Ertugliflozin for Functional Mitral Regurgitation

• Status: Recruiting
• Trial end date: 2022-09-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Asan Medical Center
• Collaborator: Merck Sharp & Dohme Corp.
• Treatments: 5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-hydroxymethyl-6,8-dioxabicyclo(3.2.1)octane-2,3,4-triol; Ertugliflozin

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