Ertugliflozin for Functional Mitral Regurgitation

NCT04231331 | Completed Phase 3 Results DMC

• 1 other identifier: 2019-1690
• Study Type: interventional
• Target: 128
• Locations: 1 country
• Sites: 3

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.

Conditions

Mitral Valve Insufficiency; Left Ventricular Systolic Dysfunction

Outcome Measures

Primary Outcomes (1)

• Change of EROA

  Change of effective regurgitant orifice area (EROA) of functional mitral regurgitation

  Baseline and 12 months

Secondary Outcomes (6)

• Change of Regurgitant Volume

  Baseline and 12 months

• Change of End-systolic Volume Index

  Baseline and 12 months

• Change of End-diastolic Volume Index

  Baseline and 12 months

• Change of NT-proBNP

  Baseline and 12 months

• Change of Left Ventricular Global Longitudinal Strain

  Baseline and 12 months

Study Arms (2)

Placebo

PLACEBO COMPARATOR

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

Ertugliflozin

ACTIVE COMPARATOR

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

Interventions

Ertugliflozin DRUG

Ertugliflozin 5mg qd for 12 months

Also known as: Steglatro

Ertugliflozin

Placebo DRUG

Placebo qd for 12 months

Placebo

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• % \< 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Asan Medical Center: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (3)

Asan Medical Center

Seoul, South Korea

Location

Samsung Medical Center

Seoul, South Korea

Location

Seoul National University Hospital

Seoul, South Korea

Location

Related Publications (1)

• 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.

  PMID: 38690659 DERIVED

MeSH Terms

Conditions

Mitral Valve Insufficiency; Ventricular Dysfunction, Left

Interventions

ertugliflozin

Condition Hierarchy (Ancestors)

Heart Valve Diseases; Heart Diseases; Cardiovascular Diseases; Ventricular Dysfunction

Limitations and Caveats

Because enrollment of trial patients was affected by the COVID-19 pandemic, the present trial did not reach the calculated sample size.

Results Point of Contact

• Title: Professor Duk-Hyun Kang
• Organization: Asan Medical Center

dhkang@amc.seoul.kr

821030103166

Study Officials

• DUK HYUN KANG, MD

  Asan Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: January 14, 2020
• First Posted: January 18, 2020
• Study Start: November 4, 2020
• Primary Completion: November 15, 2023
• Study Completion: November 15, 2023
• Last Updated: January 6, 2025
• Results First Posted: January 6, 2025

Record last verified: 2024-11

Locations

KR (3)