SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure (EMPA-HEART-3)

A Randomized Trial of SGLT2 Inhibition With Empagliflozin in Adults With Fontan Circulatory Failure (EMPA-HEART 3 CardioLink-12)

Some people are born with a birth defect where they only have one functioning ventricle (lower chamber) in their heart. This condition can be initially managed with a Fontan operation, but there is a risk of developing Fontan Circulatory Failure (FCF) later in life. FCF occurs when the single working heart ventricle is no longer strong enough to pump blood throughout the body. This also means the heart has difficulty supplying oxygen to keep up with the needs of the body. As a result, individuals living with FCF may have some challenges carrying out day to day activities. A heart transplant is currently the only therapeutic option for individuals living with FCF. The investigators are conducting this trial to determine whether a medication called empagliflozin can help these people have a better quality of life.

Study Overview

• Status: Not yet recruiting
• Conditions: Congenital Heart Disease
• Intervention / Treatment: Drug: Empagliflozin 10 mg; Other: Placebo

Detailed Description

EMPA-HEART 3 CardioLink-12 is a global, multicentre, randomized, double-blinded, placebo-controlled, parallel group trial of empagliflozin vs. placebo in addition to standard of care therapy in adults with Fontan Circulatory Failure (FCF). A total of 410 individuals who provide written informed consent and meet the inclusion criteria following screening will be randomized (1:1) to receive either empagliflozin 10 mg once daily or matching placebo. During the 12-week follow-up, there will be four in-person and three telephone/virtual assessment visits.

The primary goal of this investigation is to determine whether 12 weeks of therapy with the sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin, will improve clinical and participant-reported outcome measures in adults with FCF.

• Study Type: Interventional
• Enrollment (Estimated): 410
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • University Health Network
      • Contact: Rachel M Wald, MD; Phone Number: 416-340-5502; Email: rachel.wald@uhn.ca
      • Contact: Rachel M Wald, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults (≥18 years of age) with FCF, defined by dysfunction of the Fontan physiology that causes limitation to the individual's ability to carry out daily life activities, on standard of care therapy

Exclusion Criteria:

• Diuretic initiation or dose change ≤2 weeks prior to enrollment On a SGLT2 inhibitor currently or within 12-weeks prior to enrollment in the trial
• Allergic to or has a known intolerance to any of the ingredients in empagliflozin or other SGLT2 inhibitors
• Pregnant or planning a pregnancy during the duration of the trial or breast feeding
• Living with type 1 diabetes mellitus
• Has an unresolved acute illness (e.g., acute appendicitis, COVID-19, gastroenteritis)
• History of ketoacidosis
• Has an estimated glomerular filtration rate (eGFR) that is <30 mL/min/1.73 m2 Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2-fold upper limit of normal (ULN) at screening
• Has a baseline systolic BP that is <80 mmHg or ≥200 mmHg
• Planned hospital intervention during trial period for management of FCF defined as one of the following:
• Admission for intravenous diuretics
• Admission for intravenous inotropes
• Admission for ascites drainage
• Admission for new or worsening ascites of clinical significance
• Admission for management of arrhythmia
• Admission for management of lymphatic dysfunction
• Admission for interventional cardiological or cardiac surgical procedure within 30-days prior to screening, or consideration for any cardiac surgical or interventional cardiological procedure during trial participation
• Admission for cardiac resynchronization therapy within 90-days prior to screening, or consideration of cardiac resynchronization therapy during trial participation
• Is unable to provide written informed consent, complete the trial or comply with the requirements of the trial protocol
• Participation in other interventional studies within 30-days of the screening visit that could influence any of the trial outcomes (exclusive of observational registries)
• Received intravenous diuretic within the previous 14-days
• On a heart transplant waiting list
• Current or imminent hospitalization for management of FCF

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; Participants will take 10 mg of placebo once daily
Active Comparator: Empagliflozin	Drug: Empagliflozin 10 mg; Participants will take 10 mg of empagliflozin once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hierarchical endpoint	Primary hierarchical composite outcome will be analyzed using a win ratio based on the Finkelstein-Schoenfeld test.; All cause death (no. of participants); Listing for heart transplantation or initiation of mechanical circulatory support (no. of participants); Sustained ventricular tachycardia or aborted sudden cardiac death (no. of participants); Hospital admission for management of FCF defined by any of the following:Admission for intravenous diuretics (no. of participants)Admission for intravenous inotropes (no. of participants)Admission for ascites drainage (no. of participants)Admission for management of new or worsening ascites of clinical significance (no. of participants)Admission for management of arrhythmia (no. of participants)Admission for management of lymphatic dysfunction (no. of participants); ≥5 points change in the KCCQ-Clinical Summary Score (KCCQ-CSS) from baseline to Week 12; Change in 6-minute walk distance f	Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All cause death	All cause death (no. of participants)	Week 12
Listing for heart transplantation or initiation of mechanical circulatory support	Listing for heart transplantation or initiation of mechanical circulatory support (no. of participants)	Week 12
Sustained ventricular tachycardia or aborted sudden cardiac death	Sustained ventricular tachycardia or aborted sudden cardiac death (no. of participants)	Week 12
Hospital admission for management of FCF	Hospital admission for management of FCF (in number of participants) as defined by any of the following: Admission for intravenous diuretics (no. of participants); Admission for intravenous inotropes (no. of participants); Admission for ascites drainage (no. of participants); Admission for management of new or worsening ascites of clinical significance (no. of participants); Admission for management of arrhythmia (no. of participants); Admission for management of lymphatic dysfunction (no. of participants)	Week 12
Change in KCCQ-Clinical Summary Score	≥5 points change in the KCCQ-Clinical Summary Score (KCCQ-CSS) from baseline (no. of participants)	Week 12
Change in 6-minute walk test	Change in 6-minute walk distance (in meters)	Week 12
Time to severe FCF	Time to severe FCF, defined as the first occurrence of any of the following: Death (days); Placement on heart or combined heart and liver transplantation list (days); Initiation of palliative care because the individual is not a heart transplant candidate (days); Fontan take down surgery (days)	Week 12
Change in FCF status	Investigator-reported global change in FCF status (days)	Week 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fontan revision surgery	Time to Fontan revision surgery: atrioventricular valve replacement or repair, aortic valve replacement, Fontan conduit replacement (days)	Week 12
Fontan conversion surgery	Time to Fontan conversion surgery from right atrial-pulmonary artery to lateral tunnel or extracardiac (days)	Week 12
Change in cardiopulmonary exercise testing (CPET) variables if collected for clinical reasons	Blood pressure (BP) at baseline and peak exercise (mmHg)	Week 12
Change in cardiopulmonary exercise testing (CPET) variables if collected for clinical reasons	Heart rate at baseline and peak exercise (BPM)	Week 12
Change in cardiopulmonary exercise testing (CPET) variables if collected for clinical reasons	Peak oxygen consumption (VO2) in mL/kg/min	Week 12
Change in cardiopulmonary exercise testing (CPET) variables if collected for clinical reasons	Peak oxygen consumption (VO2) as % of predicted	Week 12
Change in cardiopulmonary exercise testing (CPET) variables if collected for clinical reasons	VO2 at anaerobic threshold in mL/kg/min	Week 12
Change in cardiopulmonary exercise testing (CPET) variables if collected for clinical reasons	VO2 at anaerobic threshold as % of predicted	Week 12
Change in cardiopulmonary exercise testing (CPET) variables if collected for clinical reasons	Ventilatory efficiency (VE)/volume of carbon dioxide produced (VCO2) ratio at anaerobic threshold and at peak exercise	Week 12
Change in cardiopulmonary exercise testing (CPET) variables if collected for clinical reasons	O2 pulse at peak exercise (% predicted)	Week 12
Change in cardiopulmonary exercise testing (CPET) variables if collected for clinical reasons	Time of exercise (min)	Week 12
Change in cardiopulmonary exercise testing (CPET) variables if collected for clinical reasons	Load of exercise (in Watts if measured on bike, or in metabolic equivalents [METs] if measured on treadmill)	Week 12
Change in cardiopulmonary exercise testing (CPET) variables if collected for clinical reasons	Ventilation (VE) at peak exercise in L/min	Week 12
Change in cardiopulmonary exercise testing (CPET) variables if collected for clinical reasons	Forced expiratory volume in 1 second (FEV1) in L	Week 12
Change in cardiopulmonary exercise testing (CPET) variables if collected for clinical reasons	Forced vital capacity (FVC) in L	Week 12
NT-proBNP	Change in N-terminal pro-B-type natriuretic peptide (pg/mL)	Week 12
Hemoglobin	Change in hemoglobin (g/L)	Week 12
Change in KCCQ score	Change in Kansas City Cardiomyopathy Questionnaire (KCCQ)-Overall Summary Score (KCCQ-OSS) and KCCQ-Total Summary Score (KCCQ-TSS) of ≥5 points. The KCCQ is scored on a scale from 0-100, with higher scores indicative of better health status.	Week 12
Absolute change in KCCQ score	Absolute change in Kansas City Cardiomyopathy Questionnaire (KCCQ)-Clinical Score Summary (KCCQ-CSS), KCCQ-Overall Summary Score (KCCQ-OSS) and KCCQ-Total Summary Score (KCCQ-TSS). The KCCQ is scored on a scale from 0-100, with higher scores indicative of better health status.	Week 12

Collaborators and Investigators

• Sponsor: Subodh Verma
• Collaborators: Boehringer Ingelheim; Applied Health Research Centre

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: March 15, 2025
• First Submitted That Met QC Criteria: April 24, 2025
• First Posted (Actual): May 2, 2025

Study Record Updates

• Last Update Posted (Actual): May 2, 2025
• Last Update Submitted That Met QC Criteria: April 24, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Double-blind; Empagliflozin; randomized; Fontan Circulatory Failure
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pathologic Processes; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Diseases; Heart Defects, Congenital; Shock; Sodium-Glucose Transporter 2 Inhibitors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Empagliflozin
• Other Study ID Numbers: 1245-0331

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No