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

May 19, 2025 updated by: Wong Chun Ka, The University of Hong Kong

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

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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:

  1. SGLT2 inhibitor Group: Dapagliflozin 10mg once daily orally from Visit 1 (Week 1) to Visit 3 (Week 12 ± 1)
  2. 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.

Study Type

Interventional

Enrollment (Estimated)

106

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Chun Ka Dr Wong, Clinical Assistant Professor
  • Phone Number: +852-22553111
  • Email: wongeck@hku.hk

Study Locations

  • Hong Kong
      • Hong Kong, Hong Kong
        • Recruiting
        • Department of Medicine, Queen Mary Hospital
        • Contact:
          • Chun Ka Dr Wong, Clinical Assistant Professor
          • Phone Number: +852-22553111
          • Email: wongeck@hku.hk
        • Principal Investigator:
          • Chun-Ka Dr Wong, Clinical Assistant Professor

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: Control Group
Routine care
Experimental: SGLT2 inhibitor Group
Dapagliflozin 10mg once daily orally from Visit 1 (Week 1) to Visit 3 (Week 12 ± 1)
Drug: SGLT2 inhibitor (Dapagliflozin 10mg)
Subjects in SGLT2 inhibitor Group will take dapagliflozin 10mg once daily orally from Visit 1 (Week 1) to Visit 3 (Week 12 ± 1)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
At Visit 3 (3 months)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
At Visit 3 (3 months)
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
At Visit 3 (3 months)
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
At Visit 3 (3 months)
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
At Visit 3 (3 months)
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
At Visit 3 (3 months)
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
At Visit 3 (3 months)
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
At Visit 3 (3 months)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The University of Hong Kong

Investigators

  • Principal Investigator: Chun-Ka Dr Wong, Clinical Assistant Professor, The University of Hong Kong/ Department of Medicine, Queen Mary Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 12, 2025

Primary Completion (Estimated)

December 31, 2026

Study Completion (Estimated)

December 31, 2026

Study Registration Dates

First Submitted

October 29, 2024

First Submitted That Met QC Criteria

October 30, 2024

First Posted (Actual)

October 31, 2024

Study Record Updates

Last Update Posted (Estimated)

May 20, 2025

Last Update Submitted That Met QC Criteria

May 19, 2025

Last Verified

May 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STEPS
  • HKU / HA HKW IRB (Other Identifier: HKU / HA HKW IRB)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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