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

This study has been completed.
Sponsor:
Collaborators:
GlaxoSmithKline
AstraZeneca
Information provided by (Responsible Party):
University of Colorado, Denver
ClinicalTrials.gov Identifier:
NCT01798992
First received: February 22, 2013
Last updated: May 1, 2013
Last verified: January 2013
  Purpose

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. Aim: Determine the changes in gene expression associated with changes in intrinsic systolic function and with functional decompensation in the intact, failing human heart.

    a. Hypothesis: Changes in the expression of select genes precede or accompany changes in left ventricular systolic function in humans with idiopathic dilated cardiomyopathy (IDC).

  2. Aim: Identify signaling mechanisms responsible for alterations in expression of key genes involved in mediation of ventricular hypertrophy or contractile dysfunction.

    a. Hypothesis: Myocardial-failure-associated regulation of select messenger ribonucleic acids and proteins are related to left ventricular wall stress and neurohormonal signaling.

  3. Aim: In the relationship between contractile dysfunction and dilatation/remodeling, determine the relationship between contractile dysfunction and structural remodeling.

    b. Hypothesis: the contractile dysfunction is primary and structural remodeling secondary.


Condition Intervention Phase
Idiopathic Dilated Cardiomyopathy
Drug: Carvedilol
Drug: Metoprolol succinate
Drug: Metoprolol succinate + doxazosin
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Beta-blocker Effect on Structural Remodeling and Gene Expression in the Failing Human Heart

Resource links provided by NLM:


Further study details as provided by University of Colorado, Denver:

Primary Outcome Measures:
  • Improvement in left ventricular ejection fraction (LVEF) at 12 months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Improvement in LVEF at 3 months [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    A secondary outcome will be LVEF response at 3 months, defined as an improvement of ≥ 5%

  • Composite of all-cause mortality, need for heart transplant or need for ventricular assist device [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    Clinical status at 18 months will be assessed at time of study completion, specifically for the composite outcome of all-cause mortality, need for heart transplant, or need for ventricular assist device.


Other Outcome Measures:
  • Change in myocardial gene expression at 3 months [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Changes in myocardial mRNA expression at 3 months compared to baseline using targeted quantitative polymerase chain reaction and genome wide microarray assays

  • Change in myocardial gene expression at 12 months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Changes in myocardial mRNA expression at 12 months compared to baseline using targeted quantitative polymerase chain reaction and Affymetrix genome-wide microarray assays

  • Change in myocardial microRNA expression at 3 months [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Changes in myocardial microRNA expression at 3 months compared to baseline using an Affymetrix microRNA microarray assay

  • Change in myocardial microRNA expression at 12 months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Changes in myocardial microRNA expression at 12 months compared to baseline using an Affymetrix microRNA microarray assay


Enrollment: 51
Study Start Date: September 2000
Study Completion Date: March 2009
Primary Completion Date: March 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: Non-failing control
Patients with normal ejection fraction who underwent a single myocardial biopsy and received no β-blocker therapy
Active Comparator: Metoprolol succinate
Idiopathic dilated cardiomyopathy patients randomized to metoprolol succinate titrated to a goal of 200 mg by mouth daily for 18 months
Drug: Metoprolol succinate
Other Name: Toprol XL
Active Comparator: Metoprolol succinate + doxazosin
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
Other Names:
  • Toprol XL
  • Cardura
  • Carduran
Active Comparator: Carvedilol
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
Other Name: Coreg

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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:

    1. Calcium channel blockers
    2. Theophylline
    3. Tricyclic antidepressants
    4. Monoamine oxidase inhibitors
    5. β-agonists
    6. β-adrenergic blocking agent (oral)
    7. Any investigational cardiovascular medication or involvement in another investigational trial
    8. 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)
  • Patient is actively abusing ethanol or illicit drugs within 3 months of randomization
  • Patient has an automatic implantable cardiac defibrillator that has fired within 3 months of randomization
  • Patient has an asymptomatic waking, resting heart rate < 50 bpm or symptomatic bradycardia < 60 bpm.
  • Patient has uncontrolled insulin-dependent diabetes mellitus with a history of frequent hypoglycemia episodes
  • Patient has a high degree atrioventricular block (Mobitz Type II or complete heart block)
  • Patient is unable to go magnetic resonance imaging procedures
  • Patient has demonstrated non-compliance with previous medical regimens
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01798992

Locations
United States, Colorado
University of Colorado Hospital
Denver, Colorado, United States, 80220
United States, Utah
University of Utah Medical Center
Salt Lake City, Utah, United States, 84132
Sponsors and Collaborators
University of Colorado, Denver
GlaxoSmithKline
AstraZeneca
Investigators
Principal Investigator: Michael R Bristow, MD PhD University of Colorado School of Medicine
  More Information

No publications provided

Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT01798992     History of Changes
Other Study ID Numbers: 00-0242, 2R01HL048013
Study First Received: February 22, 2013
Last Updated: May 1, 2013
Health Authority: United States: Institutional Review Board
United States: Data and Safety Monitoring Board
United States: Federal Government

Keywords provided by University of Colorado, Denver:
ejection fraction
beta-blocker
carvedilol
metoprolol
myocardial gene expression
human heart
ventricular remodeling
wall stress
adrenergic signaling
myosin heavy chain

Additional relevant MeSH terms:
Cardiomyopathy, Dilated
Cardiomyopathies
Cardiomegaly
Heart Diseases
Cardiovascular Diseases
Adrenergic beta-Antagonists
Metoprolol
Metoprolol succinate
Carvedilol
Doxazosin
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Antihypertensive Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Adrenergic beta-1 Receptor Antagonists
Vasodilator Agents
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists

ClinicalTrials.gov processed this record on July 26, 2014