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Enavogliflozin Outcome Trial in Functional Tricuspid Regurgitation (EVENT)

Primary Purpose

Tricuspid Regurgitation, Heart Failure With Preserved Ejection Fraction

Status
Recruiting
Phase
Phase 3
Locations
Korea, Republic of
Study Type
Interventional
Intervention
Enavogliflozin
Placebo
Sponsored by
Asan Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tricuspid Regurgitation

Eligibility Criteria

20 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Patients must agree to the study protocol and provide written informed consent Outpatients male or female between the age of 20 and 80 Non-diabetic or type2 DM patients with HbA1c 6.5-10.5% HF with dyspnea of NYHA functional class II or III Presence of moderate or severe functional TR and preserved LVEF on echocardiography TR whose vena contracta ≥ 0.3cm, effective regurgitant orifice area ≥ 0.20 cm2, or jet area > 10cm2 LVEF ≥ 50% NT-proBNP >125 pg/mL or BNP ≥35 pg/mL Exclusion Criteria: History of hypersensitivity or allergy to the study drugs, drugs of similar chemical classes, as well as known or suspected contraindications to the study drug Current use or prior use of a SGLT-2 inhibitor or combined SGLT-1 and 2 inhibitor Any evidence of structural tricuspid valve disease Any significant left-sided valve disease Left ventricular ejection fraction <50% Marked bradycardia or 2nd or 3rd degree AV block Intracardiac devices (CRT, ICD, Pacemaker) Hypertrophic or restrictive cardiomyopathy Severe pulmonary hypertension: TR Vmax > 3.5m/s at screening Medical history of hospitalization within 4 weeks Current acute decompensated heart failure or dyspnea of NYHA functional class IV Symptomatic hypotension and/or a SBP < 90 mmHg at screening Uncontrolled hypertension (SBP≥180mmHg or DBP≥110mmHg) Estimated GFR < 30 mL/min/1.73m2 History of ketoacidosis Evidence of hepatic disease as determined by any one of the following: AST or ALT values exceeding 2 x upper limit of normal (ULN) at screening visit (Visit 0), history of hepatic encephalopathy, history of esophageal varices, or history of portocaval shunt. Acute coronary syndrome, stroke, major CV surgery, PCI within 3 months Plan for cardiac surgery, PCI or ablation of atrial flutter of fibrillation History of severe pulmonary disease Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using a barrier method plus a hormonal method Pregnant or nursing (lactating) women Any clinically significant abnormality identified at the screening visit, physical examination, laboratory tests, or electrocardiogram which, in the judgment of the investigator, would preclude safe completion of the study

Sites / Locations

  • Inha University Hospital
  • Asan Medical CenterRecruiting
  • Samsung Medical CenterRecruiting
  • Seoul National University Hospital
  • Yonsei University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Enavogliflozin

Placebo

Arm Description

Enavogliflozin 0.3 mg qd for 18 months

Placebo qd for 18 months

Outcomes

Primary Outcome Measures

Cardiovascular event
A composite of cardiovascular death, hospitalization for HF, or worsening of tricuspid regurgitation that occurs during follow-up

Secondary Outcome Measures

All-cause death
All-cause death occurring during follow-up
Cardiovascular clinical event
A cardiovascular composite (cardiovascular mortality or hospitalization for HF) occurring during follow-up
Renal event
A renal composite (doubling of serum creatinine, decrease in the eGFR of 30% or more, renal replacement therapy, or renal death) occurring during follow-up
Change of TR
Change of TR on echocardiography from baseline to 18 months follow-up
Change of RV strain
Change of RV strain on echocardiography from baseline to 18 months follow-up

Full Information

First Posted
August 31, 2023
Last Updated
October 13, 2023
Sponsor
Asan Medical Center
Collaborators
Daewoong Pharmaceutical Co. LTD.
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1. Study Identification

Unique Protocol Identification Number
NCT06027307
Brief Title
Enavogliflozin Outcome Trial in Functional Tricuspid Regurgitation
Acronym
EVENT
Official Title
Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the Effects of Enavogliflozin on Outcomes in Patients With Functional Tricuspid Regurgitation and Heart Failure With Preserved Left Ventricular Ejection Fraction
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 2023 (Anticipated)
Primary Completion Date
April 2026 (Anticipated)
Study Completion Date
October 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Asan Medical Center
Collaborators
Daewoong Pharmaceutical Co. LTD.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The Enavogliflozin Outcome Trial in Functional Tricuspid Regurgitation (EVENT) was designed to examine the hypothesis that, compared with placebo, therapy with the SGLT2 inhibitor enavogliflozin would improve clinical and echocardiographic outcomes in heart failure (HF) patients with functional tricuspid regurgitation (TR) and preserved left ventricular ejection fraction (LVEF). The primary objective of the EVENT study is to test the hypothesis that, compared with placebo, therapy with enavogliflozin for 18 months would improve a composite of cardiovascular events or worsening of TR on follow-up echocardiography in HF patients with functional TR and preserved LVEF. The secondary objective is to examine whether enavogliflozin is effective in reduction of renal events and tricuspid regurgitation, and to evaluate whether beneficial effects of enavogliflozin on primary outcomes are associated with reduction of all-cause mortality.
Detailed Description
Functional tricuspid regurgitation (TR) develops due to functional and structural alterations related to heart failure (HF), mitral valve disease and atrial fibrillation. An increase in cardiac filling pressure due to left ventricular (LV) systolic or diastolic dysfunction leads to left atrial, right atrial (RA) and right ventricular (RV) remodeling, which causes tricuspid annular dilatation and TR. The development of significant functional TR causes RV dysfunction and further dilation of RV, which deteriorates TR. Functional TR may occur with HF with preserved or reduced ejection fraction (EF), and the prevalence of moderate-to-severe functional TR is around 19% in patients with HF. Regardless of LVEF or pulmonary artery pressure, presence of moderate or severe functional TR is associated with more symptoms, reduced cardiac output, and worse renal function. A vicious cycle of significant TR, RV volume overload, adverse remodeling of RA, RV, and tricuspid annulus, and consequent aggravation of TR is suggested as a pathophysiologic mechanism of the poor clinical outcomes of patients with TR, and the presence of moderate or severe functional TR is a strong independent determinant of mortality in patients with HF. Because functional TR has a strong prognostic impact and plays an important pathophysiologic role in patients with HF, functional TR is suggested as a therapeutic target in HF. However, there have been no proven medical therapies for TR and only loop diuretics are cautiously recommended for relief of congestive symptoms in patients with severe TR and signs of RV failure. In patients with functional TR associated with systolic dysfunction, medical therapy for HF with a reduced EF may diminish functional TR by improving LV systolic function. Otherwise, the morbidity and mortality of patients with functional TR remain high and a novel therapeutic agent is needed to improve clinical outcomes of HF patients with functional TR and a preserved LV ejection fraction. Sodium-glucose co-transporter 2 (SGLT2) inhibitors induce urinary excretion of glucose and sodium by blocking the SGLT2 transporter in the proximal tubule (8). SGLT2 inhibitor-induced natriuresis lower cardiac preload and reduce pulmonary congestion and systemic edema. SGLT2 inhibitors also restore tubuloglomerular feedback and lower the intraglomerular pressure by vasoconstriction of the afferent arterioles and consequently reduce hyperfiltration-related renal damage. The beneficial effects of SGLT2 inhibitors on the heart and kidneys may halt the vicious cardiorenal cycle in patients with functional TR (9), which results in deterioration of renal function, hospitalization for heart failure, and cardiovascular mortality. Accordingly, the Enavogliflozin Outcome Trial in Functional Tricuspid Regurgitation (EVENT) will test the hypothesis that, compared with placebo, therapy with the SGLT2 inhibitor enavogliflozin for 18 months would improve clinical and echocardiographic outcomes in HF patients with functional TR and preserved LVEF.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tricuspid Regurgitation, Heart Failure With Preserved Ejection Fraction

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
540 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Enavogliflozin
Arm Type
Experimental
Arm Description
Enavogliflozin 0.3 mg qd for 18 months
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo qd for 18 months
Intervention Type
Drug
Intervention Name(s)
Enavogliflozin
Other Intervention Name(s)
Envlo (brand name)
Intervention Description
All study patients will receive enavogliflozin in addition to their prior medications. They will receive optimal medical treatment for their underlying disease such as hypertension, diabetes, arrhythmia and/or coronary artery disease.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
All study patients will receive placebo in addition to their prior medications. They will receive optimal medical treatment for their underlying disease such as hypertension, diabetes, arrhythmia and/or coronary artery disease.
Primary Outcome Measure Information:
Title
Cardiovascular event
Description
A composite of cardiovascular death, hospitalization for HF, or worsening of tricuspid regurgitation that occurs during follow-up
Time Frame
18 months
Secondary Outcome Measure Information:
Title
All-cause death
Description
All-cause death occurring during follow-up
Time Frame
18 months
Title
Cardiovascular clinical event
Description
A cardiovascular composite (cardiovascular mortality or hospitalization for HF) occurring during follow-up
Time Frame
18 months
Title
Renal event
Description
A renal composite (doubling of serum creatinine, decrease in the eGFR of 30% or more, renal replacement therapy, or renal death) occurring during follow-up
Time Frame
18 months
Title
Change of TR
Description
Change of TR on echocardiography from baseline to 18 months follow-up
Time Frame
18 months
Title
Change of RV strain
Description
Change of RV strain on echocardiography from baseline to 18 months follow-up
Time Frame
18 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must agree to the study protocol and provide written informed consent Outpatients male or female between the age of 20 and 80 Non-diabetic or type2 DM patients with HbA1c 6.5-10.5% HF with dyspnea of NYHA functional class II or III Presence of moderate or severe functional TR and preserved LVEF on echocardiography TR whose vena contracta ≥ 0.3cm, effective regurgitant orifice area ≥ 0.20 cm2, or jet area > 10cm2 LVEF ≥ 50% NT-proBNP >125 pg/mL or BNP ≥35 pg/mL Exclusion Criteria: History of hypersensitivity or allergy to the study drugs, drugs of similar chemical classes, as well as known or suspected contraindications to the study drug Current use or prior use of a SGLT-2 inhibitor or combined SGLT-1 and 2 inhibitor Any evidence of structural tricuspid valve disease Any significant left-sided valve disease Left ventricular ejection fraction <50% Marked bradycardia or 2nd or 3rd degree AV block Intracardiac devices (CRT, ICD, Pacemaker) Hypertrophic or restrictive cardiomyopathy Severe pulmonary hypertension: TR Vmax > 3.5m/s at screening Medical history of hospitalization within 4 weeks Current acute decompensated heart failure or dyspnea of NYHA functional class IV Symptomatic hypotension and/or a SBP < 90 mmHg at screening Uncontrolled hypertension (SBP≥180mmHg or DBP≥110mmHg) Estimated GFR < 30 mL/min/1.73m2 History of ketoacidosis Evidence of hepatic disease as determined by any one of the following: AST or ALT values exceeding 2 x upper limit of normal (ULN) at screening visit (Visit 0), history of hepatic encephalopathy, history of esophageal varices, or history of portocaval shunt. Acute coronary syndrome, stroke, major CV surgery, PCI within 3 months Plan for cardiac surgery, PCI or ablation of atrial flutter of fibrillation History of severe pulmonary disease Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using a barrier method plus a hormonal method Pregnant or nursing (lactating) women Any clinically significant abnormality identified at the screening visit, physical examination, laboratory tests, or electrocardiogram which, in the judgment of the investigator, would preclude safe completion of the study
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
DUK HYUN KANG, MD
Phone
82-2-3010-3166
Email
dhkang@amc.seoul.kr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
DUK HYUN KANG, MD
Organizational Affiliation
Asan Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Inha University Hospital
City
Incheon
Country
Korea, Republic of
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sung-Hee Shin, M.D.
Email
ssshin@inha.ac.kr
Facility Name
Asan Medical Center
City
Seoul
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
DUK HYUN KANG
Facility Name
Samsung Medical Center
City
Seoul
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sung-Ji Park
Facility Name
Seoul National University Hospital
City
Seoul
Country
Korea, Republic of
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hyung-Kwan Kim, MD, PhD
First Name & Middle Initial & Last Name & Degree
Hyung-Kwan Kim, MD,PhD
Facility Name
Yonsei University Medical Center
City
Seoul
Country
Korea, Republic of
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Chi-Young Shim, MD, PhD
First Name & Middle Initial & Last Name & Degree
Chi-Young Shim, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Enavogliflozin Outcome Trial in Functional Tricuspid Regurgitation

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