Pharmacological Reduction of Right Ventricular Enlargement

NCT04345796 | Completed Phase 3 DMC

• 1 other identifier: 2020-0127
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

Tricuspid Regurgitation; Right Ventricular Dilatation

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Change of RV end-diastolic volume index

  from baseline to 12 months follow-up

• Change of RV ejection fraction

  from baseline to 12 months follow-up

• Change of vena contract width of TR

  from baseline to 12 months follow-up

• Occurrences of death from cardiovascular causes or hospitalization for heart failure

  the entire follow-up period (continuing until 12 months after the last patient was enrolled)

• Occurrences of death from any causes

  the entire follow-up period (continuing until 12 months after the last patient was enrolled)

Study Arms (4)

carvedilol+empagliflozin

ACTIVE COMPARATOR

Patients will receive carvedilol SR 16mg and empagliflozin 10mg qd.

Drug: Carvedilol+Empagliflozin

carvedilol alone

ACTIVE COMPARATOR

Patients will receive carvedilol SR 16mg alone.

Drug: Carvedilol

empagliflozin alone

ACTIVE COMPARATOR

Patients will receive empagliflozin 10mg and matching placebo of carvedilol.

Drug: Empagliflozin

placebo

PLACEBO COMPARATOR

Patients will receive matching placebo of carvedilol.

Drug: Placebo

Interventions

Carvedilol+Empagliflozin DRUG

Group A

Also known as: Dilatrend SR+Jardiance

carvedilol+empagliflozin

Carvedilol DRUG

Group B

Also known as: Dilatrend SR

carvedilol alone

Empagliflozin DRUG

Group C

Also known as: Jardiance

empagliflozin alone

Placebo DRUG

Group D

Also known as: Matching placebo of Dilatrend SR

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
• 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 ≥ 50%
• Dyspnea of NYHA functional class II or III

You may not qualify if:

• 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

Sponsors & Collaborators

• Asan Medical Center: lead
• Chong Kun Dang Pharmaceutical Corporation: collaborator

Study Sites (3)

Asan Medical Center

Seoul, 138-736, South Korea

Location

Samsung Medical Center

Seoul, South Korea

Location

Seoul National University Hospital

Seoul, South Korea

Location

MeSH Terms

Conditions

Tricuspid Valve Insufficiency

Interventions

Carvedilol; empagliflozin

Condition Hierarchy (Ancestors)

Heart Valve Diseases; Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Carbazoles; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 3-Ring

Study Officials

• DUK HYUN KANG

  Asan Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: To study efficacy of carvedilol, participants will be assigned to a carvedilol or to placebo and the identity of the treatment will be concealed by the use of study drugs that are identical in packaging, labeling, appearance and odor. Participants allocated to the SGLT2 inhibitor arm will receive empagliflozin 10mg. All imaging studies will be analyzed by core laboratory investigators who will be blinded to treatment assignment from the time of randomization until database lock.
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: 2 x 2 factorial

Study Record Dates

• First Submitted: April 12, 2020
• First Posted: April 14, 2020
• Study Start: February 15, 2021
• Primary Completion: June 3, 2024
• Study Completion: June 3, 2024
• Last Updated: April 6, 2025

Record last verified: 2025-04

Locations

KR (3)