3 (3 months) | Paediatric Quality of Life (PedsQL) as completed with Fontan patients for effect of SGLT2 inhibitors. The Total Scale Score is transformed to a scale ranging from a minimum of 0 to a maximum of 100. Higher scores mean a better outcome, indicating fewer problems and better health-related quality of life. |
| Time to first occurrence of clinical events | At Visit 3 (3 months) | Time to first occurrence of clinical events, including heart failure hospitalization, incident arrhythmia, and cardiovascular mortality in 3 months safety as assessed for tolerability of SGLT2 inhibitors in Fontan patients |
| Occurrence of adverse events | At Visit 3 (3 months) | Occurrence of adverse events in 3 months as assessed for safety and tolerability SGLT2 inhibitors in Fontan patients |
Countries
Hong Kong
Contacts
CONTACTProf Yiu Fai Cheung
PRINCIPAL_INVESTIGATORProf Yiu Fai Cheung
The University of Hong Kong
Outcome results
None listed