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)

Overview

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.

Interventions

• Drug Enavogliflozin
  0.3 mg 1 tablet once daily
• Drug Standard-of-Care
  Standard-of-Care medical therapy plus Enavogliflozin matching placebo

Primary outcome measures

• Time from randomization to first occurrence of a composite of major adverse cardiovascular events* or hospitalization for heart failure [Time frame: 12 months]

Secondary outcome measures (10)

• Event rate of death from any cause [Time frame: 12 months]
• Event rate of nonfatal myocardial infarction [Time frame: 12 months]
• Event rate of nonfatal stroke [Time frame: 12 months]
• Event rate of hospitalization for heart failure [Time frame: 12 months]
• Event rate of Composite renal endpoint [Time frame: 12 months]
• Event rate of Rehospitalization for any reason [Time frame: 12 months]
• Changes in measures of cardiac volume and function assessed by serial echocardiography [Time frame: 12 months]
• Changes in New York Heart Association (NYHA) functional class and the Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score [Time frame: 12 months]
• Serial change in NT-proBNP [Time frame: 12 months]
• Event rate of the safety events [Time frame: 12 months]

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:

• 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

• 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.
• 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.
• Known allergy, hypersensitivity, or previous intolerance to an SGLT2 inhibitors.
• HF with reduced ejection fraction (LVEF <40%).
• Type 1 diabetes mellitus or diabetes 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 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.
• 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.
• 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.
• 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.
• 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.

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

Quadruple blind

Primary purpose

Treatment

Study locations

South Korea · 31 centers

• Bucheon Sejong Hospital — Bucheon-si
• Gyeongsang National University Changwon Hospital — Changwon
• Daegu Catholic University Medical Center — Daegu
• Keimyung University Dongsan Medical Center — Daegu
• Kyungpook National University Hospital — Daegu
• Yeungnam University Medical Center — Daegu
• Chungnam National University Hospital — Daejeon
• The Catholic University of Korea, Daejeon ST. Mary's Hospital — Daejeon
• … and 23 more centers

Identifiers

NCT: NCT05672836 · AMCCV2023-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗