Ertugliflozin for Functional Mitral Regurgitation (EFFORT)

Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 3 Study to Assess the Efficacy of Ertugliflozin on Reduction of Mitral Regurgitation in Patients With Functional Mitral Regurgitation Secondary to Left Ventricular Dysfunction

In patients with heart failure (HF) and left ventricular (LV) dilation, adverse LV remodeling causes tethering of mitral valve (MV) preventing sufficient coaptation of normal leaflets and resulting in functional MR. Because secondary functional MR usually develops as a result of LV dysfunction, guideline-directed medical therapy for HF forms the mainstay of therapy. However, beta blockers, angiotensin-converting-enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARB) fail to reverse adverse LV remodeling and functional MR, and the morbidity and mortality of patients with functional MR remain high despite standard medical therapy. Randomized trials to explore cardiovascular (CV) benefit of the sodium-glucose co-transporter-2 (SGLT2) inhibitor have been performed and showed a significant reduction on the risk of CV death or hospitalization for HF. However, its effect on cardiac structure and function was not evaluated and further mechanistic studies are needed to interpret beneficial clinical effects of the SGLT2 inhibitors. Based on studies demonstrating SGLT2 inhibitors' favorable effects on LV modeling, investigators hypothesize that SGLT2 inhibitor, ertugliflozin, is effective on improving MR in patients with functional MR secondary to LV dysfunction and try to examine this hypothesis in a multicenter, double-blind, randomized comparison study using echocardiography.

Study Overview

• Status: Completed
• Conditions: Mitral Valve Insufficiency; Left Ventricular Systolic Dysfunction
• Intervention / Treatment: Drug: Placebo; Drug: Ertugliflozin

Detailed Description

In patients with heart failure (HF) and left ventricular (LV) dilation, adverse LV remodeling causes tethering of mitral valve (MV) preventing sufficient coaptation of normal leaflets and resulting in functional MR. Because secondary functional MR usually develops as a result of LV dysfunction, guideline-directed medical therapy for HF forms the mainstay of therapy. However, beta blockers, angiotensin-converting-enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARB) fail to reverse adverse LV remodeling and functional MR, and the morbidity and mortality of patients with functional MR remain high despite standard medical therapy. A recent randomized trial proved that reduction of functional MR by transcatheter MV repair resulted in a lower rate of hospitalization for HF and lower mortality in patients with HF and significant secondary MR, and investigators recently demonstrated that the angiotensin receptor-neprilysin inhibitor (ARNI) is more effective in improving functional MR associated with HF than the ARB in a double-blind, randomized trial. In this trial, investigators enrolled 118 stable HF patients with functional MR, whose effective regurgitant orifice area (EROA) larger than 0.1 cm2, lasting > 6 months despite standard medical treatment, and the primary end point of change in EROA was significantly different between the ARNI group and the ARB group (-0.058±0.095 versus -0.018±0.105 cm2; P=0.032), and a decrease in end-diastolic volume index of the LV was also significantly greater in the ARNI group than in the ARB group (P=0.044).

Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce cardiac preload and afterload by natriuresis and lowering arterial stiffness, similar to the neprilysin inhibitor that facilitates sodium excretion and has vasodilating effects. In addition, effects on blood pressure reduction and weight loss may ultimately have a beneficial effect on LV remodeling. Recently it has been reported that SGLT2 inhibitors have a multifaceted effect on cardiac function including improvement in endothelial dysfunction and aortic stiffness, reduction in epicardial fat accumulation as well as in visceral adipocyte hypertrophy. Randomized trials to explore cardiovascular (CV) benefit of the SGLT2 inhibitor have been performed and showed a significant reduction on the risk of CV death or hospitalization for HF. However, its effect on cardiac structure and function was not evaluated and further mechanistic studies are needed to interpret beneficial clinical effects of the SGLT2 inhibitors. Based on studies demonstrating SGLT2 inhibitors' favorable effects on LV modeling, investigators hypothesize that SGLT2 inhibitor, ertugliflozin, is effective on improving MR in patients with functional MR secondary to LV dysfunction and try to examine this hypothesis in a multicenter, double-blind, randomized comparison study using echocardiography.

• Study Type: Interventional
• Enrollment (Actual): 128
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: DUK HYUN KANG, MD; Phone Number: +82230103166; Email: dhkang@amc.seoul.kr

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Seoul National University Hospital
  • Seoul, Korea, Republic of
    • Asan Medical Center
  • Seoul, Korea, Republic of
    • Samsung Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must agree to the study protocol and provide written informed consent
• Outpatients ≥ 20 years of age, male or female
• Non-diabetic or type2 DM patients with HbA1c 7.0-10.5%

• Patients with secondary functional MR (stage B and C) and LV dysfunction

  • Symptoms due to coronary ischemia or heart failure may be present but symptoms due to MR should be absent
  • Normal mitral valve leaflets and chords
  • Regional or global wall motion abnormalities with mild or severe tethering of leaflet
  • MR whose ERO > 0.10 cm2 and which lasted > 6 months under medical treatment with a β-blocker and an ACE inhibitor (or ARB)
  • 35% < LV ejection fraction < 50%
• Dyspnea of NYHA functional class II or III
• Titration of HF medications should be completed and patients must take a stable, optimized dose of a β-blocker and an ACE inhibitor (or ARB) for at least 4 weeks prior to study entry

Exclusion Criteria:

• History of hypersensitivity or allergy to the study drug, drugs of similar chemical classes, or SGLT-2 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
• Known history of angioedema
• Any evidence of structural mitral valve disease, including prolapse of mitral leaflets and rupture of chords or papillary muscles
• Current acute decompensated heart failure or dyspnea of NYHA functional class IV
• Medical history of hospitalization within 6 weeks
• Symptomatic hypotension and/or a SBP < 100 mmHg at screening
• Estimated GFR < 45 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 portacaval shunt.
• Acute coronary syndrome, stroke, major CV surgery, PCI within 3 months
• Substantial myocardial ischemia requiring coronary revascularization, a plan of coronary revascularization or mitral valve intervention within 1 year
• Indication of cardiac resynchronization therapy, a plan of heart transplantation or implantation of cardiac resynchronization therapy
• History of severe pulmonary disease
• Significant aortic valve 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

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
Placebo Comparator: Placebo; All patients will receive placebo in addition to their usual medications. Titration of HF medications should be completed and patients must take a stable, optimized dose of a β-blocker and an ACE inhibitor (or ARB) for at least 4 weeks prior to study entry.	Drug: Placebo; Placebo qd for 12 months
Active Comparator: Ertugliflozin; All patients will receive ertugliflozin 5 mg qd in addition to their usual medications. Titration of HF medications should be completed and patients must take a stable, optimized dose of a β-blocker and an ACE inhibitor (or ARB) for at least 4 weeks prior to study entry.	Drug: Ertugliflozin; Ertugliflozin 5mg qd for 12 months; Other Names: Steglatro

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of EROA	Change of effective regurgitant orifice area (EROA) of functional mitral regurgitation	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of regurgitant volume	Change of regurgitant volume of functional mitral regurgitation	12 months
Change of end-systolic volume	Change of left ventricular end-systolic volume	12 months
Change of end-diastolic volume	Change of left ventricular end-diastolic volume	12 months
Change of NT-proBNP	Change of NT-proBNP (N-terminal of the prohormone brain natriuretic peptide)	12 months
Change of GLS	Change of left ventricular global longitudinal strain	12 months
Change of LA volume	Change of left atrial volume index	12 months

Collaborators and Investigators

• Sponsor: Asan Medical Center
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: DUK HYUN KANG, MD, Asan Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): November 4, 2020
• Primary Completion (Actual): November 15, 2023
• Study Completion (Actual): November 15, 2023

Study Registration Dates

• First Submitted: January 14, 2020
• First Submitted That Met QC Criteria: January 14, 2020
• First Posted (Actual): January 18, 2020

Study Record Updates

• Last Update Posted (Estimated): November 21, 2023
• Last Update Submitted That Met QC Criteria: November 18, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Valve Diseases; Ventricular Dysfunction; Mitral Valve Insufficiency; Ventricular Dysfunction, Left; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Ertugliflozin
• Other Study ID Numbers: 2019-1690

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