A Phase 3 interventional study of Ertugliflozin and Placebo in Mitral Valve Insufficiency and Left Ventricular Systolic Dysfunction, sponsored by Asan Medical Center. Completed at 3 sites in Korea, Republic of. Open to participants aged 20 Years and older. Per ClinicalTrials.gov, last updated 2025-01-06.
Sponsored by Asan Medical Center · Phase 3, Interventional, and Treatment
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.
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.
459 studies on the registry are indexed under Mitral Valve Insufficiency; 148 are open to participants now.
This study's enrollment of 128 is above the median of 61 across 274 interventional studies indexed under Mitral Valve Insufficiency.
Browse Mitral Valve Insufficiency studies →Asan Medical Center is the lead sponsor of 562 studies on the registry; 71 are open to participants now.
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Patients with secondary functional MR (stage B and C) and LV dysfunction
Exclusion Criteria:
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
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
Also known as: Steglatro
Placebo qd for 12 months
Change of EROA
Change of effective regurgitant orifice area (EROA) of functional mitral regurgitation
Time frame: Baseline and 12 months
Change of Regurgitant Volume
Change of regurgitant volume of functional mitral regurgitation
Time frame: Baseline and 12 months
Change of End-systolic Volume Index
Left ventricular end-systolic volume was measured with the use of echocardiography. Left ventricular end-systolic volume index was obtained by dividing end-systolic volume by body surface area.
Time frame: Baseline and 12 months
Change of End-diastolic Volume Index
Left ventricular end-diastolic volume was measured with the use of echocardiography. Left ventricular end-diastolic volume index was obtained by dividing end-diastolic volume by body surface area.
Time frame: Baseline and 12 months
Change of NT-proBNP
Change of NT-proBNP (N-terminal of the prohormone brain natriuretic peptide)
Time frame: Baseline and 12 months
Change of Left Ventricular Global Longitudinal Strain
Myocardial strain is a measure of percenage shortening of myocardium. Myocardial strain measurement was performed with a semiautomated alogithm using speckle-tracking echocardiogrphy. Measurements of eft ventricular global longitudinal strain were made in the 3 standard apical views and averaged.
Time frame: Baseline and 12 months
Change of LA End-systolic Volume Index
Left atrial end-systolic volume was measured with the use of echocardiography. Left atrial end-systolic volume index was obtained by dividing end-systolic volume by body surface area.
Time frame: Baseline and 12 months
| Milestone | Placebo | Ertugliflozin |
|---|---|---|
| Started | 65 | 63 |
| Completed | 56 | 58 |
| Not completed | 9 | 5 |
Change of effective regurgitant orifice area (EROA) of functional mitral regurgitation
| square cm | Placebo | Ertugliflozin |
|---|---|---|
| Change of EROA | 0.03 ± 0.12 | -0.05 ± 0.06 |
Change of regurgitant volume of functional mitral regurgitation
| mL | Placebo | Ertugliflozin |
|---|---|---|
| Change of Regurgitant Volume | 39.3 ± 31.1 | 24.6 ± 14.3 |
Left ventricular end-systolic volume was measured with the use of echocardiography. Left ventricular end-systolic volume index was obtained by dividing end-systolic volume by body surface area.
| mL/square m | Placebo | Ertugliflozin |
|---|---|---|
| Change of End-systolic Volume Index | -3.6 ± 13.4 | -4.1 ± 8.1 |
Left ventricular end-diastolic volume was measured with the use of echocardiography. Left ventricular end-diastolic volume index was obtained by dividing end-diastolic volume by body surface area.
| mL/square m | Placebo | Ertugliflozin |
|---|---|---|
| Change of End-diastolic Volume Index | -5.7 ± 17.2 | -4.7 ± 11.0 |
Change of NT-proBNP (N-terminal of the prohormone brain natriuretic peptide)
| pg/mL | Placebo | Ertugliflozin |
|---|---|---|
| Change of NT-proBNP | 126 ± 1112 | -154 ± 815 |
Myocardial strain is a measure of percenage shortening of myocardium. Myocardial strain measurement was performed with a semiautomated alogithm using speckle-tracking echocardiogrphy. Measurements of eft ventricular global longitudinal strain were made in the 3 standard apical views and averaged.
| percent change of myocardial length | Placebo | Ertugliflozin |
|---|---|---|
| Change of Left Ventricular Global Longitudinal Strain | 0.10 ± 2.68 | -1.34 ± 2.57 |
Left atrial end-systolic volume was measured with the use of echocardiography. Left atrial end-systolic volume index was obtained by dividing end-systolic volume by body surface area.
| mL/square m | Placebo | Ertugliflozin |
|---|---|---|
| Change of LA End-systolic Volume Index | 3.2 ± 17.7 | -2.8 ± 13.8 |
Collected over 12 months. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo | 3/65 (4.6%) | 3/65 (4.6%) | 0/65 (0%) |
| Ertugliflozin | 0/63 (0%) | 1/63 (1.6%) | 0/63 (0%) |
| Event | Placebo | Ertugliflozin |
|---|---|---|
| Heart failure hospitalizationCardiac disorders | 3/65 | 1/63 |
| Event | Placebo | Ertugliflozin |
|---|---|---|
| Heart failure hospitalizationCardiac disorders | 0/65 | 0/63 |
| Age, Categorical(Participants) | Placebo | Ertugliflozin | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 50 | 50 | 100 |
| >=65 years | 15 | 13 | 28 |
| Age, Continuous(years) | Placebo | Ertugliflozin | Total |
|---|---|---|---|
| Mean | 67 ± 11 | 65 ± 12 | 66 ± 11 |
| Sex: Female, Male(Participants) | Placebo | Ertugliflozin | Total |
|---|---|---|---|
| Female | 27 | 23 | 50 |
| Male | 38 | 40 | 78 |
| Race and Ethnicity Not Collected(Participants) | Placebo | Ertugliflozin | Total |
|---|---|---|---|
| Count of participants | — | — | 0 |
| Diabetes(Participants) | Placebo | Ertugliflozin | Total |
|---|---|---|---|
| Count of participants | 9 | 7 | 16 |
| Atrial fibrillation(Participants) | Placebo | Ertugliflozin | Total |
|---|---|---|---|
| Count of participants | 32 | 33 | 65 |
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Asan Medical Center