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

Primary Purpose

Idiopathic Dilated Cardiomyopathy

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Carvedilol
Metoprolol succinate
Metoprolol succinate + doxazosin
Sponsored by
University of Colorado, Denver
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Idiopathic Dilated Cardiomyopathy focused on measuring ejection fraction, beta-blocker, carvedilol, metoprolol, myocardial gene expression, human heart, ventricular remodeling, wall stress, adrenergic signaling, myosin heavy chain

Eligibility Criteria

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

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 tolerate magnetic resonance imaging procedures
  • Patient has demonstrated non-compliance with previous medical regimens

Sites / Locations

  • University of Colorado Hospital
  • University of Utah Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

No Intervention

Active Comparator

Active Comparator

Active Comparator

Arm Label

Non-failing control

Metoprolol succinate

Metoprolol succinate + doxazosin

Carvedilol

Arm Description

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

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

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Improvement in LVEF at 3 Months
A secondary outcome will be LVEF response at 3 months, defined as an improvement of ≥ 5% 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.
Composite of All-cause Mortality, Need for Heart Transplant or Need for Ventricular Assist Device.
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. Outcomes 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.

Full Information

First Posted
February 22, 2013
Last Updated
July 16, 2018
Sponsor
University of Colorado, Denver
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), GlaxoSmithKline, AstraZeneca
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1. Study Identification

Unique Protocol Identification Number
NCT01798992
Brief Title
Effect of Beta-blockers on Structural Remodeling and Gene Expression in the Failing Human Heart
Acronym
BORG
Official Title
Beta-blocker Effect on Structural Remodeling and Gene Expression in the Failing Human Heart
Study Type
Interventional

2. Study Status

Record Verification Date
July 2018
Overall Recruitment Status
Completed
Study Start Date
September 2000 (undefined)
Primary Completion Date
March 2009 (Actual)
Study Completion Date
March 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Colorado, Denver
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), GlaxoSmithKline, AstraZeneca

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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: 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). 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Idiopathic Dilated Cardiomyopathy
Keywords
ejection fraction, beta-blocker, carvedilol, metoprolol, myocardial gene expression, human heart, ventricular remodeling, wall stress, adrenergic signaling, myosin heavy chain

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
56 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Non-failing control
Arm Type
No Intervention
Arm Description
Patients with normal ejection fraction who underwent a single myocardial biopsy and received no β-blocker therapy
Arm Title
Metoprolol succinate
Arm Type
Active Comparator
Arm Description
Idiopathic dilated cardiomyopathy patients randomized to metoprolol succinate titrated to a goal of 200 mg by mouth daily for 18 months
Arm Title
Metoprolol succinate + doxazosin
Arm Type
Active Comparator
Arm Description
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
Arm Title
Carvedilol
Arm Type
Active Comparator
Arm Description
Idiopathic dilated cardiomyopathy patients who were randomized to receive carvedilol titrated to a goal of 25 mg by mouth twice daily for 18 months
Intervention Type
Drug
Intervention Name(s)
Carvedilol
Other Intervention Name(s)
Coreg
Intervention Type
Drug
Intervention Name(s)
Metoprolol succinate
Other Intervention Name(s)
Toprol XL
Intervention Type
Drug
Intervention Name(s)
Metoprolol succinate + doxazosin
Other Intervention Name(s)
Toprol XL, Cardura, Carduran
Primary Outcome Measure Information:
Title
Improvement in Left Ventricular Ejection Fraction (LVEF) at 12 Months
Description
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.
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Improvement in LVEF at 3 Months
Description
A secondary outcome will be LVEF response at 3 months, defined as an improvement of ≥ 5% 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.
Time Frame
3 months
Title
Composite of All-cause Mortality, Need for Heart Transplant or Need for Ventricular Assist Device.
Description
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. Outcomes 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.
Time Frame
18 months
Other Pre-specified Outcome Measures:
Title
Change in Myocardial Gene Expression at 3 Months
Description
Changes in myocardial mRNA expression at 3 months compared to baseline using targeted quantitative polymerase chain reaction and genome wide microarray assays. Due to the large number of results genes interrogated (~ 20,000 genes), these results will instead be uploaded to the Gene Expression Omnibus.
Time Frame
3 months
Title
Change in Myocardial Gene Expression at 12 Months
Description
Changes in myocardial mRNA expression at 12 months compared to baseline using targeted quantitative polymerase chain reaction and Affymetrix genome-wide microarray assays. 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.
Time Frame
12 months
Title
Change in Myocardial microRNA Expression at 3 Months
Description
Changes in myocardial microRNA expression at 3 months compared to baseline using an Affymetrix microRNA microarray assay. 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.
Time Frame
3 months
Title
Change in Myocardial microRNA Expression at 12 Months
Description
Changes in myocardial microRNA expression at 12 months compared to baseline using an Affymetrix microRNA microarray assay. 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.
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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: 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) 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 tolerate magnetic resonance imaging procedures Patient has demonstrated non-compliance with previous medical regimens
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael R Bristow, MD PhD
Organizational Affiliation
University of Colorado School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Colorado Hospital
City
Denver
State/Province
Colorado
ZIP/Postal Code
80220
Country
United States
Facility Name
University of Utah Medical Center
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
28138556
Citation
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.
Results Reference
derived
PubMed Identifier
25637602
Citation
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.
Results Reference
derived

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

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