Effects of Chimeric Natriuretic Peptide Versus Placebo in Stable Heart Failure and Moderate Renal Dysfunction

Study Overview
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Brief Summary
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The overall aim is to conduct a human physiologic study to assess the renal and neurohumoral effects of CD-NP vs placebo in older subjects with stable chronic systolic heart failure and moderate renal dysfunction.

Detailed Description
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The investigators will evaluate the renal and neurohumoral effects of dual receptor (NPR-A and NPR-B) activation with CD-NP. This is a clinically relevant patient population who is at increased risk of developing diuretic resistance during the treatment of HF exacerbations.

Official Title
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A Human Physiologic Study to Evaluate the Renal and Neurohumoral Effects of Dual NPR-A and NPR-B Activation With a Novel Chimeric Natriuretic Peptide (CD-NP)in Subjects With Stable Chronic Heart Failure and Moderate Renal Dysfunction

Conditions
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Heart Failure, Renal Insufficiency

Intervention / Treatment
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* Drug: CD-NP
* Drug: 5% Dextrose in Water


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and non-pregnant female with stable chronic HF of primary cardiac etiology, resting left ventricular ejection fraction (LVEF) ≤ 40 % documented within the last 2 years. Moderate renal dysfunction with creatinine clearance of 30-60 ml.min-1.1.73m-2, as calculated by Cockcroft-Gault formula24 and adjusted for body surface area within the past year or at screening, or requirement for dialysis. Be willing to provide informed consent. Exclusion Criteria: Known allergy or other adverse reactions to exogenous natriuretic peptides (CD-NP or its components, nesiritide, other natriuretic peptides, or related compounds). Women who are pregnant, or breast-feeding, on hormonal contraceptives or hormone replacement therapy. (Women should be in the post-menopausal state, defined as the absence of menses for ≥ 1 year and serum follicle-stimulating hormone ≥ 20 IU/L; or should be previously sterilized defined as bilateral tubal occlusion for ≥ 6 months, bilateral oophorectomy, or complete hysterectomy) Having received nesiritide for within 7 days prior to prior to entry into the study. Having received any investigational drug or device within 30 days prior to entry into the study. Clinically unstable patients (e.g. systolic blood pressure < 90 mmHg, ongoing requirement for vasopressors or mechanical circulatory support, or mechanical ventilation). Recent hospitalization for decompensated HF or recent defibrillation for cardiac resuscitation within 30 days prior to randomization. Prior organ transplantation, being on a waiting list for organ transplantation, or ongoing requirement for long-term vasoactive support. Prior requirement for dialysis or ultrafiltration Active urinary tract infection Patients with guarded prognosis who are unlikely to derive meaningful benefit from CD-NP. Use of sulfonamides, non-steroidal anti-inflammatory drugs, probenecid, or other drugs that are known to alter renal function within one week of the first dose of CD-NP or placebo. Presence of cardiac lesions or comorbidities that may contraindicate the use of natriuretic peptides, such as clinically significant cardiac valvular stenosis, hypertrophic cardiomyopathy, restrictive cardiomyopathy, constrictive pericarditis, primary pulmonary hypertension, or uncorrected congenital heart disease that contraindicates the use of vasodilators. History of blood pressure > 190/115 mmHg or unexplained syncope within the past 3 months. Symptomatic carotid artery disease, known critical carotid stenosis, or stroke within the past 3 months Clinically significant renal artery stenosis Baseline hemoglobin < 10.0 g/dl. Serum sodium < 130 mEq/L, potassium < 3.6 mEq/L, or magnesium < 1.7 mEq/L. Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at least 5 times the upper limit of normal or bilirubin at least 3 times the upper limit of normal History of alcohol abuse within the past 6 months. Consumption of a phosphodiesterase-5 inhibitor (sildenafil, vardenafil, or tadalafil) within 72 hours of receiving CD-NP or placebo. Inability to communicate effectively with study personnel. BMI >38

Ages Eligible for Study
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Minimum Age: 45 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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 5% Dextrose in Water<br>Infusion of D5W | Drug: 5% Dextrose in Water<br>* four hour infusion IV<br>* Other names: D5W;|
| Active Comparator: CD-NP<br>CD-NP as a four hour infusion at 10 ng/kg/min IV | Drug: CD-NP<br>* CD-NP as a four hour infusion at 10 ng/kg/min IV<br>* Other names: Chimeric natriuretic peptide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in renal parameters | Renal parameters Glomerular filtration rate, tubular function Renal plasma flow Urine output Urinary sodium and potassium excretion Urinary NGAL for early, acute alterations in renal function Change in value = [(Value during C2 + Value during C3)/2 ] - Value during C1 | 1-hour period before drug or placebo infusion (baseline) and average of two 2-hour periods of drug or placebo infusion collected in a 5-hour period on the study day | 
| Change in hormonal parameters | Hormonal parameters Plasma cyclic GMP, ANP, BNP, NT-proBNP, CNP, renin, angiotensin II, aldosterone, and norepinephrine Urinary cyclic GMP, ANP, BNP, CNP Plasma and urinary CD-NP Change in value = [(Value during C2 + Value during C3)/2 ] - Value during C1 | 1-hour period before drug or placebo infusion (baseline) and average of two 2-hour periods of drug or placebo infusion collected in a 5-hour period on the study day | 
| Change in hemodynamic parameters | Hemodynamic parameters • Mean arterial pressure, heart rate Change in value = [(Value during C2 + Value during C3)/2 ] - Value during C1 | 1-hour period before drug or placebo infusion (baseline) and average of two 2-hour periods of drug or placebo infusion collected in a 5-hour period on the study day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CD NP, dual receptor, NPR A, NPR B, Adult, aged over 45