Clinical trial NCT05672836: ENAVOgliflozin Outcome Trial in Patients With Severe Aortic Stenosis After Transcatheter Aortic Valve Replacement
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Aortic Valve Stenosis
Heart Failure
Keywords: Transcatheter Aortic Valve Implantation
heart failure with preserved ejection fraction
Sodium-glucose cotransporter-2 inhibitor
transcatheter aortic valve replacement
Lead sponsor: Asan Medical Center
Sponsor class: OTHER
Collaborators: name: CardioVascular Research Foundation, Korea
name: Daewoong Pharmaceutical Co. LTD.
First posted: 2023-01-05
Enrollment: 1040
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Time from randomization to first occurrence of a composite of major adverse cardiovascular events* or hospitalization for heart failure
timeFrame: 12 months
Secondary outcomes:
measure: Event rate of death from any cause
timeFrame: 12 months
measure: Event rate of nonfatal myocardial infarction
timeFrame: 12 months
measure: Event rate of nonfatal stroke
timeFrame: 12 months
measure: Event rate of hospitalization for heart failure
timeFrame: 12 months
measure: Event rate of Composite renal endpoint
timeFrame: 12 months
measure: Event rate of Rehospitalization for any reason
timeFrame: 12 months
measure: Changes in measures of cardiac volume and function assessed by serial echocardiography
timeFrame: 12 months
measure: Changes in New York Heart Association (NYHA) functional class and the Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score
timeFrame: 12 months
measure: Serial change in NT-proBNP
timeFrame: 12 months
measure: Event rate of the safety events
timeFrame: 12 months
Other outcomes:
Locations:
city: Bucheon
country: Korea, Republic of
facility: Bucheon Sejong Hospital
city: Changwon
country: Korea, Republic of
facility: Gyeongsang National University Changwon Hospital
city: Daegu
country: Korea, Republic of
facility: Daegu Catholic University Medical Center
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Medical Center
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital
city: Daegu
country: Korea, Republic of
facility: Yeungnam University Medical Center
city: Daejeon
country: Korea, Republic of
facility: Chungnam National University Hospital
city: Daejeon
country: Korea, Republic of
facility: The Catholic University of Korea, Daejeon ST. Mary's Hospital
city: Gangneung
country: Korea, Republic of
facility: Gangneung Asan Hospital
city: Gwangju
country: Korea, Republic of
facility: Chonnam National University Hospital
city: Ilsan
country: Korea, Republic of
facility: Inje University Ilsan Paik Hospital
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Hospital
city: Incheon
country: Korea, Republic of
facility: Incheon Sejong Hospital
city: Incheon
country: Korea, Republic of
facility: Inha University Hospital
city: Incheon
country: Korea, Republic of
facility: The Catholic University of Korea, Incheon St. Mary's Hospital
city: Pusan
country: Korea, Republic of
facility: Dong-A Medical Center
city: Pusan
country: Korea, Republic of
facility: Inje University Pusan Paik Hospital
city: Pusan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Seongnam-si
country: Korea, Republic of
facility: Seoul university Bundang hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Ewha Womans University Mokdong Hospital
city: Seoul
country: Korea, Republic of
facility: Ewha Womans University Seoul Hospital
city: Seoul
country: Korea, Republic of
facility: Hanyang University Seoul Hospital
city: Seoul
country: Korea, Republic of
facility: Konkuk University Medical Center
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Seoul
country: Korea, Republic of
facility: SNU Boramae Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic Univ. of Korea Eunpyeong St. Mary's hospital
city: Suwon
country: Korea, Republic of
facility: The Catholic University of Korea, ST. Vincent's Hospital
city: Uijeongbu
country: Korea, Republic of
facility: Uijeongbu Eulji Medical Center, Eulji University
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hospital
Study officials:
affiliation: Professor, Cardiology, Asan Medical Center Heart Institute, Valvular Heart Disease Center, Ischemic Heart Disease Center
name: Seung-jung Park, MD
role: STUDY_CHAIR
References: