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

Cardiac Hormone Replacement With BNP in Heart Failure: A Novel Therapeutic Strategy

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.

Study Overview

• Status: Completed
• Conditions: Congestive Heart Failure; Cardiomyopathy
• Intervention / Treatment: Drug: B-type Natriuretic Peptide (BNP); Other: Placebo

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 Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Left Ventricular (LV) Volume Index at 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.	Baseline and 8 weeks
Change in Left Ventricular (LV) Mass Index at 8 Weeks		Baseline and 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Left Ventricular (LV) Filling Pressure at 8 Weeks	Filling pressure determined by ratio of E/e' [Echocardiograph Doppler mitral inflow velocity (E) to mitral annulus tissue Doppler velocity (e') ratio]	Baseline and 8 weeks
Change in Plasma Renin Activity at 8 Weeks	Plasma renin is synthesized within circulation or at tissue sites, causing vasoconstriction or vasodilation.	Baseline and 8 weeks
Change in Renal Function as Measured by Glomerular Filtration Rate (GFR) at 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.	Baseline and 8 weeks
Change in Heart Rate at 8 Weeks	Heart rate was measured when MRI was performed	Baseline and 8 weeks
Change in Blood Pressure at 8 Weeks	Blood pressure was measured during the MRI	Baseline and 8 weeks
Change in Left Ventricular Ejection Fraction at 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).	Baseline and 8 weeks

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Chen HH, Glockner JF, Schirger JA, Cataliotti A, Redfield MM, Burnett JC Jr. Novel protein therapeutics for systolic heart failure: chronic subcutaneous B-type natriuretic peptide. J Am Coll Cardiol. 2012 Dec 4;60(22):2305-12. doi: 10.1016/j.jacc.2012.07.056. Epub 2012 Nov 1.

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start: January 1, 2000
• Primary Completion (Actual): July 1, 2008
• Study Completion (Actual): June 1, 2010

Study Registration Dates

• First Submitted: November 10, 2005
• First Submitted That Met QC Criteria: November 10, 2005
• First Posted (Estimate): November 11, 2005

Study Record Updates

• Last Update Posted (Estimate): December 20, 2012
• Last Update Submitted That Met QC Criteria: December 19, 2012
• Last Verified: December 1, 2012

More Information

Terms related to this study

• Keywords: Heart failure; Nesiritide; CHF; Kidney; Natrecor; Natriuretic peptides; B-type natriuretic peptide
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Cardiomyopathies; Physiological Effects of Drugs; Natriuretic Agents; Natriuretic Peptide, Brain
• Other Study ID Numbers: 69-00; P01HL076611 (U.S. NIH Grant/Contract); UL1RR024150 (U.S. NIH Grant/Contract); R01HL036634 (U.S. NIH Grant/Contract); R01HL084155 (U.S. NIH Grant/Contract)