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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Heart Failure; Renal Insufficiency
• Intervention / Treatment: Drug: 5% Dextrose in Water; Drug: CD-NP

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: John A. Schirger
• Collaborators: National Institutes of Health (NIH)
• Investigators: Principal Investigator: John Schirger, MD, Mayo Clinic

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: July 27, 2011
• First Submitted That Met QC Criteria: August 1, 2011
• First Posted (Estimate): August 2, 2011

Study Record Updates

• Last Update Posted (Estimate): June 17, 2014
• Last Update Submitted That Met QC Criteria: June 16, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Keywords: CD NP; dual receptor; NPR A; NPR B; Adult, aged over 45
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Kidney Diseases; Urologic Diseases; Heart Failure; Renal Insufficiency
• Other Study ID Numbers: 09-008619