Dapagliflozin Effect on FunctiOnal Mitral Regurgitation and Myocardial Remodeling (DEFORM)

Functional mitral regurgitation (FMR) leads to various adverse outcomes. Cardiac remodeling (CR) and myocardial fibrosis (MF) are closely related to FMR, forming a vicious circle of CR-FMR-MF and resulting in the end-stage heart failure (HF). The optimal therapeutic strategies of FMR require to effectively break the vicious circle of CR-FMR-MF and still remain full of controversy, especially in the appropriate selection of patients suitable for transcatheter treatment. Regardless, adequate guideline-directed medical therapy (GDMT) is always the most important therapy of FMR. Currently GDMT for FMR included β-blockers, renin-angiotensin system (RAS) inhibitors and mineralocorticoid receptor antagonists (MRA). Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, have been proven to be effectively in reducing cardiovascular death and worsening HF in HF patients. However, there is still no evidence support the use of SGLT2i in FMR therapy due to the lack of relevant clinical trial. The DEFORM trial aims to assess the efficacy of dapagliflozin in reducing the extent of mitral regurgitation and myocardial fibrosis in FMR patients. DEFORM trial is a multi-center, prospective, randomized, parallel controlled, investigator-initiated trial enrolling a planned 98 FMR patients. Patients will be randomly assigned in a 1:1 ratio to either dapagliflozin 10mg once daily for 3 months or placebo. The primary outcome is the change in effective regurgitant orifice area (EROA) of mitral regurgitation measured by echocardiography. Secondary end-points include change change in regurgitant volume (RV), left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV) (echocardiography), change in NT-proBNP levels and occurrence of major adverse cardiac events (MACEs).

Study Overview

• Status: Recruiting
• Conditions: Functional Mitral Regurgitation
• Intervention / Treatment: Drug: Dapagliflozin; Other: guideline-directed medical therapy (GDMT)

Detailed Description

Inclusion criteria:

• Patients aged >18 years and <90 years
• LVEF<60% and EROA of mitral regurgitation≥0.2cm2 on echocardiography
• The structure of mitral valve leaf and chordae tendineae is normal
• Patients have received GDMT for FMR including a stable, optimized dose of β-blocker and RAAS inhibitors for at least 2 weeks
• No intravenous anti-heart failure drugs used for the past 2 weeks
• Written informed consent

Exclusion criteria:

• Allergic to dapagliflozin, or angioedema
• Already taking dapagliflozin or other SGLT2 inhibitors
• Presence of primary structural damage to the mitral valve, such as rheumatic heart disease, mitral valve prolapses
• Non-dialysis chronic kidney disease (CKD) patients with eGFR <30ml/min/1.73m2 or dialysis patients
• Acute myocardial infarction and acute myocarditis occurred within 3 months
• Revascularization procedure, CRT, TMVR, surgical valve repair or replacement were performed or planed 3 months before or after enrollment
• Combining significant aortic valve diseases (moderate or severe regurgitation or stenosis)
• Combining hyperthyroidism while thyroid function has not returned to normal
• Pregnant or lactation women

• Study Type: Interventional
• Enrollment (Anticipated): 98
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Xiaodong Zhuang, Dr; Phone Number: +86 02087338190; Email: zhuangxd3@mail.sysu.edu.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510000
      • Recruiting
      • The Third Affiliated Hospital of Sun Yat-Sen University
      • Contact: Zhuoshan Huang, Dr; Phone Number: 86 85252168; Email: huangzhsh3@mail.sysu.edu.cn
    • Guangzhou, Guangdong, China, 510620
      • Recruiting
      • The First Affiliated Hospital of Sun Yat-sen University
      • Contact: Xiaodong Zhuang, Dr; Phone Number: +86 02087338190; Email: zhuangxd3@mail.sysu.edu.cn
    • Meizhou, Guangdong, China, 514799
      • Recruiting
      • The Third Affiliated Hospital of Sun Yat-sen University Yuedong Hospital
      • Contact: Jinlai Liu, Prof; Phone Number: 13503060663; Email: liujinl@mail.sysu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients aged >18 years and <90 years
• LVEF<60% and EROA of mitral regurgitation≥0.2cm2 on echocardiography
• The structure of mitral valve leaf and chordae tendineae is normal
• Patients have received GDMT for FMR including a stable, optimized dose of β-blocker and RAAS inhibitors for at least 2 weeks

Exclusion Criteria:

• Allergic to dapagliflozin, or angioedema
• Already taking dapagliflozin or other SGLT2 inhibitors
• Presence of primary structural damage to the mitral valve, such as rheumatic heart disease, mitral valve prolapses
• Non-dialysis chronic kidney disease (CKD) patients with eGFR <30ml/min/1.73m2 or dialysis patients
• Acute myocardial infarction and acute myocarditis occurred within 3 months
• Revascularization procedure, CRT, TMVR, surgical valve repair or replacement were performed or planed 3 months before or after enrollment
• Combining significant aortic valve diseases (moderate or severe regurgitation or stenosis)
• Combining hyperthyroidism while thyroid function has not returned to normal
• Pregnant or lactation women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: dapagliflozin group; GDMT and dapagliflozin 10mg once daily	Drug: Dapagliflozin; dapagliflozin 10mg once daily for 3 months after randomization; Other: guideline-directed medical therapy (GDMT); guideline-directed medical therapy (GDMT)
Active Comparator: control group; GDMT only	Other: guideline-directed medical therapy (GDMT); guideline-directed medical therapy (GDMT)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EROA of FMR	Change in EROA of mitral regurgitation evaluated by echocardiography from baseline to 12 weeks follow-up	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
cardiac structure	Change in RV measured by echocardiography from baseline to 12 weeks follow-up	3 months
MACE	Occurrence of MACE in 12 weeks follow-up	3 months
cardiac function	Change in serum NT-proBNP levels from baseline to 12 weeks follow-up	3 months

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Investigators: Study Chair: Xiaodong Zhuang, Dr, First Affiliated Hospital, Sun Yat-Sen University

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2022
• Primary Completion (Anticipated): June 30, 2023
• Study Completion (Anticipated): July 31, 2023

Study Registration Dates

• First Submitted: October 30, 2022
• First Submitted That Met QC Criteria: November 4, 2022
• First Posted (Actual): November 7, 2022

Study Record Updates

• Last Update Posted (Estimate): February 28, 2023
• Last Update Submitted That Met QC Criteria: February 26, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Valve Diseases; Mitral Valve Insufficiency; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: DEFORM trial

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No