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NCT Number: NCT06668389

Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial

Repaired Tetralogy of Fallot (rTOF) is the leading cause of congenital cyanotic heart disease worldwide, involving up to 7-10% of congenital heart disease. With advances in open-heart surgical repair techniques and medical therapies, there is a significant increase in patients with rTOF surviving till late adulthood. One sequalae that nearly all rTOF patients develop during their lifetime is significant pulmonary regurgitation. Pulmonary regurgitation causes progressive right ventricular dilatation and systolic dysfunction, which in turn impairs cardio-pulmonary function and overall survival.

There is currently no pharmacological therapy proven to improve cardio-pulmonary function in rTOF patients. In a double-blind, placebo controlled, randomized controlled trial involving 33 rTOF patients, the use of beta-adrenergic receptor blocker Bisoprolol failed to improve maximal oxygen uptake (VO2 max) in the treatment group. Furthermore, there was no significant change in dimension of right ventricle on cardiac imaging, or heart failure biomarkers including brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP). In the APPROPRIATE trial involving 64 patients, angiotensin-converting-enzyme inhibitor (ACEI) Ramipril similarly failed to improve VO2 max despite an improved right ventricular long-axis shortening. In REDEFINE trial, 95 rTOF patients were randomized in to receive angiotensin receptor blocker (ARB) Losartan and control. At the end of study, there was no significant difference between the two groups in VO2 max, right ventricular ejection fraction, and other key outcomes.

Sodium-glucose cotransporter 2 (SGLT2) inhibitor is a promising therapy for rTOF patients. Clinical trials consistently demonstrated that SGLT2 inhibitors reduce heart failure hospitalization and mortality among patients with heart failure with or without diabetes mellitus. There have been growing body of evidence that demonstrate that SGLT2 inhibitors improve right ventricular function. In a preclinical study of rat with pulmonary hypertension induced right ventricular failure, empagliflozin was found to reduce pulmonary pressure, alleviate right ventricular hypertrophy and reduce myocardial fibrosis. In a pilot study involving 10 patients with adult congenital heart disease and systemic right ventricular failure, SGLT2 inhibitors improved cardio-pulmonary function as reflected by 6-minute walk test performance and New York Heart Association functional status. Most recently, investigators from DAPA-SERVE randomized controlled trial reported that among 92 patients with systemic right ventricular failure, those randomized to receive SGLT2 inhibitors had superior systemic right ventricular function with larger fractional area change (FAC) and more negative free-wall global longitudinal strain. Nevertheless, as these trials involve patients with right ventricular connections to the systemic circulation rather than pulmonary circulation in rTOF, it is uncertain whether the trial results can be extrapolated to the rTOF population. The critical knowledge gap our proposed randomized controlled trial seeks to address is whether SGLT2 inhibitors improve cardio-pulmonary function in rTOF patients.

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Key information

Conditions

Congenital Heart Disease Cardiovascular Abnormalities Cardiovascular Diseases Congenital Abnormalities Congenital, Hereditary, and Neonatal Diseases and Abnormalities Dapagliflozin (Forxiga) Heart Defects, Congenital Heart Diseases Heart Valve Diseases Pulmonary Regurgitation Pulmonary Valve Insufficiency Repaired Tetralogy of Fallot (rTOF) Sodium-glucose Cotransporter 2 (SGLT2) Inhibitor

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Department of Medicine, Queen Mary Hospital

Hong Kong

Location status: Recruiting

Location contact

Chun Ka Dr Wong, Clinical Assistant Professor

CONTACT

[email protected]

+852-22553111

Chun-Ka Dr Wong, Clinical Assistant Professor

PRINCIPAL_INVESTIGATOR

About this study

Patients with repaired TOF fulfilling inclusion and exclusion criteria will be recruited from Queen Mary Hospital, Hong Kong.

Patients who fulfill the inclusion and exclusion criteria will be interviewed by research staff and given a detailed explanation of the clinical trial. Written informed consent will be obtained if the patient agrees to enroll in the trial.

Assessments will be performed at Visit 1 (week 1): Review of medical history and history taking, Physical examination of vital signs (including blood pressure, pulse rate, and oxygen saturation by pulse oximetry), and cardiovascular system (12-lead electrocardiography (ECG), Blood tests (if not already done within 3 months): Complete blood count, Renal function test, Liver function test, Calcium and phosphate levels, N-terminal pro b-type natriuretic peptide (Nt-pro-BNP), High sensitive troponin T, Creatinine kinase, Hemoglobin A1c (HbA1c), Fasting glucose, Lipid profile , Erythropoietin, Multi-omic studies including proteomics, metabolomics, and lipidomics, Genetic test and geneticist consultation, Echocardiography (if not already done within 3 years), Cardiopulmonary test (CPX), Urine pregnancy test in women of childbearing age.

Randomization will be performed on the day of recruitment. An allocation sequence will be generated prior to initiation of the clinical trial using random numbers generated by computer. After entering a subject's information on the clinical trial system, the allocated group for the subject will be revealed. If a subject found to be ineligible for the clinical trial after randomization, the original assignment will be allocated to the next eligible subject. Subjects will be randomized in a 1:1 ratio to 1 of the 2 treatment arms:

  • SGLT2 inhibitor Group: Dapagliflozin 10mg once daily orally from Visit 1 (Week 1) to Visit 3 (Week 12 ± 1)
  • Control Group: Routine care.

CPX will be performed on Visit 1 (week 4 ± 1) and Visit 3 (week 12 ± 1) under supervision of cardiologist blinded to randomization results. VO2 max, which represent the maximal amount of oxygen consumed during peak exercise, will be measured. In addition, other parameters including metabolic equivalents (METs) achieved, oxygen pulse, anaerobic threshold (VO2 AT), ventilatory equivalent for oxygen (VE/VO2) will be evaluated. Participant will concurrently be Apple Watch Series 9 (Apple, USA) smartwatch for pre- and post-SaO2 and VO2max assessment.

Echocardiography will be performed on Visit 1 and Visit 3 by independent echocardiographer blinded to randomization result. Right ventricular function will be assessed by measuring fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), lateral tricuspid annulus peak systolic velocity (RVS'). Right ventricular diastolic diameter including basal (RVD1), mid ventricle (RVD2) and longitudinal (RVD3) will be measured. Tricuspid regurgitation severity will be graded using vena contracta with <0.2 cm as mild, 0.2-0.6 cm as moderate, and ≥0.7 cm as severe. Pulmonary regurgitation severity will be graded using semi-quantitative approach using right ventricular outflow view and parasternal short axis view with pressure half time <100 ms to be graded as severe.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • rTOF
  • Aged 18 years or above
  • Voluntarily agrees to participate in the clinical trial and provide written informed consent

Exclusion criteria

  • Heart failure with reduced ejection fraction (HFrEF) with LVEF < 40%
  • Planned cardiac and/or non-cardiac surgery in 3 months
  • Chronic kidney disease stages 4 to 5
  • Unable 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 contraindication to SGLT2 inhibitor
  • Pregnancy or breast feeding

Treatment and study plan

SGLT2 inhibitor (Dapagliflozin 10mg)

Drug

Subjects in SGLT2 inhibitor Group will take dapagliflozin 10mg once daily orally from Visit 1 (Week 1) to Visit 3 (Week 12 ± 1)

Primary outcomes

  1. Maximal oxygen uptake (VO2 max) on cardiopulmonary exercise (CPX) at 3 months

    Time frame: 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 rTOF patients at 3 months

Secondary outcomes

  1. Right ventricular systolic function and dimension

    Time frame: At Visit 3 (3 months)

    Effect of SGLT2 inhibitors on right ventricular dimension and function in rTOF patients as assessed by performing echocardiography at 3 months

  2. Pulmonary and tricuspid regurgitation severity

    Time frame: At Visit 3 (3 months)

    Effect of SGLT2 inhibitors on as pulmonary and tricuspid regurgitation severity as assessed by echocardiography at 3 months

  3. Other cardiopulmonary test (CPX) parameters

    Time frame: At Visit 3 (3 months)

    Metabolic equivalents (METs) achieved, oxygen pulse, anaerobic threshold (VO2 AT), and ventilatory equivalent for oxygen (VE/VO2) are assessed during CPX for effect of of SGLT2 inhibitors in rTOF patients

  4. Cardiac biomarkers level

    Time frame: At Visit 3 (3 months)

    Cardiac biomarkers level, including NT-proBNP and high sensitive troponin T in rTOF patients at 3 months as assessed via blood tests for effect of SGLT2 inhibitors

  5. Minnesota Living with Heart Failure Questionnaire/ Kansa City Cardiomyopathy Questionnaire (KCCQ) score

    Time frame: At Visit 3 (3 months)

    Minnesota Living with Heart Failure Questionnaire/ Kansa City Cardiomyopathy Questionnaire (KCCQ) score as completed with rTOF patients for effect of SGLT2 inhibitors

  6. Time to first occurrence of clinical events

    Time frame: 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 rTOF patients

  7. Occurrence of adverse events

    Time frame: At Visit 3 (3 months)

    Occurrence of adverse events in 3 months as assessed for safety and tolerability SGLT2 inhibitors in rTOF patients

Study contacts

Contact information is provided by the study sponsor or research team.

Chun Ka Dr Wong, Clinical Assistant Professor

CONTACT

[email protected]

+852-22553111

Sponsors and collaborators

Lead sponsor

The University of Hong Kong

Other

Registry information

Official study title

Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial (STEPS Trial)

Acronym: STEPS

Important dates

Study start
2025
Primary completion
2026
Study completion
2026
First posted
Oct 31, 2024
Registry last updated
May 20, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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