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

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT01798992
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), GlaxoSmithKline (Industry), AstraZeneca (Industry)
• Enrollment: 56
• Locations: 2
• Arms: 4
• Duration (Months): 101.9
• Patients Per Site: 28
• Patients Per Site Per Month: 0.3

Study Details

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:

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.

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

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

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

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

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

Condition or Disease	Intervention/Treatment	Phase
Idiopathic Dilated Cardiomyopathy	Drug: Carvedilol; Drug: Metoprolol succinate; Drug: Metoprolol succinate + doxazosin	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 56 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Beta-blocker Effect on Structural Remodeling and Gene Expression in the Failing Human Heart
• Study Start Date: Sep 1, 2000
• Actual Primary Completion Date: Mar 1, 2009
• Actual Study Completion Date: Mar 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
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 Names: 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 Names: Coreg

Outcome Measures

Primary Outcome Measures

1. Improvement in Left Ventricular Ejection Fraction (LVEF) at 12 Months [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

1. Improvement in LVEF at 3 Months [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.

2. Composite of All-cause Mortality, Need for Heart Transplant or Need for Ventricular Assist Device. [18 months]

   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.

Other Outcome Measures

1. Change in Myocardial Gene Expression at 3 Months [3 months]

   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.

2. Change in Myocardial Gene Expression at 12 Months [12 months]

   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.

3. Change in Myocardial microRNA Expression at 3 Months [3 months]

   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.

4. Change in Myocardial microRNA Expression at 12 Months [12 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Hospital	Denver	Colorado	United States	80220
2	University of Utah Medical Center	Salt Lake City	Utah	United States	84132

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Michael R Bristow, MD PhD, University of Colorado School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT01798992
• Other Study ID Numbers: 00-0242; 2R01HL048013
• First Posted: Feb 26, 2013
• Last Update Posted: Aug 14, 2018
• Last Verified: Jul 1, 2018

• 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: Cardiomyopathies; Cardiomyopathy, Dilated; Metoprolol; Carvedilol; Doxazosin

Study Results

Participant Flow

Recruitment Details	Patients were recruited between 9/1/2000 and 3/1/2008 from outpatient general cardiology and heart failure specialty clinics at the University of Colorado Hospital and University of Utah Health Sciences Center.
Pre-assignment Detail	65 patients met screening criteria and provided consent. Exclusions included personal preference (4), administrative reasons such as relocation (2), normalization of LVEF prior to assignment (2), and lack of central venous access (1).

Arm/Group Title	Non-failing Control	Metoprolol Succinate	Metoprolol Succinate + Doxazosin	Carvedilol
Arm/Group 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 Metoprolol succinate	Idiopathic dilated cardiomyopathy patients who were randomized to receive metoprolol succinate and doxazosin mesylate titrated to goals of 200 mg (metoprolol succinate) and 8 mg (doxazosin mesylate) by mouth daily for 18 months Metoprolol succinate + doxazosin	Idiopathic dilated cardiomyopathy patients who were randomized to receive carvedilol titrated to a goal of 25 mg by mouth twice daily for 18 months Carvedilol
Period Title: Overall Study
STARTED	4	19	16	17
COMPLETED	4	17	14	16
NOT COMPLETED	0	2	2	1

Baseline Characteristics

Arm/Group Title	Non-failing Control	Metoprolol Succinate	Metoprolol Succinate + Doxazosin	Carvedilol	Total
Arm/Group 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 Metoprolol succinate	Idiopathic dilated cardiomyopathy patients who were randomized to receive metoprolol succinate and doxazosin mesylate titrated to goals of 200 mg (metoprolol succinate) and 8 mg (doxazosin mesylate) by mouth daily for 18 months Metoprolol succinate + doxazosin	Idiopathic dilated cardiomyopathy patients who were randomized to receive carvedilol titrated to a goal of 25 mg by mouth twice daily for 18 months Carvedilol	Total of all reporting groups
Overall Participants	4	19	16	17	56
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.0 (17.1)	45.9 (13.6)	46.0 (7.5)	44.9 (15.1)	45.3 (12.8)
Sex: Female, Male (Count of Participants)
Female	1 25%	4 21.1%	6 37.5%	5 29.4%	16 28.6%
Male	3 75%	15 78.9%	10 62.5%	12 70.6%	40 71.4%
Race/Ethnicity, Customized (participants) [Number]
European Ancestry	4 100%	15 78.9%	9 56.3%	13 76.5%	41 73.2%
African Ancestry	0 0%	1 5.3%	4 25%	0 0%	5 8.9%
Hispanic	0 0%	2 10.5%	1 6.3%	4 23.5%	7 12.5%
Other	0 0%	1 5.3%	2 12.5%	0 0%	3 5.4%
Region of Enrollment (participants) [Number]
United States	4 100%	19 100%	16 100%	17 100%	56 100%
LV ejection fraction (%) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [%]	58.8 (7.4)	22.5 (7.1)	28.5 (8.7)	28.6 (8.7)	28.6 (11.9)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Idiopathic dilated cardiomyopathy patients naive to beta-blocker therapy

Arm/Group Title	Metoprolol Succinate	Metoprolol Succinate + Doxazosin	Carvedilol
Arm/Group Description	Idiopathic dilated cardiomyopathy patients randomized to metoprolol succinate titrated to a goal of 200 mg by mouth daily for 18 months Metoprolol succinate	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 Metoprolol succinate + doxazosin	Idiopathic dilated cardiomyopathy patients who were randomized to receive carvedilol titrated to a goal of 25 mg by mouth twice daily for 18 months Carvedilol
Measure Participants	17	14	16
Number [LVEF responders]	12	10	9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metoprolol Succinate, Metoprolol Succinate + Doxazosin, Carvedilol
	Comments	The null hypothesis is that there is no difference in rate of LVEF improvement according to treatment group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.685
	Comments
	Method	Fisher Exact
	Comments

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metoprolol Succinate	Metoprolol Succinate + Doxazosin	Carvedilol
Arm/Group Description	Idiopathic dilated cardiomyopathy patients randomized to metoprolol succinate titrated to a goal of 200 mg by mouth daily for 18 months Metoprolol succinate	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 Metoprolol succinate + doxazosin	Idiopathic dilated cardiomyopathy patients who were randomized to receive carvedilol titrated to a goal of 25 mg by mouth twice daily for 18 months Carvedilol
Measure Participants	17	14	16
Number [LVEF responders]	16	10	10

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metoprolol Succinate, Metoprolol Succinate + Doxazosin, Carvedilol
	Comments	The null hypothesis is that there is no difference in rate of LVEF improvement according to treatment group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.071
	Comments
	Method	Fisher Exact
	Comments

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Idiopathic dilated cardiomyopathy patients randomized to different beta-blocker strategies. Data does not include non-failing controls, as these patients only underwent baseline evaluation with no treatment or follow-up, given that they did not have heart failure.

Arm/Group Title	Metoprolol Succinate	Metoprolol Succinate + Doxazosin	Carvedilol
Arm/Group Description	Idiopathic dilated cardiomyopathy patients randomized to metoprolol succinate titrated to a goal of 200 mg by mouth daily for 18 months Metoprolol succinate	Idiopathic dilated cardiomyopathy patients who were randomized to receive metoprolol succinate and doxazosin mesylate titrated to goals of 200 mg (metoprolol succinate) and 8 mg (doxazosin mesylate) by mouth daily for 18 months Metoprolol succinate + doxazosin	Idiopathic dilated cardiomyopathy patients who were randomized to receive carvedilol titrated to a goal of 25 mg by mouth twice daily for 18 months Carvedilol
Measure Participants	17	14	16
Number [participants]	1 25%	0 0%	0 0%

4. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	18 months
Arm/Group Title	Metoprolol Succinate		Metoprolol Succinate + Doxazosin		Carvedilol
Arm/Group Description	Idiopathic dilated cardiomyopathy patients randomized to metoprolol succinate titrated to a goal of 200 mg by mouth daily for 18 months Metoprolol succinate		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 Metoprolol succinate + doxazosin		Idiopathic dilated cardiomyopathy patients who were randomized to receive carvedilol titrated to a goal of 25 mg by mouth twice daily for 18 months Carvedilol
All Cause Mortality
	Metoprolol Succinate		Metoprolol Succinate + Doxazosin		Carvedilol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Metoprolol Succinate		Metoprolol Succinate + Doxazosin		Carvedilol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/14 (0%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	Metoprolol Succinate		Metoprolol Succinate + Doxazosin		Carvedilol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/14 (0%)		0/16 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.