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Pharmacological Reduction of Right Ventricular Enlargement (PROVE)

Primary Purpose

Tricuspid Regurgitation, Right Ventricular Dilatation

Status

Recruiting

Phase

Phase 3

Locations

Korea, Republic of

Study Type

Interventional

Intervention

Carvedilol+Empagliflozin

Carvedilol

Empagliflozin

Placebo

About this trial

This is an interventional treatment trial for Tricuspid Regurgitation

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Asan Medical CenterRecruiting
Samsung Medical Center
Seoul National University Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Placebo Comparator

Arm Label

carvedilol+empagliflozin

carvedilol alone

empagliflozin alone

placebo

Arm Description

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

Patients will receive carvedilol SR 16mg alone.

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

Patients will receive matching placebo of carvedilol.

Outcomes

Primary Outcome Measures

Change of RV end-systolic volume index

Change of RV end-systolic volume index by cardiac MRI

Secondary Outcome Measures

Change of RV end-diastolic volume index

Change of RV end-diastolic volume index by cardiac MRI

Change of RV ejection fraction

Change of RV ejection fraction by cardiac MRI

Change of vena contract width of TR

Change of vena contract width of TR by echocardiography

Occurrences of death from cardiovascular causes or hospitalization for heart failure

Clinical outcome

Occurrences of death from any causes

Clinical outcome

Full Information

NCT ID

NCT04345796

First Posted

April 12, 2020

Last Updated

July 19, 2023

Sponsor

Asan Medical Center

Collaborators

Chong Kun Dang Pharmaceutical Company

1. Study Identification

Unique Protocol Identification Number

NCT04345796

Brief Title

Pharmacological Reduction of Right Ventricular Enlargement

Acronym

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Recruiting

Study Start Date

February 15, 2021 (Actual)

Primary Completion Date

December 2024 (Anticipated)

Study Completion Date

December 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Asan Medical Center

Collaborators

Chong Kun Dang Pharmaceutical Company

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Tricuspid Regurgitation, Right Ventricular Dilatation

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Factorial Assignment

Model Description

2 x 2 factorial

Masking

Outcomes Assessor

Masking Description

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.

Allocation

Randomized

Enrollment

180 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

carvedilol+empagliflozin

Arm Type

Active Comparator

Arm Description

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

Arm Title

carvedilol alone

Arm Type

Active Comparator

Arm Description

Patients will receive carvedilol SR 16mg alone.

Arm Title

empagliflozin alone

Arm Type

Active Comparator

Arm Description

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

Arm Title

placebo

Arm Type

Placebo Comparator

Arm Description

Patients will receive matching placebo of carvedilol.

Intervention Type

Drug

Intervention Name(s)

Carvedilol+Empagliflozin

Other Intervention Name(s)

Dilatrend SR+Jardiance

Intervention Description

Group A

Intervention Type

Drug

Intervention Name(s)

Carvedilol

Other Intervention Name(s)

Dilatrend SR

Intervention Description

Group B

Intervention Type

Drug

Intervention Name(s)

Empagliflozin

Other Intervention Name(s)

Jardiance

Intervention Description

Group C

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

Matching placebo of Dilatrend SR

Intervention Description

Group D

Primary Outcome Measure Information:

Title

Change of RV end-systolic volume index

Description

Change of RV end-systolic volume index by cardiac MRI

Time Frame

from baseline to 12 months follow-up

Secondary Outcome Measure Information:

Title

Change of RV end-diastolic volume index

Description

Change of RV end-diastolic volume index by cardiac MRI

Time Frame

from baseline to 12 months follow-up

Title

Change of RV ejection fraction

Description

Change of RV ejection fraction by cardiac MRI

Time Frame

from baseline to 12 months follow-up

Title

Change of vena contract width of TR

Description

Change of vena contract width of TR by echocardiography

Time Frame

from baseline to 12 months follow-up

Title

Occurrences of death from cardiovascular causes or hospitalization for heart failure

Description

Clinical outcome

Time Frame

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

Title

Occurrences of death from any causes

Description

Clinical outcome

Time Frame

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

20 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

DUK HYUN KANG, MD

Phone

82-2-3010-3166

dhkang@amc.seoul.kr

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

DUK HYUN KANG

Organizational Affiliation

Asan Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Asan Medical Center

City

Seoul

ZIP/Postal Code

138-736

Country

Korea, Republic of

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Duk Hyun Kang, MD, PhD

Phone

82-2-3010-3166

dhkang@amc.seoul.kr

First Name & Middle Initial & Last Name & Degree

Seung-Ah Lee, MD

First Name & Middle Initial & Last Name & Degree

Duk Hyun Kang, MD, PhD

Facility Name

Samsung Medical Center

City

Seoul

Country

Korea, Republic of

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Seung Woo Park, MD, PhD

parksmc@gmail.com

First Name & Middle Initial & Last Name & Degree

Seung Woo Park, MD, PhD

Facility Name

Seoul National University Hospital

City

Seoul

Country

Korea, Republic of

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Yong-Jin Kim, MD, PhD

kimdamas@snu.ac.kr

First Name & Middle Initial & Last Name & Degree

Yong-Jin Kim, MD,PhD

12. IPD Sharing Statement

Plan to Share IPD

Undecided

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Pharmacological Reduction of Right Ventricular Enlargement

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