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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Congestive Heart Failure, Cardiomyopathy

Intervention / Treatment
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* Drug: B-type Natriuretic Peptide (BNP)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years 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.) New York Heart Association (NYHA) Class I (with previous symptoms of heart failure), Class II and III 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: Myocardial infarction (MI) within 3 months of screening. Unstable angina within 14 days of screening, or any evidence of myocardial ischemia. Valvular stenosis, hypertrophic, restrictive or obstructive cardiomyopathy, constrictive pericarditis, primary pulmonary hypertension, or biopsy proven active myocarditis. Sustained ventricular tachycardia (VT) or ventricular fibrillation (V-fib) within 14 days of screening. Second or third degree atrioventricular (AV) block without a permanent cardiac pacemaker. Cerebrovascular accident (CVA) within 3 months of screening, or other evidence of significantly compromised central nervous system (CNS) perfusion. Serum creatinine of >3.0 mg/dL. Serum sodium of <125 milliequivalents per decaLiter (mEq/dL) or > 160 mEq/dL. Serum potassium of < 3.5 mEq/dL or > 5.2 mEq/dL. Serum digoxin level of > 2.0 ng/ml. Systolic pressure of <85 mmHg immediately prior to the first injection of study drug/placebo. LVEF > 35% by within 24 months of screening. Unable to self-administer subcutaneous injection twice a day. Diagnosed with AIDS or known positive HIV titer. 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. Received an investigational drug within 1 month prior to dosing. 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. In the opinion of the investigator, is unlikely to comply with the study protocol or is unsuitable for any reasons. Patient in atrial fibrillation or who have a pacemaker or implantable cardioverter defibrillator (ICD) Hemoglobin < 10g/dl. Patients with an allergy to iodine.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: B-type Natriuretic Peptide (BNP)<br>BNP (nesiritide) administered subcutaneously twice daily for 8 weeks at 10 mcg/kg. | Drug: B-type Natriuretic Peptide (BNP)<br>* BNP hormone self-administered subcutaneously twice daily for 8 weeks at 10 mcg/kg.<br>* Other names: Nesiritide;|
| Placebo Comparator: Placebo<br>Placebo self-administered subcutaneously twice daily for 8 weeks. | Other: Placebo<br>* Placebo self-administered subcutaneously twice daily for 8 weeks.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart failure, Natriuretic peptides, B-type natriuretic peptide, Kidney, Nesiritide, Natrecor, CHF