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

NCT06668389 | Recruiting Phase 4 FDA Drug

• 2 other identifiers: STEPSHKU / HA HKW IRB
• Study Type: interventional
• Target: 106
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Congenital Heart Disease; Repaired Tetralogy of Fallot (rTOF); Pulmonary Regurgitation; Sodium-glucose Cotransporter 2 (SGLT2) Inhibitor; Dapagliflozin (Forxiga)

Keywords

Congenital Heart Disease; Repaired Tetralogy of Fallot (rTOF); Pulmonary Regurgitation; Sodium-glucose cotransporter 2 (SGLT2) inhibitor; Dapagliflozin (Forxiga)

Outcome Measures

Primary Outcomes (1)

• Maximal oxygen uptake (VO2 max) on cardiopulmonary exercise (CPX) at 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

  At Visit 3 (3 months)

Secondary Outcomes (7)

• Right ventricular systolic function and dimension

  At Visit 3 (3 months)

• Pulmonary and tricuspid regurgitation severity

  At Visit 3 (3 months)

• Other cardiopulmonary test (CPX) parameters

  At Visit 3 (3 months)

• Cardiac biomarkers level

  At Visit 3 (3 months)

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

  At Visit 3 (3 months)

Study Arms (2)

SGLT2 inhibitor Group

EXPERIMENTAL

Dapagliflozin 10mg once daily orally from Visit 1 (Week 1) to Visit 3 (Week 12 ± 1)

Drug: SGLT2 inhibitor (Dapagliflozin 10mg)

Control Group

NO INTERVENTION

Routine care

Interventions

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)

SGLT2 inhibitor Group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• The University of Hong Kong: lead

Study Sites (1)

Department of Medicine, Queen Mary Hospital

Hong Kong, Hong Kong

RECRUITING

Related Publications (19)

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  PMID: 37622666 BACKGROUND

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MeSH Terms

Conditions

Heart Defects, Congenital; Pulmonary Valve Insufficiency

Interventions

Sodium-Glucose Transporter 2 Inhibitors; dapagliflozin

Condition Hierarchy (Ancestors)

Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Heart Valve Diseases

Intervention Hierarchy (Ancestors)

Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Hypoglycemic Agents; Physiological Effects of Drugs

Study Officials

• Chun-Ka Dr Wong, Clinical Assistant Professor

  The University of Hong Kong/ Department of Medicine, Queen Mary Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Chun Ka Dr Wong, Clinical Assistant Professor

CONTACT

+852-22553111; wongeck@hku.hk

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Assistant Professor

Study Record Dates

• First Submitted: October 29, 2024
• First Posted: October 31, 2024
• Study Start: May 12, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: May 20, 2025

Record last verified: 2025-05

Locations

HK (1)