Ertugliflozin for Functional Mitral Regurgitation

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Mitral Valve Insufficiency, Left Ventricular Systolic Dysfunction

Intervention / Treatment
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* Drug: Ertugliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>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<br>* Placebo qd for 12 months<br>|
| Active Comparator: Ertugliflozin<br>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<br>* Ertugliflozin 5mg qd for 12 months<br>* Other names: Steglatro;|

What is the study measuring?
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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 |