ENAVOgliflozin Outcome Trial in Patients With Severe Aortic Stenosis After Transcatheter Aortic Valve Replacement

Study Overview
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Brief Summary
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The goal of this trial is to determine whether the use of a novel SGLT2 inhibitor(Sodium-glucose Cotransporter-2), Enavogliflozin is safe and effective for the improvement of adverse clinical outcomes and the reversal of adverse cardiac remodelling among patients who had undergone TAVR as compared with the standard-of-care therapy.

Official Title
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A Randomized, Open-Label, Parallel Group Trial to Evaluate the Effect of ENAVOgliflozin Compared With Standard-of-Care on Reduction of Adverse Clinical Events and Cardiac Reverse Remodeling in Patients Who Underwent Transcatheter Aortic Valve Implantation

Conditions
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Aortic Valve Stenosis

Intervention / Treatment
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* Drug: Enavogliflozin
* Drug: Standard-of-Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Patients aged ≥19 with symptomatic aortic stenosis who underwent successful Transcatheter aortic valve implantation (TAVI)* (either native valve or valve in valve with any approved/marketed device). * A successful TAVI is defined as device success according to the VARC-2(Valve Academic Research Consortium 2) and VARC-3 criteria: correct positioning of a single prosthetic heart valve into the proper anatomical location AND intended performance of the prosthetic heart valve (mean aortic valve gradient <20 mmHg, peak velocity <3 m/s, no moderate or severe prosthetic valve regurgitation) AND absence of periprocedural complications (any type of stroke, life-threatening bleeding, acute coronary artery obstruction requiring intervention, major vascular complication requiring intervention, unresolved acute valve thrombosis, or any requirement of a repeat procedure). 2. Heart Failure with Mildly Reduced or Preserved Ejection Fraction Left ventricular ejection fraction (LVEF) ≥40% structural heart disease_Left ventricular hypertrophy (LVH) or Left atrial enlargement A. Left ventricular hypertrophy (LVH) with septal thickness or posterior wall thickness ≥ 1.1 cm or B. Left atrial (LA) enlargement with at least one of the following: LA width (diameter) ≥3.8 cm or LA length ≥ 5.0 cm, or LA area ≥ 20cm2, or LA volume ≥ 55mL or LA volume index ≥ 29mL/m. NT-proBNP ≥ 300 pg/mL (for patients without ongoing atrial fibrillation) or NT-proBNP must be ≥ 600 pg/mL (for patients with ongoing atrial fibrillation). 3. Patients who voluntarily participated in the written agreement Exclusion Criteria: Receiving therapy with an SGLT2(Sodium-glucose Cotransporter 2) inhibitor within 4 weeks prior to randomization; discontinuation of an SGLT2 inhibitor or combined inhibitor of SGLT1 and SGLT2 inhibitor for the purposes of study enrolment is not permitted. According to the judgment of the investigator, patients who are deemed unsuitable for participation in this clinical trial based on their condition (e.g., acute illnesses and major surgical procedures within the last three months). Known allergy, hypersensitivity, or previous intolerance to SGLT2 inhibitors. Left ventricular ejection fraction (LVEF) < 40% Type I Diabetes Mellitus or diabetic ketoacidosis Chronic cystitis and/or recurrent urinary tract infection (≥2 times within 1 year). Stroke or transient ischemic attack within 12 weeks prior to enrollment. Symptomatic persistent hypotension and/or a systolic blood pressure (SBP) < 95 mm Hg at screening or at randomization. SBP ≥180 mmHg irrespective of treatment or SBP ≥160 mmHg with at least ≥3 antihypertensive drugs at screening or randomization. Heart failure due to any of the following: known infiltrative cardiomyopathy (e.g. amyloid, sarcoid, lymphoma, endomyocardial fibrosis), active myocarditis, constrictive pericarditis, cardiac tamponade, known genetic hypertrophic cardiomyopathy or obstructive hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy/dysplasia, or uncorrected primary valvular disease. Renal insufficiency (eGFR <30 ml/min/1.73 m2 of body-surface area) or requiring dialysis at the time of screening. Acute or chronic liver disease with severe impairment of liver function (e.g., ascites, esophageal varices, coagulopathy) or moderate and severe liver failure (alanine transaminase (ALT) or aspartate transaminase (AST) > 2x normal upper limit. Significant chronic pulmonary disease requiring home oxygen or primary pulmonary arterial hypertension. Current or suspicious malignancy or history of malignancy within 5 years Uncontrolled anaemia or haemoglobin <9g/dl Uncontrolled hypothyroidism or arrhythmia or tachycardia Current ongoing alcoholic or drug addict Subjects with non-cardiac co-morbidities with life expectancy less than 12 months Planned major high-risk operation after transcatheter aortic valve replacement (TAVR) Women of childbearing age who have not reached a consensus on the use of highly effective contraception. Pregnancy or breastfeeding. Participation in other clinical trials, However, where at least one or more conditions are satisfied, it could be an exception according to an investigator's discretion; Participating in the observational study expected no effect on the safety and/or effectiveness evaluation of this trial. Screening failed before any interventional factor is involved. Participants who have completed their involvement in clinical trials and have surpassed a 4-week period since their last administration of the investigational drug. Participated in academic trials like strategic or medical device comparison studies conducted under standard therapy provided that there is no additional risk or a specific procedure to a subject and no interference between this trial and other studies.

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enavogliflozin Group<br>0.3 mg 1 tablet once daily | Drug: Enavogliflozin<br>* 0.3 mg 1 tablet once daily<br>|
| Active Comparator: Standard-of-Care Group<br>Guideline-directed medical therapy. | Drug: Standard-of-Care<br>* Standard-of-Care medical therapy plus Enavogliflozin matching placebo<br>* Other names: Standard-of-Care medical therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time from randomization to first occurrence of a composite of major adverse cardiovascular events* or hospitalization for heart failure | Time from randomization to the first occurrence of a composite of major adverse cardiovascular events* or hospitalization for heart failure at 12 months after randomization. *Major adverse cardiovascular events included death from any causes, nonfatal myocardial infarction, or nonfatal stroke. A composite endpoint is an endpoint that is a combination of multiple clinical endpoints. An event is considered to have occurred if any one of several different events is observed. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event rate of death from any cause |  | 12 months | 
| Event rate of nonfatal myocardial infarction |  | 12 months | 
| Event rate of nonfatal stroke |  | 12 months | 
| Event rate of hospitalization for heart failure |  | 12 months | 
| Event rate of Composite renal endpoint | Composite renal endpoint, defined as time to first occurrence of (1) chronic dialysis; (2) renal transplantation; (3) sustained reduction of ≥40% in estimated glomerular filtration rate (GFR); or (4) sustained estimated GFR <15 mL/min/1.73 m2 for patients with baseline estimated GFR ≥30 mL/min/1.73 m2. | 12 months | 
| Event rate of Rehospitalization for any reason |  | 12 months | 
| Changes in measures of cardiac volume and function assessed by serial echocardiography | left ventricular ejection fraction(LVEF), LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), left atrial volume index (LAVI), and the ratio of early transmitral Doppler velocity/early diastolic annular velocity (E/e') | 12 months | 
| Changes in New York Heart Association (NYHA) functional class and the Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score | New York Heart Association (NYHA) Functional Classification on a scale from I to IV, with higher scores indicating severe symptoms and physical limitations associated with heart failure. the Kansas City Cardiomyopathy Questionnaire (KCCQ)on a scale from 0 to 100, with higher scores indicating fewer symptoms and physical limitations associated with heart failure. | 12 months | 
| Serial change in NT-proBNP | N-terminal (NT)-pro hormone BNP (NT-proBNP) | 12 months | 
| Event rate of the safety events | The safety events are defined as; Serious adverse events Adverse events leading to treatment discontinuation Adverse events of special interest(AESI) Hypoglycemia, genitourinary infections, hepatic injury, decreased renal function, ketoacidosis, events leading to lower limb amputation AESIs leading to treatment discontinuation | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transcatheter Aortic Valve Implantation, Angiotensin Receptor-Neprilysin Inhibitor