SubqBNP: Cardiac Hormone Replacement With Brain Natriuretic Peptide (BNP) in Heart Failure

• Sponsor: Horng Chen (Other)
• Overall Status: Completed
• CT.gov ID: NCT00252187
• Collaborator: American Heart Association (Other), Scios, Inc. (Industry), National Heart, Lung, and Blood Institute (NHLBI) (NIH), National Center for Research Resources (NCRR) (NIH)
• Enrollment: 45
• Location: 1
• Arms: 2
• Duration (Months): 125
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the effects of subcutaneous injection of Human BNP (nesiritide), a hormone produced by the heart, on the pumping ability of the heart, kidney function, and hormonal function in persons with heart failure.

Condition or Disease	Intervention/Treatment	Phase
Congestive Heart Failure; Cardiomyopathy	Drug: B-type Natriuretic Peptide (BNP); Other: Placebo	Phase 1/Phase 2

Detailed Description

The cardiac hormone brain natriuretic peptide (BNP) plays an important role in the pathophysiology of congestive heart failure (CHF). Studies have established that BNP mediates natriuresis, renin and aldosterone (RAAS) inhibition, vasodilation and lusitropism. Acute cardiac hormone replacement with intravenous infusion of BNP has been shown to possess potent vasodilating actions in humans with acute decompensated CHF resulting in improvement of clinical symptoms. Natrecor (nesiritide) a sterile, purified preparation of human BNP is approved by the FDA for intravenous administration in the treatment of patients with acute decompensated congestive heart failure. However, chronic cardiac hormone replacement with BNP as therapeutic strategy in CHF has been limited by the need to administer BNP intravenously. The objective of this study is to define the cardiorenal and humoral actions of short term (eight weeks) chronic cardiac hormone replacement with subcutaneous (SQ) BNP in human NYHA class II-III CHF. Systolic and diastolic function, left ventricular remodeling as assessed by its volume, renal function, neurohumoral profiling and exercise capacity will be assessed prior to and after eight weeks of treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Cardiac Hormone Replacement With BNP in Heart Failure: A Novel Therapeutic Strategy
• Study Start Date: Jan 1, 2000
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Jun 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: B-type Natriuretic Peptide (BNP) BNP (nesiritide) administered subcutaneously twice daily for 8 weeks at 10 mcg/kg.	Drug: B-type Natriuretic Peptide (BNP); BNP hormone self-administered subcutaneously twice daily for 8 weeks at 10 mcg/kg.; Other Names: Nesiritide
Placebo Comparator: Placebo Placebo self-administered subcutaneously twice daily for 8 weeks.	Other: Placebo; Placebo self-administered subcutaneously twice daily for 8 weeks.

Outcome Measures

Primary Outcome Measures

1. Change in Left Ventricular (LV) Volume Index at 8 Weeks [Baseline and 8 weeks]

   LV volume was measured for systolic volume and diastolic volume using a cardiac Magnetic Resonance Imaging (MRI) scan. All cardiac MRI images were reviewed by an independent cardiologist in a blinded fashion.

2. Change in Left Ventricular (LV) Mass Index at 8 Weeks [Baseline and 8 weeks]

Secondary Outcome Measures

1. Change in Left Ventricular (LV) Filling Pressure at 8 Weeks [Baseline and 8 weeks]

   Filling pressure determined by ratio of E/e' [Echocardiograph Doppler mitral inflow velocity (E) to mitral annulus tissue Doppler velocity (e') ratio]

2. Change in Plasma Renin Activity at 8 Weeks [Baseline and 8 weeks]

   Plasma renin is synthesized within circulation or at tissue sites, causing vasoconstriction or vasodilation.

3. Change in Renal Function as Measured by Glomerular Filtration Rate (GFR) at 8 Weeks [Baseline and 8 weeks]

   Kidney function was measured by GFR determined by iothalamate clearance. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney measured in milliliters per minute per 1.73 m^2 of body-surface area. A lower GFR means the kidney is not filtering normally.

4. Change in Heart Rate at 8 Weeks [Baseline and 8 weeks]

   Heart rate was measured when MRI was performed

5. Change in Blood Pressure at 8 Weeks [Baseline and 8 weeks]

   Blood pressure was measured during the MRI

6. Change in Left Ventricular Ejection Fraction at 8 Weeks [Baseline and 8 weeks]

   Left Ventricle Ejection Fraction (LVEF)is a clinical parameter used by cardiologists to describe how well the heart is pumping. LVEF is a measure of the amount of blood pumped out of the lower chamber (ventricle) of the heart during a heartbeat, measured by Magnetic Resonance Imaging (MRI).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Age > 18 years

2. Resting left ventricular ejection fraction (LVEF) of 35% or less (determined within 48 months of recruitment by echocardiography, multiple gate acquisition scan (MUGA) or left ventriculogram.)

3. New York Heart Association (NYHA) Class I (with previous symptoms of heart failure), Class II and III

4. Female subjects not menopausal or surgically sterilized will need to have a negative pregnancy test the day before the study day and be on contraception.

Exclusion Criteria:

1. Myocardial infarction (MI) within 3 months of screening.

2. Unstable angina within 14 days of screening, or any evidence of myocardial ischemia.

3. Valvular stenosis, hypertrophic, restrictive or obstructive cardiomyopathy, constrictive pericarditis, primary pulmonary hypertension, or biopsy proven active myocarditis.

4. Sustained ventricular tachycardia (VT) or ventricular fibrillation (V-fib) within 14 days of screening.

5. Second or third degree atrioventricular (AV) block without a permanent cardiac pacemaker.

6. Cerebrovascular accident (CVA) within 3 months of screening, or other evidence of significantly compromised central nervous system (CNS) perfusion.

7. Serum creatinine of >3.0 mg/dL.

8. Serum sodium of <125 milliequivalents per decaLiter (mEq/dL) or > 160 mEq/dL.

9. Serum potassium of < 3.5 mEq/dL or > 5.2 mEq/dL.

10. Serum digoxin level of > 2.0 ng/ml.

11. Systolic pressure of <85 mmHg immediately prior to the first injection of study drug/placebo.

12. LVEF > 35% by within 24 months of screening.

13. Unable to self-administer subcutaneous injection twice a day.

14. Diagnosed with AIDS or known positive HIV titer.

15. Other acute or chronic medical conditions or laboratory abnormality, which may increase the risks, associated with study participation or may interfere with interpretation of the data.

16. Received an investigational drug within 1 month prior to dosing.

17. Unable to undergo cardiac magnetic resonance imaging (MRI). Contraindications to MRI include pacemaker or defibrillator, pregnant women, atrial fibrillation or other arrhythmia, cerebral aneurysm clips, or severe claustrophobia.

18. In the opinion of the investigator, is unlikely to comply with the study protocol or is unsuitable for any reasons.

19. Patient in atrial fibrillation or who have a pacemaker or implantable cardioverter defibrillator (ICD)

20. Hemoglobin < 10g/dl.

21. Patients with an allergy to iodine.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Horng Chen
• American Heart Association
• Scios, Inc.
• National Heart, Lung, and Blood Institute (NHLBI)
• National Center for Research Resources (NCRR)

Investigators

• Principal Investigator: Horng H. Chen, M.D., Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

None provided.

• Responsible Party: Horng Chen, MD, Professor of Medicine, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00252187
• Other Study ID Numbers: 69-00; R01HL036634; R01HL084155; P01HL076611; UL1RR024150
• First Posted: Nov 11, 2005
• Last Update Posted: Dec 20, 2012
• Last Verified: Dec 1, 2012

• Keywords provided by Horng Chen, MD, Professor of Medicine, Mayo Clinic: Heart failure; Natriuretic peptides; B-type natriuretic peptide; Kidney; Nesiritide; Natrecor; CHF
• Additional relevant MeSH terms: Heart Failure; Cardiomyopathies; Natriuretic Peptide, Brain

Study Results

Participant Flow

Recruitment Details	Participants were recruited from May 2003 to May 2008 at the Mayo Clinic in Rochester, Minnesota.

Arm/Group Title	B-type Natriuretic Peptide (BNP)	Placebo
Arm/Group Description	BNP (nesiritide) hormone self-administered subcutaneously twice daily for 8 weeks at 10 mcg/kg.	Placebo self-administered subcutaneously twice daily for 8 weeks.
Period Title: Overall Study
STARTED	24	21
COMPLETED	20	20
NOT COMPLETED	4	1

Baseline Characteristics

Arm/Group Title	B-type Natriuretic Peptide (BNP)	Placebo	Total
Arm/Group Description	BNP (nesiritide) hormone self-administered subcutaneously twice daily for 8 weeks at 10 mcg/kg.	Placebo self-administered subcutaneously twice daily for 8 weeks.	Total of all reporting groups
Overall Participants	24	21	45
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	11 45.8%	11 52.4%	22 48.9%
>=65 years	13 54.2%	10 47.6%	23 51.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66 (10)	65 (11)	66 (11)
Sex: Female, Male (Count of Participants)
Female	4 16.7%	8 38.1%	12 26.7%
Male	20 83.3%	13 61.9%	33 73.3%
Region of Enrollment (participants) [Number]
United States	24 100%	21 100%	45 100%
Blood pressure (mmHg) [Mean (Standard Deviation) ]
Systolic blood pressure	131 (18)	127 (17)	129 (17)
Diastolic blood pressure	72 (11)	72 (14)	72 (12)
New York Heart Association (NYHA) CHF Classification (participants) [Number]
NYHA CHF Class II	13 54.2%	10 47.6%	23 51.1%
NYHA CHF Class III	2 8.3%	1 4.8%	3 6.7%
Left Ventricle Ejection Fraction (Echo) (Percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage]	32 (9)	31 (7)	31 (8)
Heart Rate (beats per minute) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [beats per minute]	65 (13)	68 (12)	67 (13)
Plasma BNP (picograms/milliliter) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [picograms/milliliter]	51	63	53
Glomerular Filtration Rate (ml/min/1.73 m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ml/min/1.73 m^2]	73 (22)	77 (21)	75 (22)
History or concomitant medical conditions (participants) [Number]
History of peripheral vascular diseases	2 8.3%	1 4.8%	3 6.7%
History of chronic obstructive pulmonary disease	3 12.5%	1 4.8%	4 8.9%
History of Coronary Artery Disease	11 45.8%	11 52.4%	22 48.9%
History of hypertension	10 41.7%	17 81%	27 60%
History of arrythmia	5 20.8%	4 19%	9 20%
History of smoking	10 41.7%	8 38.1%	18 40%
History of diabetes	11 45.8%	7 33.3%	18 40%
History of high cholesterol	15 62.5%	17 81%	32 71.1%
Concomitant Medication(s) (participants) [Number]
ACE I inhib, Angio II receptor blocker or nitrates	23 95.8%	20 95.2%	43 95.6%
Digoxin	8 33.3%	9 42.9%	17 37.8%
Beta blocker	23 95.8%	20 95.2%	43 95.6%
Coumadin	3 12.5%	1 4.8%	4 8.9%
Antiarrhythmics	5 20.8%	0 0%	5 11.1%
Diuretic (loop)	18 75%	15 71.4%	33 73.3%
Diuretic (thiazide)	4 16.7%	3 14.3%	7 15.6%
Diuretic (potassium sparing)	5 20.8%	4 19%	9 20%
Diuretic (Thiazide)	4 16.7%	3 14.3%	7 15.6%

Outcome Measures

1. Primary Outcome

Title	Change in Left Ventricular (LV) Volume Index at 8 Weeks
Description	LV volume was measured for systolic volume and diastolic volume using a cardiac Magnetic Resonance Imaging (MRI) scan. All cardiac MRI images were reviewed by an independent cardiologist in a blinded fashion.
Time Frame	Baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

Per protocol population

Arm/Group Title	B-type Natriuretic Peptide (BNP)	Placebo
Arm/Group Description	BNP (nesiritide) hormone self-administered subcutaneously twice daily for 8 weeks at 10 mcg/kg.	Placebo self-administered subcutaneously twice daily for 8 weeks.
Measure Participants	20	20
End-systolic LV volume index	-5.2 (13)	5.8 (9.6)
End-diastolic LV volume index	-10.0 (15.4)	6.1 (12.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	B-type Natriuretic Peptide (BNP), Placebo
	Comments	Change in end systolic LV volume index compared between two groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	B-type Natriuretic Peptide (BNP), Placebo
	Comments	Change in LV end diastolic volume was compared between two groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Chi-squared
	Comments

2. Secondary Outcome

Title	Change in Left Ventricular (LV) Filling Pressure at 8 Weeks
Description	Filling pressure determined by ratio of E/e' [Echocardiograph Doppler mitral inflow velocity (E) to mitral annulus tissue Doppler velocity (e') ratio]
Time Frame	Baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

Per protocol population

Arm/Group Title	B-type Natriuretic Peptide (BNP)	Placebo
Arm/Group Description	BNP (nesiritide) hormone self-administered subcutaneously twice daily for 8 weeks at 10 mcg/kg.	Placebo self-administered subcutaneously twice daily for 8 weeks.
Measure Participants	20	20
Mean (Standard Deviation) [E/e']	-2.3 (2.5)	1.1 (3.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	B-type Natriuretic Peptide (BNP), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Chi-squared
	Comments

3. Secondary Outcome

Title	Change in Plasma Renin Activity at 8 Weeks
Description	Plasma renin is synthesized within circulation or at tissue sites, causing vasoconstriction or vasodilation.
Time Frame	Baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

Per protocol population

Arm/Group Title	B-type Natriuretic Peptide (BNP)	Placebo
Arm/Group Description	BNP (nesiritide) hormone self-administered subcutaneously twice daily for 8 weeks at 10 mcg/kg.	Placebo self-administered subcutaneously twice daily for 8 weeks.
Measure Participants	20	20
Mean (Standard Deviation) [nanograms per milliliter per hour]	-3.5 (7.1)	2.3 (4.8)

4. Secondary Outcome

Title	Change in Renal Function as Measured by Glomerular Filtration Rate (GFR) at 8 Weeks
Description	Kidney function was measured by GFR determined by iothalamate clearance. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney measured in milliliters per minute per 1.73 m^2 of body-surface area. A lower GFR means the kidney is not filtering normally.
Time Frame	Baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

Per protocol population

Arm/Group Title	B-type Natriuretic Peptide (BNP)	Placebo
Arm/Group Description	BNP (nesiritide) hormone self-administered subcutaneously twice daily for 8 weeks at 10 mcg/kg.	Placebo self-administered subcutaneously twice daily for 8 weeks.
Measure Participants	20	20
Mean (Standard Deviation) [ml/min/1.73 m^2 of body-surface area]	6.9 (14.2)	-2.8 (24.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	B-type Natriuretic Peptide (BNP), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.14
	Comments
	Method	Chi-squared
	Comments

5. Primary Outcome

Title	Change in Left Ventricular (LV) Mass Index at 8 Weeks
Time Frame	Baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

Per protocol population

Arm/Group Title	B-type Natriuretic Peptide (BNP)	Placebo
Arm/Group Description	BNP (nesiritide) hormone self-administered subcutaneously twice daily for 8 weeks at 10 mcg/kg.	Placebo self-administered subcutaneously twice daily for 8 weeks.
Measure Participants	20	20
Mean (Standard Deviation) [mg/m^2]	-4.4 (9.8)	6.2 (12.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	B-type Natriuretic Peptide (BNP), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Chi-squared
	Comments

6. Secondary Outcome

Title	Change in Heart Rate at 8 Weeks
Description	Heart rate was measured when MRI was performed
Time Frame	Baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

Per protocol population

Arm/Group Title	B-type Natriuretic Peptide (BNP)	Placebo
Arm/Group Description	BNP (nesiritide) hormone self-administered subcutaneously twice daily for 8 weeks at 10 mcg/kg.	Placebo self-administered subcutaneously twice daily for 8 weeks.
Measure Participants	20	20
Mean (Standard Deviation) [beats per minute]	-1.6 (8.3)	-0.9 (7.2)

7. Secondary Outcome

Title	Change in Blood Pressure at 8 Weeks
Description	Blood pressure was measured during the MRI
Time Frame	Baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

Per protocol population

Arm/Group Title	B-type Natriuretic Peptide (BNP)	Placebo
Arm/Group Description	BNP (nesiritide) hormone self-administered subcutaneously twice daily for 8 weeks at 10 mcg/kg.	Placebo self-administered subcutaneously twice daily for 8 weeks.
Measure Participants	20	20
Change in systolic blood pressure	-4.9 (22.2)	4.5 (17.7)
Change in diastolic blood pressure	-2.4 (8.5)	0.9 (12.1)

8. Secondary Outcome

Title	Change in Left Ventricular Ejection Fraction at 8 Weeks
Description	Left Ventricle Ejection Fraction (LVEF)is a clinical parameter used by cardiologists to describe how well the heart is pumping. LVEF is a measure of the amount of blood pumped out of the lower chamber (ventricle) of the heart during a heartbeat, measured by Magnetic Resonance Imaging (MRI).
Time Frame	Baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

Per protocol population

Arm/Group Title	B-type Natriuretic Peptide (BNP)	Placebo
Arm/Group Description	BNP (nesiritide) hormone self-administered subcutaneously twice daily for 8 weeks at 10 mcg/kg.	Placebo self-administered subcutaneously twice daily for 8 weeks.
Measure Participants	20	20
Mean (Standard Deviation) [percentage]	0.0 (7.5)	-1.1 (4.2)

Adverse Events

Time Frame	Adverse events were collected over the 8 week study period
Arm/Group Title	BPN Group		Placebo
Arm/Group Description	BNP (nesiritide) administered subcutaneously twice daily for 8 weeks at 10 mcg/kg.		Placebo self-administered subcutaneously twice daily for 8 weeks
All Cause Mortality
	BPN Group		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	BPN Group		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/24 (12.5%)		1/21 (4.8%)
Cardiac disorders
hypotension	1/24 (4.2%)	1	0/21 (0%)	0
lightheadedness	1/24 (4.2%)	2	0/21 (0%)	0
worsening heart failure symptoms	0/24 (0%)	0	1/21 (4.8%)	1
Eye disorders
visual disturbances	1/24 (4.2%)	1	0/21 (0%)	0
Other (Not Including Serious) Adverse Events
	BPN Group		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/24 (83.3%)		17/21 (81%)
Blood and lymphatic system disorders
Flushing	3/20 (15%)	3	1/20 (5%)	1
Edema	1/20 (5%)	1	0/20 (0%)	0
Cardiac disorders
Lightheadedness	3/20 (15%)	3	0/20 (0%)	0
Shortness of Breath and Fatigue	3/20 (15%)	3	7/20 (35%)	7
Atrial Fibrillation	0/20 (0%)	0	1/20 (5%)	1
Gastrointestinal disorders
Loose stools	2/20 (10%)	2	0/20 (0%)	0
GI bleed prior to study drug administration	1/20 (5%)	1	0/20 (0%)	0
General disorders
Flu-like symptoms	1/20 (5%)	1	2/20 (10%)	2
Hepatobiliary disorders
Choledocholithiasis	0/20 (0%)	0	1/20 (5%)	1
Infections and infestations
Head congestion and productive cough	0/20 (0%)	0	1/20 (5%)	1
Metabolism and nutrition disorders
Hyperkalemia	1/20 (5%)	1	1/20 (5%)	1
Renal and urinary disorders
Increased voiding	1/20 (5%)	1	0/20 (0%)	0
Skin and subcutaneous tissue disorders
Injection site sting/itchy	4/20 (20%)	4	3/20 (15%)	3

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.