ENavogliflozin DElivering Alleviation of Ventricular Diastolic Dysfunction in nonObstRuctive Hypertrophic CardioMyopathy

Official title

ENavogliflozin DElivering Alleviation of Ventricular Diastolic Dysfunction in nonObstRuctive Hypertrophic CardioMyopathy: a Prospective, Multicenter, Randomized, Double-blind, Placebo-controlled Study (ENDEAVOR-HCM)

Overview

The primary objective of this study is to investigate the effect of enavogliflozin, an Sodium-glucose transporter 2 (SGLT2) inhibitor, compared with placebo on left ventricular diastolic function in patients with nonobstructive hypertrophic cardiomyopathy. The secondary objective of this study is to investigate the effect of enavogliflozin on exercise capacity, symptoms, serum biomarkers, and arrhythmic burden in patients with nonobstructive hypertrophic cardiomyopathy.

Detailed description

Most of the medication used in HCM(hypertrophic cardiomyopathy) targets dynamic left ventricular obstruction and hypercontractility. Guidelines recommend that beta-blockers and calcum channels can also be used to lower heart rate and improve diastolic function in symptomatic nonobstructive HCM(hypertrophic cardiomyopathy), and that diuretics may be considered next, but there is a paucity of evidence supporting these recommendations. Left ventricular diastolic dysfunction is the main pathophysiological mechanism in nonobstructive HCM. SGLT2(Sodium-glucose transporter 2) inhibitors have been shown to reduce heart failure events and mortality in patients with heart failure with preserved ejection fraction, and have also been reported to improve left ventricular diastolic function. This study will investigate the efficacy and safety of enavogliflozin, an SGLT2(Sodium-glucose transporter 2) inhibitor, compared with placebo in patients with nonobstructive hypertrophic cardiomyopathy, over a period of 6 months.

Patients with hypertrophic cardiomyopathy and without evidence of dynamic left ventricular outflow tract obstruction at resting or on provocation by Valsalva maneuver or exercise will be enrolled. Participants will be randomly assigned to the enavogliflozin 0.3mg group and the placebo group in a 1:1 ratio and will continue the medication for 24 weeks. Changes in left ventricular diastolic reserve assessed by diastolic stress echocardiography will be compared between the treatment groups at 24 weeks. Changes in other parameters of diastolic function and exercise capacity will be assessed by diastolic stress echocardiography and compared between the treatment groups. Symptom status, serum biomarker levels, and arrhythmic burden on 24 hour ambulatory electrocardiogram will also be compared between the treatment groups. Post-trial follow-up will be performed at 52 weeks.

Interventions

• Drug enavogliflozin 0.3mg
  Enavogliflozin 0.3mg, 1 tablet once a day, is prescribed for a period of 24 weeks. Patients who are eligible for all of the criteria and who do not qualify as exclusion criteria should be enrolled in the study and randomly enrolled in a 1: 1 dose of enavogliflozin 0.3 mg once daily or placebo.
• Drug enavogliflozin Placebo
  A placebo pill identical to enavogliflozin, 1 tablet once a day, is prescribed for a period of 24 weeks. Patients who are eligible for all of the criteria and who do not qualify as exclusion criteria should be enrolled in the study and randomly enrolled in a 1: 1 dose of enavogliflozin 0.3 mg once daily or placebo.

Primary outcome measures

• Change from baseline in left ventricular diastolic reserve (Δe') assessed by diastolic stress echocardiography [Time frame: 24 weeks, 52 weeks]

Secondary outcome measures (5)

• Comparison of Diastolic Stress Echocardiography Parameters [Time frame: 24 weeks, 52 weeks]
• Comparison of Cardiopulmonary Exercise Testing Parameters [Time frame: 24 weeks, 52 weeks]
• Comparison of Blood Biomarkers [Time frame: 24 weeks, 52 weeks]
• Comparison of Symptom Survey [Time frame: 24 weeks, 52 weeks]
• Comparison of Arrhythmic Burden on 24-Hour Ambulatory Electrocardiogram [Time frame: 24 weeks, 52 weeks]

Eligibility criteria

Inclusion criteria

• A patient who understands the research protocol and fills out a consent form
• Adults over 19 years of age and under 80 years of age
• Non-diabetic or type 2 diabetic patients (HbA1c 6.5-10.5%)
• Patients with non-obstructive hypertrophic cardiomyopathy who do not show significant dynamic left ventricular outflow tract obstruction at rest or during Valsalva maneuver or exercise stress on echocardiography within 3 months of the screening visit.

• Non-obstructive hypertrophic cardiomyopathy: corresponds to maximum left ventricular outflow tract pressure gradient <30mmHg.
• Maximum left ventricular wall thickness ≥15mm if there is no family history of hypertrophic cardiomyopathy, or maximum left ventricular wall thickness ≥13mm if there is a family history of hypertrophic cardiomyopathy or positive for related genetic mutation.
• For hypertrophic cardiomyopathy, existing beta blockers, calcium channel blockers, diuretics and Renin-angiotension-system(RAS) blockers (beta-blocker, non-dihydropyridine Calcium Cannel Blocker, loop diuretics, thiazide and thiazide-like diuretics, mineralocorticoid receptor antagonist, angiotensin converting enzyme inhibitor/angiotensin) For patients using receptor blocker/angiotensin receptor neprilysin inhibitor), the drug dose was stable for 2 weeks before screening and no change in dose is expected throughout the study period.
• Women of childbearing age who agree to use contraception (hormones, intrauterine device, tubal ligation, spouse's vasectomy, etc.) for 30 days from the time of screening, during the clinical trial period, and after taking the clinical trial drug.
• New York Heart Association (NYHA) Class 1\~3

Exclusion criteria

• History of hypersensitivity to clinical trial drugs
• If you are currently taking Sodium-glucose transporter 2 (SGLT2) inhibitors or within 4 weeks

\- For diabetic patients, any type of hypoglycemic agent other than Sodium-glucose transporter 2 (SGLT2) inhibitors can be used.

• Patients who cannot undergo diastolic stress echocardiography
• Patients on dialysis or with chronic renal failure with an estimated glomerular filtration rate <30 mL/min/1.73m2
• Patients with Cardiac implantable electronic device (CIED)
• Currently pregnant or lactating
• ASpartate Transaminase(AST) or ALanine Transaminase(ALT) value more than 3 times the upper limit of normal during liver function test, history of hepatic coma, history of esophageal varices, history of porto-caval anastomosis.
• Uncontrolled hypertension (SBP≥180mmHg or DBP≥110mmHg) or severe hypotension (SBP<90mmHg)
• Severe aortic or mitral stenosis with the possibility of surgery during the clinical trial period
• Those waiting for a heart transplant or those who have received a heart transplant
• Persons with diseases that need to be differentiated from heart failure symptoms at the investigator's discretion, such as severe anemia (hemoglobin <7 g/dL), uncontrolled arrhythmia, severe lung disease, etc.
• If you have cancer undergoing chemotherapy/radiation/surgical treatment or if your life expectancy is expected to be less than 1 year.
• Untreated alcohol or drug abuse
• If you are participating in the administration of another clinical trial drug or clinical trial device test, or have completed participation for less than 30 days.
• Patients with type 1 diabetes or diabetic ketoacidosis
• New York Heart Association (NYHA) class 4

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

South Korea · 1 center

• Division of Cardiology, Yonsei Cardiovascular Hospital, Yonsei University College of Medic — Seoul

Identifiers

NCT: NCT06580717 · 4-2024-0089

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗