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
  Purpose

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.


Condition Intervention Phase
Congestive Heart Failure
Drug: Nesiritide
Drug: Placebo
Drug: Saline
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Basic Science
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Enrollment: 58
Study Start Date: February 2006
Study Completion Date: August 2009
Primary Completion Date: August 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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: 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.
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

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00387621

Locations
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Horng Chen
Investigators
Principal Investigator: Horng H. Chen, M.D. Mayo Clinic
  More Information

Additional Information:
Publications:
Responsible Party: Horng Chen, MD, Professor of Medicine, Mayo Clinic
ClinicalTrials.gov Identifier: NCT00387621     History of Changes
Obsolete Identifiers: NCT00818974
Other Study ID Numbers: 05-004027, P01HL076611, R01HL084155, UL1RR024150
Study First Received: October 12, 2006
Results First Received: October 26, 2011
Last Updated: April 18, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Mayo Clinic:
heart failure
diastolic dysfunction
systolic dysfunction
preclinical
natriuretic peptide
B-type natriuretic peptide
cyclic guanosine monophosphate

Additional relevant MeSH terms:
Heart Failure
Cardiovascular Diseases
Heart Diseases
Natriuretic Peptide, Brain
Cardiovascular Agents
Natriuretic Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014