Pharmacological Reduction of Right Ventricular Enlargement

Tricuspid Regurgitation Clinical Trial

— PROVE  

Official title:

Multicenter, Randomized, 2 x 2 Factorial, Phase 3 Study to Assess the Efficacy of Carvedilol and Empagliflozin on Improvement of Right Ventricular Remodeling in Patients With Severe Functional Tricuspid Regurgitation

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04345796
• Other study ID #: 2020-0127
• Status: Recruiting
• Phase: Phase 3
• Start date: February 15, 2021
• Est. completion date: December 2024

Study information

• Verified date: July 2023
• Source: Asan Medical Center
• Contact: DUK HYUN KANG, MD
• Phone: 82-2-3010-3166
• Email: dhkang[@]amc.seoul.kr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Functional tricuspid regurgitation (TR) has been regarded as a secondary phenomenon of heart failure (HF), mitral valve (MV) disease or atrial fibrillation. Regardless of left ventricular (LV) function or pulmonary artery pressure, presence of moderate or greater functional TR is associated with poor prognosis. When a patient develops functional TR, it causes RV dilation and tricuspid annular enlargement, which also lead to deterioration of TR. A vicious cycle of significant TR, RV volume overload, tricuspid annular dilation and consequent aggravation of TR is accepted as a main determinant of the poor clinical outcome of patients with TR. Therefore, therapies that induce reverse remodeling of the RV and consequently reduce TR, may improve clinical outcomes. However, there have been no proven medical therapies for TR. The investigators hypothesize that carvedilol or empagliflozin is effective on improving RV remodeling in patients with functional severe TR and try to examine this hypothesis in a multicenter, 2x2 factorial, and randomized comparison study using cardiac MRI.

Description:

Functional tricuspid regurgitation (TR) has been regarded as a secondary phenomenon of heart failure (HF), mitral valve (MV) disease or atrial fibrillation. The prevalence of functional TR was reported to be 25-64% in patients with either ischemic or non-ischemic cardiomyopathy. Regardless of left ventricular (LV) function or pulmonary artery pressure, presence of moderate or greater functional TR is associated with poor prognosis. When a patient develops functional TR, it causes RV dilation and tricuspid annular enlargement, which also lead to deterioration of TR. A vicious cycle of significant TR, RV volume overload, tricuspid annular dilation and consequent aggravation of TR is accepted as a main determinant of the poor clinical outcome of patients with TR. Because the quantitative assessment of RV size and function using echocardiography is often limited due to the complex geometry of RV, cardiac magnetic resonance imaging (MRI) has emerged as a gold standard for evaluating RV volume and function with excellent accuracy and reproducibility. The investigators previously reported that RV end-systolic volume index (ESVI) and RV end-diastolic volume index (EDVI) measured by MRI were significantly larger in severe TR patients, and also found that preoperative RV ESVI and RV ejection fraction (EF) on MRI were independent predictors of cardiac death and postoperative adverse events in patients who underwent TV surgery for severe functional TR. Therefore, therapies that induce reverse remodeling of the RV and consequently reduce TR, may improve clinical outcomes. However, there have been no proven medical therapies for TR. The morbidity and mortality of patients with functional TR remain high and novel therapeutic agents are needed to improve the prognosis of patients with functional TR. The investigators hypothesize that carvedilol or empagliflozin is effective on improving RV remodeling in patients with functional severe TR and try to examine this hypothesis in a multicenter, 2x2 factorial, and randomized comparison study using cardiac MRI.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 180
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years and older

Eligibility

Inclusion Criteria:

• Patients must agree to the study protocol and provide written informed consent

• Outpatients = 20 years of age, male or female

• Patients with severe functional tricuspid regurgitation

• TR whose vena contracta =0.7cm or central jet area > 10 square cm and which lasted > 6 months under medical treatment

• LV ejection fraction = 40%

• Dyspnea of NYHA functional class II or III

Exclusion Criteria:

• History of hypersensitivity or allergy to the study drugs, drugs of similar chemical classes, 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

• Significant left-sided valve disease

• Left ventricular ejection fraction <40%

• Marked bradycardia (<50 beats/min) or 2nd or 3rd degree AVB, sinus node dysfunction

• Severe pulmonary hypertension: TR Vmax >4m/s at screening (including Cor pulmonale)

• Medical history of hospitalization within 6 weeks

• Current acute decompensated heart failure or dyspnea of NYHA functional class IV

• Symptomatic hypotension and/or a SBP < 90 mmHg at screening Estimated GFR < 30 mL/min/1.73 square m

• History of ketoacidosis, Type 1 diabetes

• 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 portocaval shunt.

• Acute coronary syndrome, stroke, severe peripheral artery disease or major CV surgery or PCI within 3 months

• History of severe pulmonary disease (asthma, COPD with bronchial hypersensitivity)

• Secondary hypertension such as pheochromocyotoma

• Acute pulmonary thromboembolism

• Variant angina, vocal cord edema, severe allergic rhinitis

• 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

• Contraindication for MRI

• Presence of pacemaker or ICD, implanted metallic objects, claustrophobia

• Severe beat-to-beat variation

• Galactose intolerance, Lapp lactose deficiency, glucose-galactose malabsorption

• 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

Related Conditions & MeSH terms

• Right Ventricular Dilatation
• Tricuspid Regurgitation
• Tricuspid Valve Insufficiency

Intervention

Drug:
• Carvedilol+Empagliflozin
Group A
• Carvedilol
Group B
• Empagliflozin
Group C
• Placebo
Group D

Locations

Country	Name	City	State
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul

Sponsors (2)

Lead Sponsor	Collaborator
Asan Medical Center	Chong Kun Dang Pharmaceutical Company

Country where clinical trial is conducted

Korea, Republic of, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change of RV end-systolic volume index	Change of RV end-systolic volume index by cardiac MRI	from baseline to 12 months follow-up
Secondary	Change of RV end-diastolic volume index	Change of RV end-diastolic volume index by cardiac MRI	from baseline to 12 months follow-up
Secondary	Change of RV ejection fraction	Change of RV ejection fraction by cardiac MRI	from baseline to 12 months follow-up
Secondary	Change of vena contract width of TR	Change of vena contract width of TR by echocardiography	from baseline to 12 months follow-up
Secondary	Occurrences of death from cardiovascular causes or hospitalization for heart failure	Clinical outcome	the entire follow-up period (continuing until 12 months after the last patient was enrolled)
Secondary	Occurrences of death from any causes	Clinical outcome	the entire follow-up period (continuing until 12 months after the last patient was enrolled)