ENAVOgliflozin Outcome Trial in Patients With Severe Aortic Stenosis After Transcatheter Aortic Valve Replacement (ENAVO-TAVR)

A Randomized, Double-Blind, Placebo-controlled Trial to Evaluate Efficacy and Safety of a Novel Sodium-Glucose Cotransporter 2 Inhibitor, Enavogliflozin Compared to Placebo on Reducing Major Cardiovascular Events or Worsening Heart Failure in Patients With Severe Aortic Stenosis Who Underwent Transcatheter Aortic Valve Replacement (TAVR) and With Heart Failure With Preserved Ejection Fraction (HFpEF)

The goal of this trial is to to determine whether use of a novel SGLT2 inhibitor, Enavogliflozin 0.3 mg once daily is superior to placebo, when added to standard-of-care, in reducing the composite of major cardiovascular events and Heart Failure events (hospitalization for Heart Failure or urgent Heart Failure visit) among patients who underwent transcatheter aortic valve replacement for severe aortic stenosis and with heart failure with preserved ejection fraction.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Aortic Valve Stenosis
• Intervention / Treatment: Drug: Enavogliflozin; Drug: Standard-of-Care

• Study Type: Interventional
• Enrollment (Estimated): 1040
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jeong-youn Bae, Project manager; Phone Number: 82230107259; Email: cvcrc10@amc.seoul.kr

Study Locations

• South Korea
  • Bucheon-si, South Korea
    • Recruiting
    • Bucheon Sejong Hospital
    • Contact: Young-jin Choi, MD
    • Principal Investigator: Young-jin Choi, MD
  • Changwon, South Korea
    • Recruiting
    • Gyeongsang National University Changwon Hospital
    • Contact: Jae-seok Bae, MD
    • Principal Investigator: Jae-seok Bae, MD
  • Daegu, South Korea
    • Recruiting
    • Keimyung University Dongsan Medical Center
    • Contact: Chul-hyun Lee, MD
    • Principal Investigator: Chul-hyun Lee, MD
  • Daegu, South Korea
    • Recruiting
    • Kyungpook National University Hospital
    • Contact: Dong-heon Yang, MD
    • Principal Investigator: Dong-heon Yang, MD
  • Daegu, South Korea
    • Not yet recruiting
    • Yeungnam University Medical Center
    • Principal Investigator: Woong Kim, MD
    • Contact: Woong Kim, MD
  • Daegu, South Korea
    • Recruiting
    • Daegu Catholic University Medical Center
    • Principal Investigator: Jin-bae Lee, MD
    • Contact: Jin-bae Lee, MD
  • Daejeon, South Korea
    • Recruiting
    • Chungnam National University Hospital
    • Contact: Pil-sang Song, MD
    • Principal Investigator: Pil-sang Song, MD
  • Daejeon, South Korea
    • Recruiting
    • The Catholic University of Korea, Daejeon St. Mary's Hospital
    • Contact: Man-won Park, MD
    • Principal Investigator: Man-won Park, MD
  • Gangneung, South Korea
    • Recruiting
    • GangNeung Asan Hospital
    • Contact: Han-bit Park, MD
    • Principal Investigator: Han-bit Park, MD
  • Gwangju, South Korea
    • Recruiting
    • Chonnam National University Hospital
    • Contact: Ju-han Kim, MD
    • Principal Investigator: Ju-han Kim, MD
  • Ilsan, South Korea
    • Recruiting
    • Inje University Ilsan Paik Hospital
    • Contact: Seong-wook Kwon, MD
    • Principal Investigator: Seong-wook Kwon, MD
  • Incheon, South Korea
    • Recruiting
    • Inha University Hospital
    • Contact: Sang-don Park, MD
    • Principal Investigator: Sang-don Park, MD
  • Incheon, South Korea
    • Recruiting
    • The Catholic University of Korea, Incheon St. Mary's Hospital
    • Contact: Ik-joon Choi, MD
    • Principal Investigator: Ik-joon Choi, MD
  • Incheon, South Korea
    • Recruiting
    • Gachon University Gil Hospital
    • Contact: Woong-cheol Kang, MD
    • Principal Investigator: Woong-cheol Kang, MD
  • Incheon, South Korea
    • Recruiting
    • Incheon Sejong Hospital
    • Contact: Rak-kyoung Choi, MD
    • Principal Investigator: Rak-kyoung Choi, MD
  • Pusan, South Korea
    • Recruiting
    • Dong-A Medical Center
    • Principal Investigator: Yong-rak Cho, MD
    • Contact: Yong-rak Cho, MD
  • Pusan, South Korea
    • Recruiting
    • Inje University Pusan Paik Hospital
    • Contact: Tae-hyun Yang, MD
    • Principal Investigator: Tae-hyun Yang, MD
  • Pusan, South Korea
    • Recruiting
    • Pusan National University Hospital
    • Contact: Han-cheol Lee, MD
    • Principal Investigator: Han-cheol Lee, MD
  • Seongnam-si, South Korea
    • Not yet recruiting
    • Seoul university Bundang hospital
    • Contact: In-ho Chae, MD
    • Principal Investigator: In-ho Chae, MD
  • Seoul, South Korea
    • Recruiting
    • Ewha Womans University MokDong Hospital
    • Contact: In-sook Kang, MD
    • Principal Investigator: In-sook Kang, MD
  • Seoul, South Korea
    • Recruiting
    • Asan Medical Center
    • Contact: Duk-woo Park, MD
    • Principal Investigator: Duk-woo Park, MD
  • Seoul, South Korea
    • Recruiting
    • Korea University Guro Hospital
    • Contact: Cheol-ung Choi, MD
    • Principal Investigator: Cheol-ung Choi, MD
  • Seoul, South Korea
    • Recruiting
    • Korea University Anam Hospital
    • Contact: Chul-woong Yoo, MD
    • Principal Investigator: Chul-woong Yoo, MD
  • Seoul, South Korea
    • Recruiting
    • Konkuk University Medical Center
    • Contact: Bum-seong Kim, MD
    • Principal Investigator: Bum-seong Kim, MD
  • Seoul, South Korea
    • Recruiting
    • Ewha Womans University Seoul Hospital
    • Contact: Sang-hoon Shin, MD
    • Principal Investigator: Sang-hoon Shin, MD
  • Seoul, South Korea
    • Recruiting
    • Hanyang University Seoul Hospital
    • Contact: Young-hyo Lim, MD
    • Principal Investigator: Young-hyo Lim, MD
  • Seoul, South Korea
    • Recruiting
    • SNU Boramae Medical Center
    • Contact: Woo-young Jeong, MD
    • Principal Investigator: Woo-young Jeong, MD
  • Seoul, South Korea
    • Recruiting
    • The Catholic Univ. of Korea Eunpyeong St. Mary's Hospital
    • Contact: Jeong-hoon Lee, MD
    • Principal Investigator: Jeong-hoon Lee, MD
  • Suwon, South Korea
    • Recruiting
    • The Catholic University of Korea, St. Vincent'S Hospital
    • Contact: Sung-ho Hur, MD
    • Principal Investigator: Sung-ho Hur, MD
  • Uijeongbu-si, South Korea
    • Not yet recruiting
    • Uijeongbu Eulji Medical Center, Eulji University
    • Contact: Sung-hoon Park, MD
    • Principal Investigator: Sung-hoon Park, MD
  • Ulsan, South Korea
    • Recruiting
    • Ulsan University Hospital
    • Contact: Kyoung-min Park, MD
    • Principal Investigator: Kyoung-min Park, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients aged ≥19 with symptomatic aortic stenosis who underwent successful transcatheter aortic valve replacement (TAVR)* (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:

1. correct positioning of a single prosthetic heart valve into the proper anatomical location AND
2. 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
3. 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

1. Left ventricular ejection fraction (LVEF) ≥40%

2. 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.

3. 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:

1. Acute decompensated Heart Failure (exacerbation of chronic Heart Failure) requiring intravenous diuretics, vasodilators, inotropic agents, or mechanical support, or hemodynamic instability following the transcatheter aortic valve replacement procedure.
2. Currently receiving therapy with an SGLT2 inhibitor within 4 weeks prior to randomization; discontinuation of current use of SGLT2 inhibitor for the purposes of study enrolment is not permitted.
3. Known allergy, hypersensitivity, or previous intolerance to an SGLT2 inhibitors.
4. HF with reduced ejection fraction (LVEF <40%).
5. Type 1 diabetes mellitus or diabetes ketoacidosis.
6. Chronic cystitis and/or recurrent urinary tract infection (≥2 times within 1 year).
7. Stroke or transient ischemic attack within 12 weeks prior to enrollment.
8. Symptomatic persistent hypotension and/or a systolic blood pressure (SBP) < 95 mm Hg at screening or at randomization.
9. SBP ≥180 mmHg irrespective of treatment or SBP ≥160 mmHg with at least ≥3 antihypertensive drugs at screening or randomization.
10. Heart failure due to any of the following causes; known infiltrative cardiomyopathy (e.g. amyloid, sarcoid, lymphoma, endomyocardial fibrosis, haemochromatosis, Fabry disease), active myocarditis, constrictive pericarditis, cardiac tamponade, known hypertrophic obstructive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVD), or uncorrected primary valvular disease.
11. Severe renal insufficiency (eGFR <30 ml/min/1.73 m2 of body-surface area based on the Modification of Diet in Renal Disease (MDRD) formula) or end-stage renal disease or requiring dialysis at the time of screening.
12. Acute or chronic liver disease with severe impairment of liver function (e.g., ascites, esophageal varices, coagulopathy) or serum levels of transminases or alkaline phosphatase more than two times the upper limit of normal at screening.
13. Chronic pulmonary disease requiring home oxygen, oral steroid therapy or hospitalization for exacerbation within 12 months, or significant chronic pulmonary disease in the Investigator's opinion, or primary pulmonary arterial hypertension.
14. Current or suspicious malignancy or history of malignancy within 5 years
15. Uncontrolled anaemia or haemoglobin <9g/dl
16. Uncontrolled hypothyroidism or arrhythmia or tachycardia
17. Current ongoing alcoholic or drug addict
18. Subjects with non-cardiac co-morbidities with life expectancy less than 12 months
19. Planned major high-risk operation after transcatheter aortic valve replacement (TAVR)
20. Women of childbearing age who have not reached a consensus on the use of highly effective contraception. Pregnancy or breastfeeding.

21. 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.

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
Experimental: Enavogliflozin Group; 0.3 mg 1 tablet once daily	Drug: Enavogliflozin; 0.3 mg 1 tablet once daily
Placebo Comparator: placebo as add-on to standard of care treatment group; Placebo matching enavogliflozin	Drug: Standard-of-Care; Standard-of-Care medical therapy plus Enavogliflozin matching placebo; Other Names: Standard-of-Care medical therapy

What is the study measuring?

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 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
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

Collaborators and Investigators

• Sponsor: Duk-Woo Park, MD
• Collaborators: CardioVascular Research Foundation, Korea; Daewoong Pharmaceutical Co. LTD.
• Investigators: Study Chair: Seung-jung Park, MD, Professor, Cardiology, Asan Medical Center Heart Institute, Valvular Heart Disease Center, Ischemic Heart Disease Center

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): April 1, 2027

Study Registration Dates

• First Submitted: January 1, 2023
• First Submitted That Met QC Criteria: January 4, 2023
• First Posted (Actual): January 5, 2023

Study Record Updates

• Last Update Posted (Estimated): December 15, 2025
• Last Update Submitted That Met QC Criteria: December 8, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: heart failure with preserved ejection fraction; Transcatheter Aortic Valve Implantation; transcatheter aortic valve replacement; Sodium-glucose cotransporter-2 inhibitor
• Additional Relevant MeSH Terms: Aortic Valve Disease; Cardiovascular Diseases; Heart Diseases; Heart Valve Diseases; Ventricular Outflow Obstruction; Heart Failure; Aortic Valve Stenosis; Health Services Administration; Health Care Quality, Access, and Evaluation; Quality of Health Care; Quality Indicators, Health Care; Standard of Care; Enavogliflozin
• Other Study ID Numbers: AMCCV2023-01

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