Hypertension
Conditions
Brief summary
Hypothesis: If the use of B-type natriuretic peptide (BNP) is proven to be effective in controlling high blood pressure, it may lead to a reduction of standard therapy and improved cardiovascular and kidney protection.
Detailed description
Hypertension remains a global burden in cardiovascular disease leading to stroke, myocardial infarction, and heart failure. Its myocardial complications result from increased mechanical load on the heart. Under physiological conditions of increased myocardial load and resulting myocardial stretch, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) synthesis and secretion occur contributing to maintenance of optimal cardiorenal and blood pressure homeostasis. However, studies indicate that in subjects with cardiovascular diseases the biological structure of these hormones may be altered, thus reducing their favorable protective activities. New studies indicate that early and moderate hypertension is associated with a derangement of the natriuretic peptide system which is characterized by the lack of activation of biologically active ANP and BNP, while severe hypertension is characterized by cardiac release of altered molecular forms of ANP and BNP that have reduced biological properties and/or enhanced degradation. The broad objective of proposal is to advance the biology and therapeutics of the natriuretic peptides (NPs) with a special focus on the cardiac peptide BNP in human hypertension. The investigators' proposal is based upon the biological properties of BNP (i.e., natriuretic, renin-angiotensin-aldosterone suppressing, vasodilating, anti-fibrotic, anti-hypertrophic and positive lusitropic), its mechanistic role in human hypertension, and thus its potential as an innovative chronic protein therapeutic to enhance the treatment of patients with uncontrolled and or resistant hypertension. Importantly, BNP is an endocrine hormone normally produced by the human heart, and its use as therapeutic agent has been approved in USA for more than a decade and has been proven to be safe.
Interventions
DRUGNesiritide (BNP)
NATRECOR® (nesiritide) is a sterile, purified preparation of human B-type natriuretic peptide (hBNP), and is manufactured from E. coli using recombinant DNA technology. Each 1.5 mg vial contains a white- to off-white lyophilized powder for intravenous (IV) administration after reconstitution.
DRUGPlacebo
Placebo will be administered subcutaneously instead of active drug (nesiritide) in a blind fashion in the second arm of the study.
Sponsors
National Center for Research Resources (NCRR)
John C Burnett
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Subjects with resistant hypertension as defined by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines, systolic blood pressure and/or diastolic blood pressure \> 140/90 mm Hg. For patients with hypertension and diabetes or renal disease, blood pressure \> 130/80 mm Hg despite treatment with diuretic, sympathetic depressant and vasodilators. Medications may include a three drug regimen including: * diuretic at therapeutic dose * a second line agent such as sympatholytic (e.g. beta-blockade, central agent such as clonidine) or angiotensin converting enzyme inhibitor (ACEi) / angiotensin receptor blocker (ARB) or calcium channel blocker (CCB). * third line agent including one of the above and/or direct vasodilator, such as hydralazine or minoxidil.
Exclusion criteria
* Congestive Heart Failure (any New York Heart Association (NYHA) class) * Ejection Fraction \< 50% * Known renal artery stenosis * Myocardial infarction within 3 months of screening * Unstable angina within 14 days of screening, or any evidence of myocardial ischemia * Moderate to severe pulmonary hypertension * Valvular stenosis, hypertrophic, restrictive or obstructive cardiomyopathy, constrictive pericarditis, primary pulmonary hypertension, or biopsy proven active myocarditis * Sustained ventricular tachycardia or ventricular fibrillation within 14 days of screening * Sustained Atrial Fibrillation * Second or third degree atrioventricular (AV) block without a permanent cardiac pacemaker * Cerebral vascular accident within 3 months of screening, or other evidence of significantly compromised central nervous system perfusion * Total bilirubin of \> 1.5 mg/dL or aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 1.5 times the upper limit of normal range * Renal insufficiency assessed by calculated Glomerular Filtration Rate (GFR) \< 30 ml/min (Cockcroft-Gault equation) * Serum sodium of \< 125 milliequivalent (mEq)/dL or \> 160 mEq/dL * Serum potassium of \< 3.0 mEq/dL or \> 5.5 mEq/dL * Women taking hormonal contraceptives * Pregnancy * Body mass index (BMI) \> 35
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Systolic Blood Pressure (BP) | baseline, treatment day 1, treatment day 2 | The change in BP with treatment over 7 days was assessed by the mean BP on admission, (treatment day 1) mean BP 23 hours after the first injection of BNP, and mean BP 23 hours after the second injection of BNP (treatment day 2). Treatment day 2 was 7 days after admission. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited at Mayo Clinic in Rochester, Minnesota.
Participants by arm
| Arm | Count |
|---|---|
| Nesiritide (BNP) Subjects will receive subcutaneous (SQ) BNP bid for seven consecutive days. The initial starting dose was 5 micrograms/kg. | 12 |
| Placebo Subjects will receive SQ placebo bid for seven consecutive days. | 0 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Screen failure | 2 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Nesiritide (BNP) | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 0 Participants | 12 Participants |
| Region of Enrollment United States | 12 participants | — | 12 participants |
| Sex: Female, Male Female | 7 Participants | 0 Participants | 7 Participants |
| Sex: Female, Male Male | 5 Participants | 0 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 0 |
| other Total, other adverse events | 0 / 8 | 0 / 0 |
| serious Total, serious adverse events | 0 / 8 | 0 / 0 |
Outcome results
Primary
Changes in Systolic Blood Pressure (BP)
The change in BP with treatment over 7 days was assessed by the mean BP on admission, (treatment day 1) mean BP 23 hours after the first injection of BNP, and mean BP 23 hours after the second injection of BNP (treatment day 2). Treatment day 2 was 7 days after admission.
Time frame: baseline, treatment day 1, treatment day 2
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nesiritide (BNP) | Changes in Systolic Blood Pressure (BP) | Baseline | 153 mmHg | Standard Deviation 9.18 |
| Nesiritide (BNP) | Changes in Systolic Blood Pressure (BP) | Treatment Day 1 | 134 mmHg | Standard Deviation 9.07 |
| Nesiritide (BNP) | Changes in Systolic Blood Pressure (BP) | Treatment Day 2 | 129 mmHg | Standard Deviation 17.34 |