Natriuretic Peptide System as Therapy in Human Preclinical Left Ventricle Dysfunction

NCT00387621 | Completed Phase 1 Results DMC

• 4 other identifiers: 05-004027P01HL076611R01HL084155UL1RR024150
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Congestive Heart Failure

Keywords

heart failure; diastolic dysfunction; systolic dysfunction; preclinical; natriuretic peptide; B-type natriuretic peptide; cyclic guanosine monophosphate

Outcome Measures

Primary Outcomes (5)

• Change in Natriuresis (Urinary Sodium Excretion) in Control Subjects at 60 Minutes After Volume Expansion Compared to Baseline in Response to Placebo Treatment

  Value at 60 minutes minus value at baseline.

  baseline and 60 minutes

• Placebo Pre-Treatment Urinary Sodium Excretion After Volume Expansion (UnaV)

  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.

  Baseline, 30 min, 60 min

• Placebo Pre-Treatment Urinary cGMP Excretion After Volume Expansion (UcGMPV)

  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.

  Baseline, 30 min, 60 min

• Nesiritide Pre-Treatment Urinary Sodium Excretion After Volume Expansion (UNaV)

  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.

  Baseline, 30 min, 60 min

• Nesiritide Pre-Treatment Urinary cGMP Excretion After Volume Expansion (UcGMPV)

  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.

  Baseline, 30 min, 60 min

Secondary Outcomes (5)

• Change in Urinary Cyclic Guanosine Monophosphate (cGMP) in Control Subjects at 60 Minutes After Volume Expansion Compared to Baseline in Response to Placebo Treatment

  baseline and 60 minutes

• Change in Natriuresis (Urinary Sodium Excretion) at 30 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment

  30 minutes

• Change in Natriuresis (Urinary Sodium Excretion) at 60 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment

  60 minutes

• Change in Urinary Cyclic Guanosine Monophosphate (cGMP) at 30 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment

  30 minutes

• Change in Urinary Cyclic Guanosine Monophosphate (cGMP) at 60 Minutes in Response to Nesiritide Treatment Compared to Placebo Treatment

  60 minutes

Study Arms (2)

Placebo First, then Nesiritide (Arm A)

EXPERIMENTAL

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; Drug: Placebo; Drug: Saline

Nesiritide First, then Placebo (Arm B)

EXPERIMENTAL

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; Drug: Placebo; Drug: Saline

Interventions

Nesiritide DRUG

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.

Also known as: natrecor, human B-type natriuretic peptide (BNP)

Nesiritide First, then Placebo (Arm B); Placebo First, then Nesiritide (Arm A)

Placebo DRUG

The pharmacy created a placebo subcutaneous injection volume to match the volume of the nesiritide dose.

Nesiritide First, then Placebo (Arm B); Placebo First, then Nesiritide (Arm A)

Saline DRUG

Normal saline 0.9% 0.25 ml/kg/min for 60 minutes

Nesiritide First, then Placebo (Arm B); Placebo First, then Nesiritide (Arm A)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.
• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Horng Chen: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• National Center for Research Resources (NCRR): collaborator

Study Sites (1)

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Related Publications (1)

• 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.

  PMID: 22051332 BACKGROUND

MeSH Terms

Conditions

Heart Failure

Interventions

Natriuretic Peptide, Brain; Sodium Chloride

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Natriuretic Peptides; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Nerve Tissue Proteins; Proteins; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Limitations and Caveats

* Different baseline characteristics of the three groups of subjects * Did not define a mechanism for the impaired renal cGMP activation * Future studies needed to determine effects of chronic nesiritide therapy in preclinical HF.

Results Point of Contact

• Title: Dr Horng Chen
• Organization: Mayo Clinic

chen.horng@mayo.edu

507-284-4343

Study Officials

• Horng H. Chen, M.D.

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, Professor of Medicine

Study Record Dates

• First Submitted: October 12, 2006
• First Posted: October 13, 2006
• Study Start: February 1, 2006
• Primary Completion: August 1, 2008
• Study Completion: August 1, 2009
• Last Updated: May 17, 2012
• Results First Posted: May 17, 2012

Record last verified: 2012-04

Locations

US (1)