Ertugliflozin for Functional Mitral Regurgitation

NCT ID: NCT04231331

Last Updated: 2025-01-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 128 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-11-04
• Study Completion Date: 2023-11-15

Brief Summary

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.

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 (GDMT) 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 (COAPT) 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, but more than two-thirds of such patients either died or were hospitalized for HF within 5 years. Thus, optimization of GDMT for timely reduction of functional MR is important, because the persistence of severe functional MR despite GDMT contributes to a vicious cycle of deterioration and leads to irreversible LV dysfunction and a poorer prognosis.

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. 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. Based on remarkable outcomes of recent clinical trials, SGLT2 inhibitors are recommended for HF with reduced EF and can be beneficial in HF with preserved EF. These outcome trials of SGLT2 inhibitors did not examine their effects on cardiac structure and function, and small imaging trials reported conflicting results in terms of the effect of a SGLT2 inhibitor on LV remodeling in patients with HFrEF and diabetes. Despite current recommendations of SGLT2 inhibitors for HF, SGLT2 inhibitors are rarely used in patients with HF with functional MR, as shown in the COAPT trial, because their effects on cardiac remodeling and functional MR are uncertain. The EFFORT trial (Ertugliflozin for Functional Mitral Regurgitation) was designed to evaluate the therapeutic efficacy of the SGLT2 inhibitor, ertugliflozin, on functional MR. The major hypothesis of this trial was that ertugliflozin would be superior to placebo in reducing functional MR associated with HF with mildly or moderately reduced EF.

Conditions

Mitral Valve Insufficiency; Left Ventricular Systolic Dysfunction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo qd for 12 months

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.

Group Type: ACTIVE_COMPARATOR

Ertugliflozin

Intervention Type: DRUG

Ertugliflozin 5mg qd for 12 months

Interventions

Ertugliflozin

Ertugliflozin 5mg qd for 12 months

Intervention Type: DRUG

Placebo

Placebo qd for 12 months

Intervention Type: DRUG

Other Intervention Names

Steglatro

Eligibility Criteria

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

• Minimum Eligible Age: 20 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

Asan Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Duk-Hyun Kang

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

DUK HYUN KANG, MD

Role: PRINCIPAL_INVESTIGATOR

Asan Medical Center

Locations

Asan Medical Center

Seoul, , South Korea

Samsung Medical Center

Seoul, , South Korea

Seoul National University Hospital

Seoul, , South Korea

Countries

South Korea

References

Kang DH, Park SJ, Shin SH, Hwang IC, Yoon YE, Kim HK, Kim M, Kim MS, Yun SC, Song JM, Kang SM. Ertugliflozin for Functional Mitral Regurgitation Associated With Heart Failure: EFFORT Trial. Circulation. 2024 Jun 11;149(24):1865-1874. doi: 10.1161/CIRCULATIONAHA.124.069144. Epub 2024 May 1.

Reference Type: DERIVED

PMID: 38690659 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2019-1690

Identifier Type: -

Identifier Source: org_study_id