Pharmacological Reduction of Right Ventricular Enlargement (PROVE)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Tricuspid Regurgitation; Right Ventricular Dilatation
• Intervention / Treatment: Drug: Carvedilol+Empagliflozin; Drug: Carvedilol; Drug: Empagliflozin; Drug: Placebo

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 180
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: DUK HYUN KANG, MD; Phone Number: 82-2-3010-3166; Email: dhkang@amc.seoul.kr

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Not yet recruiting
    • Seoul National University Hospital
    • Contact: Yong-Jin Kim, MD, PhD; Email: kimdamas@snu.ac.kr
    • Principal Investigator: Yong-Jin Kim, MD,PhD
  • Seoul, Korea, Republic of, 138-736
    • Recruiting
    • Asan Medical Center
    • Contact: Duk Hyun Kang, MD, PhD; Phone Number: 82-2-3010-3166; Email: dhkang@amc.seoul.kr
    • Contact: Seung-Ah Lee, MD
    • Principal Investigator: Duk Hyun Kang, MD, PhD
  • Seoul, Korea, Republic of
    • Not yet recruiting
    • Samsung Medical Center
    • Contact: Seung Woo Park, MD, PhD; Email: parksmc@gmail.com
    • Principal Investigator: Seung Woo Park, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: carvedilol+empagliflozin; Patients will receive carvedilol SR 16mg and empagliflozin 10mg qd.	Drug: Carvedilol+Empagliflozin; Group A; Other Names: Dilatrend SR+Jardiance
Active Comparator: carvedilol alone; Patients will receive carvedilol SR 16mg alone.	Drug: Carvedilol; Group B; Other Names: Dilatrend SR
Active Comparator: empagliflozin alone; Patients will receive empagliflozin 10mg and matching placebo of carvedilol.	Drug: Empagliflozin; Group C; Other Names: Jardiance
Placebo Comparator: placebo; Patients will receive matching placebo of carvedilol.	Drug: Placebo; Group D; Other Names: Matching placebo of Dilatrend SR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of RV end-diastolic volume index	Change of RV end-diastolic volume index by cardiac MRI	from baseline to 12 months follow-up
Change of RV ejection fraction	Change of RV ejection fraction by cardiac MRI	from baseline to 12 months follow-up
Change of vena contract width of TR	Change of vena contract width of TR by echocardiography	from baseline to 12 months follow-up
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)
Occurrences of death from any causes	Clinical outcome	the entire follow-up period (continuing until 12 months after the last patient was enrolled)

Collaborators and Investigators

• Sponsor: Asan Medical Center
• Collaborators: Chong Kun Dang Pharmaceutical Company
• Investigators: Principal Investigator: DUK HYUN KANG, Asan Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2021
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: April 12, 2020
• First Submitted That Met QC Criteria: April 12, 2020
• First Posted (Actual): April 14, 2020

Study Record Updates

• Last Update Posted (Actual): July 21, 2023
• Last Update Submitted That Met QC Criteria: July 19, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Valve Diseases; Tricuspid Valve Insufficiency; Hypoglycemic Agents; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Protective Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Sodium-Glucose Transporter 2 Inhibitors; Antioxidants; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Empagliflozin; Carvedilol
• Other Study ID Numbers: 2020-0127

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No