Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Pharmacological Reduction of Right Ventricular Enlargement (PROVE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04345796
Recruitment Status : Not yet recruiting
First Posted : April 14, 2020
Last Update Posted : July 9, 2020
Sponsor:
Collaborator:
Chong Kun Dang Pharmaceutical Company
Information provided by (Responsible Party):
Duk-Hyun Kang, Asan Medical Center

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.

Condition or disease Intervention/treatment Phase
Tricuspid Regurgitation Right Ventricular Dilatation Drug: Carvedilol+Empagliflozin Drug: Carvedilol Drug: Empagliflozin Drug: Placebo Phase 3

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Intervention Model Description: 2 x 2 factorial
Masking: Single (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.

Primary Purpose: Treatment
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
Estimated Study Start Date : August 2020
Estimated Primary Completion Date : May 2023
Estimated Study Completion Date : May 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: carvedilol+empagliflozin
Patients will receive carvedilol SR 16mg and empagliflozin 10mg qd.
Drug: Carvedilol+Empagliflozin
Group A
Other Name: Dilatrend SR+Jardiance

Active Comparator: carvedilol alone
Patients will receive carvedilol SR 16mg alone.
Drug: Carvedilol
Group B
Other Name: Dilatrend SR

Active Comparator: empagliflozin alone
Patients will receive empagliflozin 10mg and matching placebo of carvedilol.
Drug: Empagliflozin
Group C
Other Name: Jardiance

Placebo Comparator: placebo
Patients will receive matching placebo of carvedilol.
Drug: Placebo
Group D
Other Name: Matching placebo of Dilatrend SR




Primary Outcome Measures :
  1. Change of RV end-systolic volume index [ Time Frame: from baseline to 12 months follow-up ]
    Change of RV end-systolic volume index by cardiac MRI


Secondary Outcome Measures :
  1. Change of RV end-diastolic volume index [ Time Frame: from baseline to 12 months follow-up ]
    Change of RV end-diastolic volume index by cardiac MRI

  2. Change of RV ejection fraction [ Time Frame: from baseline to 12 months follow-up ]
    Change of RV ejection fraction by cardiac MRI

  3. Change of vena contract width of TR [ Time Frame: from baseline to 12 months follow-up ]
    Change of vena contract width of TR by echocardiography

  4. Occurrences of death from cardiovascular causes or hospitalization for heart failure [ Time Frame: the entire follow-up period (continuing until 12 months after the last patient was enrolled) ]
    Clinical outcome

  5. Occurrences of death from any causes [ Time Frame: the entire follow-up period (continuing until 12 months after the last patient was enrolled) ]
    Clinical outcome



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04345796


Contacts
Layout table for location contacts
Contact: DUK HYUN KANG, MD 82-2-3010-3166 dhkang@amc.seoul.kr

Locations
Layout table for location information
Korea, Republic of
Asan Medical Center
Seoul, Korea, Republic of, 138-736
Samsung Medical Center
Seoul, Korea, Republic of
Seoul National University Hospital
Seoul, Korea, Republic of
Sponsors and Collaborators
Asan Medical Center
Chong Kun Dang Pharmaceutical Company
Investigators
Layout table for investigator information
Principal Investigator: DUK HYUN KANG Asan Medical Center
Layout table for additonal information
Responsible Party: Duk-Hyun Kang, Professor, Asan Medical Center
ClinicalTrials.gov Identifier: NCT04345796    
Other Study ID Numbers: 2020-0127
First Posted: April 14, 2020    Key Record Dates
Last Update Posted: July 9, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Tricuspid Valve Insufficiency
Cardiovascular Diseases
Heart Valve Diseases
Heart Diseases
Empagliflozin
Carvedilol
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Antihypertensive Agents
Antioxidants
Protective Agents
Calcium Channel Blockers
Membrane Transport Modulators
Calcium-Regulating Hormones and Agents
Vasodilator Agents
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists