Natriuretic Peptide System as Therapy in Human Preclinical Left Ventricle Dysfunction (PPG1)

This study has been completed.
Sponsor:
Collaborators:
Information provided by (Responsible Party):
Horng Chen, Mayo Clinic
ClinicalTrials.gov Identifier:
NCT00387621
First received: October 12, 2006
Last updated: April 18, 2012
Last verified: April 2012

October 12, 2006
April 18, 2012
February 2006
August 2008   (final data collection date for primary outcome measure)
  • Change in Natriuresis (Urinary Sodium Excretion) in Control Subjects at 60 Minutes After Volume Expansion Compared to Baseline in Response to Placebo Treatment [ Time Frame: baseline and 60 minutes ] [ Designated as safety issue: No ]
    Value at 60 minutes minus value at baseline.
  • Placebo Pre-Treatment Urinary Sodium Excretion After Volume Expansion (UnaV) [ Time Frame: Baseline, 30 min, 60 min ] [ Designated as safety issue: No ]
    Subjects received subcutaneous placebo in the abdomen. After 15 minutes, the acute saline load (volume expansion, VE) was administered. Subjects were asked to empty bladder spontaneously every 30 min (if unable to void every 30 min, a urinary catheter was placed). Adequate bladder emptying was insured by ultrasonography. UNaV was collected at baseline (immediately before VE) and at 30 and 60 min after initiation of VE.
  • Placebo Pre-Treatment Urinary cGMP Excretion After Volume Expansion (UcGMPV) [ Time Frame: Baseline, 30 min, 60 min ] [ Designated as safety issue: No ]
    Subjects received subcutaneous placebo in the abdomen. After 15 minutes, the acute saline load (volume expansion, VE) was administered. Subjects were asked to empty bladder spontaneously every 30 min (if unable to void every 30 min, a urinary catheter was placed). Adequate bladder emptying was insured by ultrasonography. UcGMPV was collected at baseline (immediately before VE) and at 30 and 60 min after initiation of VE.
  • Nesiritide Pre-Treatment Urinary Sodium Excretion After Volume Expansion (UNaV) [ Time Frame: Baseline, 30 min, 60 min ] [ Designated as safety issue: No ]
    Subjects received subcutaneous Nesiritide in the abdomen. After 15 minutes, the acute saline load (volume expansion, VE) was administered. Subjects were asked to empty bladder spontaneously every 30 min (if unable to void every 30 min, a urinary catheter was placed). Adequate bladder emptying was insured by ultrasonography. UNaV was collected at baseline (immediately before VE) and at 30 and 60 min after initiation of VE.
  • Nesiritide Pre-Treatment Urinary cGMP Excretion After Volume Expansion (UcGMPV) [ Time Frame: Baseline, 30 min, 60 min ] [ Designated as safety issue: No ]
    Subjects received subcutaneous Nesiritide in the abdomen. After 15 minutes, the acute saline load (volume expansion, VE) was administered. Subjects were asked to empty bladder spontaneously every 30 min (if unable to void every 30 min, a urinary catheter was placed). Adequate bladder emptying was insured by ultrasonography. UcGMPV was collected at baseline (immediately before VE) and at 30 and 60 min after initiation of VE.
  • To define in normal controls, human PSD and PDD the actions of acute SQ BNP on the cardiorenal and humoral function and the integrated response to acute sodium loading dose.
  • In
Complete list of historical versions of study NCT00387621 on ClinicalTrials.gov Archive Site
  • Change in Urinary Cyclic Guanosine Monophosphate (cGMP) in Control Subjects at 60 Minutes After Volume Expansion Compared to Baseline in Response to Placebo Treatment [ Time Frame: baseline and 60 minutes ] [ Designated as safety issue: No ]
    Value at 60 minutes minus value at baseline
  • Change in Natriuresis (Urinary Sodium Excretion) at 30 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment [ Time Frame: 30 minutes ] [ Designated as safety issue: No ]
    Value of natriuresis at 30 min on nesiritide treatment minus value of natriuresis at 30 min on placebo treatment (per subject group). The baseline was not involved in this calculation.
  • Change in Natriuresis (Urinary Sodium Excretion) at 60 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment [ Time Frame: 60 minutes ] [ Designated as safety issue: No ]
    Value of natriuresis at 60 min on nesiritide treatment minus value of natriuresis at 60 min on placebo treatment (per subject group). The baseline was not involved in this calculation.
  • Change in Urinary Cyclic Guanosine Monophosphate (cGMP) at 30 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment [ Time Frame: 30 minutes ] [ Designated as safety issue: No ]
    Value of cGMP at 30 min on nesiritide treatment minus value of cGMP at 30 min on placebo treatment (per subject group). The baseline was not involved in this calculation.
  • Change in Urinary Cyclic Guanosine Monophosphate (cGMP) at 60 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment [ Time Frame: 60 minutes ] [ Designated as safety issue: No ]
    Value of cGMP at 60 min on nesiritide treatment minus value of cGMP at 60 min on placebo treatment (per subject group). The baseline was not involved in this calculation.
  • In subjects with PSD,PDD, acute SQ BNP administration will result in improved renal response to acute sodium loading with an increase in urinary sodium excretion, urine flow, glomerular filtration rate, effective renal plasma flow as compared to placebo
  • Subjects with PSD,PDD, acute SQ BNP administration will result in improved humoral response to acute sodium loading with greater suppression of plasma renin activity, plasma angiotensin II, plasma aldosterone, plasma catecholamines as compared to placebo
Not Provided
Not Provided
 
Natriuretic Peptide System as Therapy in Human Preclinical Left Ventricle Dysfunction
To Define in Normal Controls, Human Preclinical Systolic Dysfunction (PSD) and Preclinical Diastolic Dysfunction (PDD) the Actions of Acute Subcutaneous Nesiritide (BNP) on the Cardiorenal and Humoral Function and the Integrated Response to Acute Sodium Loading

In congestive heart failure, cardiac output is low, blood pressure is high, and the body becomes congested with fluid. In normal people, when there is high blood pressure, the heart muscle cells secrete a hormone that excretes sodium and water in the urine, reducing blood pressure. The action of this hormone is called the natriuretic response. The purpose of this study is to determine if nesiritide can improve an impaired natriuretic response in subjects with asymptomatic systolic heart failure or asymptomatic diastolic heart failure.

The American Heart Association and the American College of Cardiology define stage B heart failure (HF) as asymptomatic subjects with abnormal heart structure/function. With the advancement of cardiac imaging and biomarkers, abnormal heart structure and function can be detected before the development of symptoms. Stage B HF can represent either diastolic or systolic dysfunction and both are at increased risk of adverse cardiac events and development of symptomatic HF.

The broad objective of this study is to define the integrated cardiorenal response to acute volume expansion (VE) in humans with presystolic dysfunction (PSD), prediastolic dysfunction (PDD), and normal cardiac function. We hypothesized that there is an impaired cardiorenal endocrine response to acute VE in PSD and PDD which is characterized by the lack of appropriate activation of urinary cGMP and urinary sodium excretion. Further, we hypothesized that PSD, PDD, and normal control subjects would respond similarly to exogenous administration B-type natriuretic peptide (BNP).

The natriuretic peptides (NPs) are a family of structurally similar but genetically distinct peptides with vasodilating, natriuretic, renin inhibiting, and lusitropic properties. Acute peptide therapy with brain natriuretic peptide (BNP) infusion has recently been approved by the FDA as a therapeutic strategy for the treatment of acute human decompensated congestive HF. We will determine the effects of acute subcutaneous BNP or placebo administration on the integrated cardiorenal and humoral response to acute sodium load (sodium chloride 0.9% 0.25 ml/kg/min for 1 hour) in three groups of subjects: Group 1 normal controls, Group 2 with PSD, and Group 3 with PDD. Doppler echocardiography and tonometry will be used to measure cardiac and vascular function before and during the sodium load. Renal function studies will assess sodium excretion, renal plasma flow, and glomerular filtration rate at baseline, during, and after the sodium load. Blood will be drawn for humoral analysis including catecholamines, renin, aldosterone, angiotensin II, atrial natriuretic peptide (ANP), BNP, and cyclic guanosine monophosphate (cGMP) at baseline, during, and after the sodium load.

Interventional
Phase 1
Phase 2
Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Basic Science
Congestive Heart Failure
  • Drug: Nesiritide
    The first 10 subjects in each group will receive a dose of 5 ug/kg and the next ten subjects will receive 10 ug/kg.
    Other Names:
    • natrecor
    • human B-type natriuretic peptide (BNP)
  • Drug: Placebo
    The pharmacy created a placebo subcutaneous injection volume to match the volume of the nesiritide dose.
  • Drug: Saline
    Normal saline 0.9% 0.25 ml/kg/min for 60 minutes
  • Experimental: Placebo First, then Nesiritide (Arm A)
    In the first intervention period the subjects received subcutaneous placebo given in the abdomen. After a lead in period of 15 minutes, the acute saline load was administered. There was a 2 week washout period. In the second intervention period, the subjects received subcutaneous nesiritide given in the abdomen. After a lead in period of 15 minutes, the acute saline load was administered.
    Interventions:
    • Drug: Nesiritide
    • Drug: Placebo
    • Drug: Saline
  • Experimental: Nesiritide First, then Placebo (Arm B)
    In the first intervention period the subjects received subcutaneous nesiritide given in the abdomen. After a lead in period of 15 minutes, the acute saline load was administered. There was a 2 week washout period. In the second intervention period, the subjects received subcutaneous placebo given in the abdomen. After a lead in period of 15 minutes, the acute saline load was administered.
    Interventions:
    • Drug: Nesiritide
    • Drug: Placebo
    • Drug: Saline
McKie PM, Schirger JA, Costello-Boerrigter LC, Benike SL, Harstad LK, Bailey KR, Hodge DO, Redfield MM, Simari RD, Burnett JC Jr, Chen HH. Impaired natriuretic and renal endocrine response to acute volume expansion in pre-clinical systolic and diastolic dysfunction. J Am Coll Cardiol. 2011 Nov 8;58(20):2095-103. doi: 10.1016/j.jacc.2011.07.042.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
58
August 2009
August 2008   (final data collection date for primary outcome measure)

Inclusion criteria for normal control group:

  • ejection fraction of greater 50%
  • normal Doppler diastolic function with no clinical signs or symptoms
  • history of cardiovascular and renal disease
  • no prior use of any cardiovascular medications.

Inclusion criteria for pre-systolic dysfunction group:

  • ejection fraction of less than 40% with no clinical signs or symptoms of congestive heart failure
  • ability to perform a 6-minute walk of > 450 meters
  • if subjects are not able to walk 450 meters due to pain in hips and knees and not fatigue or shortness of breath, then they will still qualify for the study
  • subjects will all be on stable doses of ACE inhibitor for two weeks prior to the active study date
  • previously prescribed cardiovascular medications are allowed, however, all medications must be at stable doses two weeks prior to the study date.

Inclusion criteria for pre-diastolic dysfunction group:

  • ejection fraction of greater than 50% with moderate or severe diastolic dysfunction as assessed by Doppler echocardiography
  • no signs or symptoms of congestive heart failure
  • ability to perform a 6-minute walk of > 450 meters
  • if subjects are not able to walk 450 meters due to pain in hips and knees and not fatigue or shortness of breath, then they will still qualify for the study
  • previously prescribed cardiovascular medications are allowed, however, all medications must be at stable doses two weeks prior to the study date.

Exclusion criteria for all groups:

  • myocardial infarction within 3 months of screening
  • unstable angina within 14 days of screening, or any evidence of myocardial ischemia
  • significant valvular stenosis, hypertrophic, restrictive or obstructive cardiomyopathy, constrictive pericarditis, primary pulmonary hypertension, or biopsy proven active myocarditis
  • severe congenital heart diseases
  • sustained ventricular tachycardia or ventricular fibrillation within 14 days of screening
  • second or third degree heart block without a permanent cardiac pacemaker
  • stroke within 3 months of screening, or other evidence of significantly compromised CNS perfusion
  • total bilirubin of > 1.5 mg/dL or other liver enzymes >1.5 times the upper limit of normal
  • serum creatinine of > 3.0 mg/dL
  • serum sodium of < 125 mEq/dL or > 160 mEq/dL
  • serum potassium of < 3.5 mEq/dL or > 5.0 mEq/dL
  • serum digoxin level of > 2.0 ng/ml
  • systolic pressure of < 85 mmHg
  • hemoglobin < 10 gm/dl
  • 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
  • patients with an allergy to iodine
  • in the opinion of the investigator, is unlikely to comply with the study protocol or is unsuitable for any reason.
Both
18 Years and older
Yes
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00387621
05-004027, P01HL076611, R01HL084155, UL1RR024150
Yes
Horng Chen, Mayo Clinic
Horng Chen
  • National Heart, Lung, and Blood Institute (NHLBI)
  • National Center for Research Resources (NCRR)
Principal Investigator: Horng H. Chen, M.D. Mayo Clinic
Mayo Clinic
April 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP