The Efficacy of Enavogliflozin in Heart Failure With Preserved Ejection Fraction (ENRICH-PEF)

The Efficacy of Enavogliflozin on Exercise Performance and Diastolic Function in Heart Failure With Preserved Ejection Fraction: A Randomized Controlled Trial

The aim of prospective, open label, single center, randomized controlled trial is to investigate the efficacy of enavogliflozin on exercise performance, diastolic dysfunction, and quality of life in patients with heart failure with preserved ejection fraction (HFpEF).

Study Overview

• Status: Not yet recruiting
• Conditions: Heart Failure, Preserved Ejection Fraction
• Intervention / Treatment: Drug: SGLT2 inhibitor

Detailed Description

HFpEF is a clinically heterogenous syndrome and has unique characteristics that differ from the other entities of heart failure. Cardiovascular and non-cardiovascular comorbidities are known to contribute to the pathogenesis of HFpEF, and consequently, the importance of HFpEF is increasingly emphasized as the population ages. In fact, HFpEF occurs in approximately 5% of the general population aged over 60 years and account for half of hospitalization for heart failure. Notwithstanding, no medication has been found to be effective for HFpEF. Only recently, Sodium glucose cotransporter 2 (SGLT2) inhibitors was proven effective in patients with HFpEF in two landmark trials, EMPEROR-Preserved and DELIVER trials. In both trials, SGLT2 inhibitor was consistently associated with reduced risk of composite outcome of cardiovascular death and hospitalization for heart failure. In this regard, 2023 focused update of the 2021 European Society of Cardiology (ESC) guidelines for heart failure recommends SGLT2 inhibitor as class 1A recommendation in patients with HFpEF.

Despite the solid evidence about the clinical benefit of SGLT2 inhibitor in patients with HFpEF, little is known about the mechanisms responsible for the beneficial cardiac effects of SGLT2 inhibitor. Patients with HFpEF are known to have impaired exercise and functional capacity, which lead to declined quality of life and debilitating symptoms. Along with unclear mechanisms responsible for the beneficial cardiac effect of SGLT2 inhibitor, the impacts of SGLT2 inhibitor on exercise and functional capacity in patients with HFpEF have also not been clearly evaluated. Therefore, this trial aim to evaluate the impact of SGLT2 inhibitor on exercise performance, diastolic function, and quality of life in patients with HFpEF using newly developed SGLT2 inhibitor, Enavogliflozin.

• Study Type: Interventional
• Enrollment (Estimated): 154
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jeong Hoon Yang, MD, PhD; Phone Number: 82-2-3410-6475; Email: jhysmc@gmail.com
• Study Contact Backup: Name: David Hong, MD; Phone Number: 82-2-3410-6475; Email: hongdawi@naver.com

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
    • Contact: Jeong Hoon Yang, MD, PhD; Phone Number: 82-2-3410-3419; Email: jhysmc@gmail.com
    • Contact: David Hong, MD; Phone Number: 82-2-3410-3419; Email: hongdawi@naver.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

1. Inclusion Criteria:

1) Age ≥19 2) New York Heart Association (NYHA) II-III dyspnea 3) Diagnosis of HFpEF (Exams conducted within 6 months from screening) [must satisfy all (1), (2), and (3)]

1. Left ventricular ejection fraction (LVEF) ≥50%
2. NT-proBNP ≥220 pg/mL or BNP ≥80 pg/mL, if in sinus rhythm NT-proBNP ≥660 pg/mL or BNP ≥240 pg/mL, if in atrial fibrillation

3. Satisfying either noninvasive or invasive criteria I. Noninvasive: Echocardiography with at least one of the following criteria

   • LAVI ≥34 ml/m2
   • Lateral E/e' ≥9
   • LVMI ≥115 g/m2 if male or ≥95 g/m2 if female

   • LV wall thickness ≥12mm II. Invasive: LVEDP ≥16mmHg or pulmonary capillary wedge pressure(PCWP) ≥15mmHg 4) Stable/chronic ambulatory patients without hospitalization within the last 30 days due to heart failure decompensation episode 5) Patients taking heart failure medication without change for at least 3 weeks before screening

     2. Exclusion Criteria:

     1. Unwillingness or inability to comply with the procedures described in this protocol
     2. The ability to walk is, in the investigator's opinion, clearly limited by joint disease or other locomotor problems or lung diseases rather than by cardiorespiratory fitness
     3. NYHA IV dyspnea
     4. Type 1 diabetes mellitus
     5. Estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2 (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula)
     6. Anemia (Hb <7g/dL)
     7. Severe hepatic impairment (Child-Pugh class C)
     8. Acute myocardial infarction or unstable angina within 30 days before inclusion or planned coronary revascularization at the time of inclusion
     9. Significant left-sided valvular heart disease (moderate to severe stenosis and severe regurgitation)
     10. Heart failure due to any of the following: infiltrative cardiomyopathy (amyloidosis, sarcoidosis), active myocarditis, constrictive pericarditis, hypertrophic cardiomyopathy
     11. Symptomatic hypotension (systolic blood pressure <90mmHg)
     12. Severe chronic obstructive pulmonary disease (postbronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity(FVC) <70% and FEV1 <50%)
     13. Treated with sodium-glucose cotransporter-2 inhibitors (SGLT2i) within 30 days before inclusion
     14. History of diabetic ketoacidosis while in treatment with SGLT2i
     15. Recurrent genitourinary tract infections
     16. History of Hypersensitivity reaction to SGLT2i
     17. Non-cardiac co-morbid conditions are present with life expectancy <2 year or that may result in protocol non-compliance (per site investigator's medical judgment)
     18. Female patients who are currently or planning to become pregnant
     19. Female patients who are lactating
     20. Patients participating in other clinical trials

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SGLT2 inhibitor group; SGLT2 inhibitor group will receive Enavogliflozin (0.3mg oral tablet once daily).	Drug: SGLT2 inhibitor; Enavogliflozin (0.3mg oral tablet once daily) will be administrated.; Other Names: SGLT2 inhibitor: Enavogliflozin (Brand names: Envlo tab)
No Intervention: Control group; Control group will not receive any SGLT2 inhibitors during the study period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in peak oxygen consumption (VO2)	Change in peak oxygen consumption (VO2) from baseline to week 24	Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in minute ventilation to carbon dioxide output ratio (VE/VCO2 slope)	Change in minute ventilation to carbon dioxide output ratio (VE/VCO2 slope) from baseline to week 24	Week 24
Change in LV wall thickness before and after maximal exercise	Change in LV wall thickness before and after maximal exercise from baseline to week 24	Week 24
Change in LV global longitudinal strain before and after maximal exercise	Change in LV global longitudinal strain before and after maximal exercise from baseline to week 24	Week 24
Change in LA strain before and after maximal exercise	Change in LA strain before and after maximal exercise from baseline to week 24	Week 24
Change in chronotropic response reserve assessed by change in heart rate from rest to peak exercise	Change in chronotropic response reserve assessed by change in heart rate from rest to peak exercise from baseline to week 24	Week 24
Change in serum iron	Change in serum iron from baseline to week 24	Week 24
Change in ferritin	Change in ferritin from baseline to week 24	Week 24
Change in total iron binding capacity	Change in total iron binding capacity from baseline to week 24	Week 24
Change in hemoglobin	Change in hemoglobin from baseline to week 24	Week 24
All-cause death	All-cause death	Week 24
Hospitalization for heart failure	Hospitalization for heart failure should include all of the following criteria: Hospitalization with primary diagnosis of heart failure; Duration of hospitalization of at least 12 hours; New or worsening symptoms of heart failure; Objective evidence of new or worsening heart failure on physical examination or laboratory findings; Initiation or intensification of heart failure treatment.	Week 24
Change in Left atrial volume index (LAVI) before and after maximal exercise	Change in LAVI before and after maximal exercise from baseline to week 24	Week 24
Change in Lateral Early diastolic transmitral filling velocity over early diastolic relaxation velocity at mitral annulus (E/e') before and after maximal exercise	Change in Lateral E/e' before and after maximal exercise from baseline to week 24	Week 24
Change in Left ventricular mass index (LVMI) before and after maximal exercise	Change in LVMI before and after maximal exercise from baseline to week 24	Week 24
Change in right ventricular (RV) free wall strain before and after maximal exercise	Change in RV free wall strain before and after maximal exercise from baseline to week 24	Week 24
Change in health-related quality of life assessed by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CS)	Change in health-related quality of life assessed by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CS) from baseline to week 24 Score ranges from 0 to 100 and higher value represents better quality of life.	Week 24
Change in N-Terminal pro-B-type Natriuretic Peptide (NT-proBNP) level	Change in NT-proBNP level from baseline to week 24	Week 24

Collaborators and Investigators

• Sponsor: Samsung Medical Center
• Investigators: Principal Investigator: Jeong Hoon Yang, MD, PhD, Samsung Medical Center

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: April 1, 2024
• First Submitted That Met QC Criteria: April 1, 2024
• First Posted (Actual): April 5, 2024

Study Record Updates

• Last Update Posted (Actual): April 8, 2024
• Last Update Submitted That Met QC Criteria: April 5, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Heart failure with preserved ejection fraction; Exercise performance; Sodium glucose cotransporter 2 inhibitors
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Heart Failure, Diastolic; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors
• Other Study ID Numbers: SMC2024-01-089-003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: After publication of first manuscript and trial results, de-identified data will be shared upon reasonable request and with permission from the principal investigator.
• IPD Sharing Time Frame: After publication of first manuscript and trial results, de-identified data will be shared upon reasonable request and with permission from the principal investigator.
• IPD Sharing Access Criteria: After publication of first manuscript and trial results, de-identified data will be shared upon reasonable request and with permission from the principal investigator.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No