Nonobstructive Hypertrophic Cardiomyopathy
Conditions
Brief summary
This study is a prospective, multicenter, randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of dapagliflozin in patients with nonobstructive hypertrophic cardiomyopathy (HCM). Patients with nonobstructive HCM frequently experience exercise intolerance, heart failure symptoms, and impaired quality of life due to diastolic dysfunction and myocardial remodeling. However, effective disease-modifying treatment options remain limited. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated clinical benefits in patients with heart failure and may improve myocardial relaxation, cardiac remodeling, and exercise capacity. Approximately 440 patients with nonobstructive HCM will be randomized in a 1:1 ratio to receive dapagliflozin 10 mg once daily or matching placebo for 24 weeks. The primary objective is to evaluate the effect of dapagliflozin on exercise capacity as measured by the change in peak oxygen consumption (peak VO₂) from baseline to Week 24. Secondary objectives include evaluation of diastolic function, echocardiographic parameters, heart failure symptoms, serum biomarkers, arrhythmic burden, and cardiac magnetic resonance imaging parameters in a predefined substudy population.
Detailed description
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is characterized by unexplained left ventricular hypertrophy in the absence of abnormal loading conditions. Patients with nonobstructive HCM frequently experience exercise intolerance, dyspnea, and heart failure symptoms despite preserved left ventricular ejection fraction. Impaired left ventricular relaxation and elevated filling pressures are important pathophysiological mechanisms contributing to symptoms and disease progression. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated beneficial cardiovascular effects in patients with heart failure, including improvements in cardiac function, myocardial remodeling, and clinical outcomes. However, the effects of SGLT2 inhibition in patients with nonobstructive HCM have not been adequately investigated. This study is designed to evaluate the efficacy and safety of enavogliflozin compared with placebo in patients with nonobstructive hypertrophic cardiomyopathy. Eligible participants will be randomized to receive either enavogliflozin or matching placebo in addition to standard medical therapy. The primary objective is to assess the effect of enavogliflozin on left ventricular diastolic function. Secondary objectives include evaluation of exercise capacity, symptoms, serum biomarkers, and arrhythmic burden. Clinical assessments, laboratory testing, electrocardiography, ambulatory rhythm monitoring, cardiopulmonary exercise testing, and echocardiographic examinations will be performed according to the study schedule to evaluate treatment effects. The results of this study are expected to provide evidence regarding the potential role of SGLT2 inhibition as a therapeutic strategy for patients with nonobstructive hypertrophic cardiomyopathy.
Interventions
DRUGDapagliflozin 10mg
Dapagliflozin 10 mg film-coated tablet administered orally once daily after breakfast for 24 weeks.
Matching placebo film-coated tablet administered orally once daily after breakfast for 24 weeks.
Sponsors
Yonsei University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
19 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Able to understand the study protocol and provide written informed consent. 2. Adults aged 19 to 80 years. 3. Nondiabetic participants or participants with type 2 diabetes mellitus (HbA1c 6.5% to 10.5%). 4. Patients with nonobstructive hypertrophic cardiomyopathy (HCM) documented by echocardiography performed within 3 months prior to screening, with no significant dynamic left ventricular outflow tract (LVOT) obstruction at rest, during the Valsalva maneuver, or with exercise provocation. * Nonobstructive HCM defined as a maximum LVOT pressure gradient \<30 mmHg. * Maximum left ventricular wall thickness ≥15 mm in participants without a family history of HCM, or ≥13 mm in participants with a family history of HCM or a pathogenic HCM-associated genetic variant. 5. Participants receiving medical therapy for HCM, including beta-blockers, non-dihydropyridine calcium channel blockers, loop diuretics, thiazide or thiazide-like diuretics, mineralocorticoid receptor antagonists, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or angiotensin receptor-neprilysin inhibitors, must have been on a stable dose for at least 2 weeks prior to randomization and be expected to remain on a stable dose throughout the study period. 6. Women of childbearing potential who agree to use effective contraception
Exclusion criteria
1. History of hypersensitivity to the investigational product. 2. Current treatment with an SGLT2 inhibitor or use within 4 weeks prior to screening. (For participants with diabetes mellitus, use of glucose-lowering medications other than SGLT2 inhibitors is permitted.) 3. Inability to perform cardiopulmonary exercise testing (CPET). 4. End-stage renal disease requiring dialysis or chronic kidney disease with estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73 m². 5. Presence of a cardiac implantable electronic device (CIED), except for an implantable cardioverter-defibrillator (ICD) implanted at least 3 months before informed consent. 6. Current pregnancy or breastfeeding. 7. AST or ALT \>3 times the upper limit of normal, history of hepatic encephalopathy, esophageal varices, or portocaval shunt surgery. 8. Uncontrolled hypertension (systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg) or severe hypotension (systolic blood pressure \<90 mmHg). 9. Severe aortic stenosis or mitral stenosis with a potential need for surgical intervention during the study period. 10. Candidates for heart transplantation or recipients of a previous heart transplantation. 11. Conditions that may confound the assessment of heart failure symptoms, including severe anemia (hemoglobin \<7 g/dL), uncontrolled arrhythmias, severe pulmonary disease, or other conditions judged by the investigator to interfere with study assessments. 12. Active malignancy receiving chemotherapy, radiation therapy, or surgical treatment, or life expectancy of less than 1 year. 13. Untreated alcohol abuse or substance abuse. 14. Participation in another investigational drug or medical device study, or participation in such a study within 30 days prior to screening. 15. Type 1 diabetes mellitus or history of diabetic ketoacidosis. 16. New York Heart Association (NYHA) Class IV. 17. Hereditary intolerance to lactose anhydrous, including galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Peak Oxygen Consumption (Peak VO₂) at Week 24 | Baseline and Week 24 | Exercise capacity will be assessed by cardiopulmonary exercise testing (CPET). The primary endpoint is the change from baseline to Week 24 in peak oxygen consumption (peak VO₂, mL/kg/min). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Cardiopulmonary Exercise Testing Parameters at Week 24 | Baseline and Week 24 | Change From Baseline in Cardiopulmonary Exercise Testing Parameters at Week 24 * Proportion of Participants Achieving an Improvement of at Least 1.5 mL/kg/min in Peak VO₂ (%) at Week 24 * Change From Baseline in Metabolic Equivalents (METs) at Week 24 * Change From Baseline in Exercise Duration (min) at Week 24 * Change From Baseline in Ventilatory Efficiency (VE/VCO₂ Ratio) at Week 24 * Change From Baseline in Ventilatory Anaerobic Threshold (VAT, mL/kg/min) at Week 24 |
| Change From Baseline in Echocardiographic Parameters at Week 24 | Baseline and Week 24 | Change From Baseline in Echocardiographic Parameters at Week 24 * Change From Baseline in Left Ventricular Global Longitudinal Strain (%) at Week 24 * Change From Baseline in Left Atrial Reservoir Strain (%) at Week 24 * Change From Baseline in Septal e' Velocity (cm/s) at Week 24 * Change From Baseline in E/e' Ratio at Week 24 * Change From Baseline in Pulmonary Artery Systolic Pressure (PASP, mmHg) at Week 24 * Change From Baseline in Left Ventricular Mass Index by Echocardiography (g/m²) at Week 24 * Change From Baseline in Left Ventricular End-Diastolic Dimension (mm) at Week 24 * Change From Baseline in Left Atrial Dimension (mm) at Week 24 |
| Change From Baseline in Blood Biomarkers at Week 24 | Baseline and Week 24 | Change From Baseline in Blood Biomarkers at Week 24 * Change From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP, pg/mL) at Week 24 * Change From Baseline in Troponin T (pg/mL) at Week 24 |
| Change From Baseline in Symptoms and Health Status at Week 24 | Baseline and Week 24 | Change From Baseline in Symptoms at Week 24 * Change From Baseline in New York Heart Association (NYHA) Functional Class (Class I-IV) at Week 24 * Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score (points) at Week 24 |
| Change From Baseline in Arrhythmic Burden on 24-Hour Ambulatory Electrocardiography at Week 24 | Baseline and Week 24 | Change From Baseline in Arrhythmic Burden Assessed by 24-Hour Ambulatory Electrocardiography at Week 24 * Change From Baseline in APC Burden (%) at Week 24 * Change From Baseline in VPC Burden (%) at Week 24 |
| Change From Baseline in Cardiac Magnetic Resonance Imaging Parameters at Week 24 | Baseline and Week 24 | Change From Baseline in Cardiac Magnetic Resonance Imaging Parameters at Week 24(Severance Hospital substudy only) |
Contacts
CONTACTGeu-Ru Hong, Professor
Outcome results
None listed