Effect of Beta-blockers on Structural Remodeling and Gene Expression in the Failing Human Heart

NCT01798992 | Completed Phase 4 Results DMC

• 2 other identifiers: 00-02422R01HL048013
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 2

Brief Summary

The primary goal of the study is to measure in the intact human heart, the alterations in gene expression over time that are associated with reverse remodeling in response to β-blockade. The second goal is to investigate the signaling mechanisms which in turn are responsible for these changes in gene expression, and the third goal is to determine the relationship between intrinsic systolic dysfunction and remodeling of the left ventricle. This will be accomplished by measuring ventricular size, function, and gene expression in myocardial tissue samples obtained by percutaneous biopsy prior to initiation of β-blockade and at 3 and 12 months after start of therapy. The specific Aims and Hypotheses to be tested are:

1. 1.Aim: Determine the changes in gene expression associated with changes in intrinsic systolic function and with functional decompensation in the intact, failing human heart.
2. 2.Aim: Identify signaling mechanisms responsible for alterations in expression of key genes involved in mediation of ventricular hypertrophy or contractile dysfunction.
3. 3.Aim: In the relationship between contractile dysfunction and dilatation/remodeling, determine the relationship between contractile dysfunction and structural remodeling.

Conditions

Idiopathic Dilated Cardiomyopathy

Keywords

ejection fraction; beta-blocker; carvedilol; metoprolol; myocardial gene expression; human heart; ventricular remodeling; wall stress; adrenergic signaling; myosin heavy chain

Outcome Measures

Primary Outcomes (1)

• Improvement in Left Ventricular Ejection Fraction (LVEF) at 12 Months

  The primary clinical outcome will be LVEF response at 12 months defined as an improvement in LVEF of ≥ 8% at 12 months or if not available, ≥5% at 3 months in the absence of an adverse clinical outcome. Data are not presented for non-failing controls, who only went baseline evaluation and did not undergo treatment, given that they did not have heart failure.

  12 months

Secondary Outcomes (2)

• Improvement in LVEF at 3 Months

  3 months

• Composite of All-cause Mortality, Need for Heart Transplant or Need for Ventricular Assist Device.

  18 months

Other Outcomes (4)

• Change in Myocardial Gene Expression at 3 Months

  3 months

• Change in Myocardial Gene Expression at 12 Months

  12 months

• Change in Myocardial microRNA Expression at 3 Months

  3 months

Study Arms (4)

Non-failing control

NO INTERVENTION

Patients with normal ejection fraction who underwent a single myocardial biopsy and received no β-blocker therapy

Metoprolol succinate

ACTIVE COMPARATOR

Idiopathic dilated cardiomyopathy patients randomized to metoprolol succinate titrated to a goal of 200 mg by mouth daily for 18 months

Drug: Metoprolol succinate

Metoprolol succinate + doxazosin

ACTIVE COMPARATOR

Idiopathic dilated cardiomyopathy patients who were randomized to receive metoprolol succinate and doxazosin titrated to a goal of 200 mg and 8 mg by mouth daily for 18 months

Drug: Metoprolol succinate + doxazosin

Carvedilol

ACTIVE COMPARATOR

Idiopathic dilated cardiomyopathy patients who were randomized to receive carvedilol titrated to a goal of 25 mg by mouth twice daily for 18 months

Drug: Carvedilol

Interventions

Carvedilol DRUG

Also known as: Coreg

Carvedilol

Metoprolol succinate DRUG

Also known as: Toprol XL

Metoprolol succinate

Metoprolol succinate + doxazosin DRUG

Also known as: Toprol XL, Cardura, Carduran

Metoprolol succinate + doxazosin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Idiopathic dilated cardiomyopathy with New York Heart Association Class II-IV symptoms
• No evidence of coronary artery disease by angiography within 2 years of randomization
• If female, patient is (a) surgically sterile or (b) practices an accepted method of birth control and has negative serum pregnancy test
• Patient has been on other conventional cardiac heart failure(CHF) therapy at least 3 weeks prior to baseline assessments (includes angiotensin converting enzyme inhibitors, digoxin, diuretics, and/or vasodilators)
• Patient has left ventricular ejection fraction \< 40% by radionuclide ventriculography within 60 days of randomization
• Patient must demonstrate mental and physical ability and willingness to follow all study-specific instructions
• Patient must voluntarily sign Institutional Review Board (IRB)-approved informed consent form prior to any study-specific procedure

You may not qualify if:

• Patient has heart failure due to or associated with uncorrected primary valvular disease, uncorrected thyroid disease, obstructive/hypertrophic cardiomyopathy, pericardial disease, amyloidosis, active myocarditis, or malfunctioning artificial heart valve.
• Patient is actively on heart transplant list or anticipated to be within 6 months of randomization
• Patient is receiving any of the following medicines:
• Calcium channel blockers
• Theophylline
• Tricyclic antidepressants
• Monoamine oxidase inhibitors
• β-agonists
• β-adrenergic blocking agent (oral)
• Any investigational cardiovascular medication or involvement in another investigational trial
• Flecainide, encainide, propafenone, sotalol, disopyramide, or amiodarone
• Patient has a contraindication to β-blockade (eg asthma)
• Patient has another life-threatening disease with life expectancy \< 2 years due to other illness
• Patient has active hepatic, renal, hematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease which may adversely affect the safety and efficacy of the study drug or life span of the patient
• Unstable decompensated heart failure (evidence of hypoperfusion, acute pulmonary edema, or hypotension with SBP \< 80 mm Hg)

Sponsors & Collaborators

• University of Colorado, Denver: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• GlaxoSmithKline: collaborator
• AstraZeneca: collaborator

Study Sites (2)

University of Colorado Hospital

Denver, Colorado, 80220, United States

Location

University of Utah Medical Center

Salt Lake City, Utah, 84132, United States

Location

Related Publications (2)

• Sucharov CC, Kao DP, Port JD, Karimpour-Fard A, Quaife RA, Minobe W, Nunley K, Lowes BD, Gilbert EM, Bristow MR. Myocardial microRNAs associated with reverse remodeling in human heart failure. JCI Insight. 2017 Jan 26;2(2):e89169. doi: 10.1172/jci.insight.89169.

  PMID: 28138556 DERIVED

• Kao DP, Lowes BD, Gilbert EM, Minobe W, Epperson LE, Meyer LK, Ferguson DA, Volkman AK, Zolty R, Borg CD, Quaife RA, Bristow MR. Therapeutic Molecular Phenotype of beta-Blocker-Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy. Circ Cardiovasc Genet. 2015 Apr;8(2):270-83. doi: 10.1161/CIRCGENETICS.114.000767. Epub 2015 Jan 30.

  PMID: 25637602 DERIVED

MeSH Terms

Conditions

Cardiomyopathy, Dilated; Ventricular Remodeling

Interventions

Carvedilol; Metoprolol; Doxazosin

Condition Hierarchy (Ancestors)

Cardiomegaly; Heart Diseases; Cardiovascular Diseases; Cardiomyopathies; Laminopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms

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; Phenoxypropanolamines; Prazosin; Quinazolines

Results Point of Contact

• Title: Dr. Michael Bristow, MD PhD
• Organization: University of Colorado, Denver

Michael.Bristow@ucdenver.edu

303-724-5453

Study Officials

• Michael R Bristow, MD PhD

  University of Colorado School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 22, 2013
• First Posted: February 26, 2013
• Study Start: September 1, 2000
• Primary Completion: March 1, 2009
• Study Completion: March 1, 2009
• Last Updated: November 29, 2023
• Results First Posted: February 20, 2017

Record last verified: 2023-11

Locations

US (2)