Nesiritide in Resistant Hypertension

This study has suspended participant recruitment.
(PI has left the institution)
Sponsor:
Information provided by (Responsible Party):
Alessandro Cataliotti, Mayo Clinic
ClinicalTrials.gov Identifier:
NCT01514357
First received: January 12, 2012
Last updated: November 8, 2013
Last verified: November 2013
  Purpose

The aim of this study is two fold: First the investigators want to determine the safe and most effective dose of subcutaneous (SQ) BNP in subjects with resistant hypertension. Second, the investigators want to demonstrate efficacy of chronically (one week) administered SQ BNP in resistant hypertension in reducing blood pressure.


Condition Intervention Phase
Hypertension
Drug: Nesiritide (BNP)
Drug: Placebo
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Natriuretic Peptides and Their Chimerics in Hypertension (Aims 1 and 2)

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Changes in blood pressure (BP) with treatment over 7 days [ Time Frame: baseline and at 7 days ] [ Designated as safety issue: No ]
    The primary endpoint of the study is the change in BP with treatment over 7 days. This will be assessed by the 24-hour ambulatory blood pressure monitoring (ABPM) recordings performed at baseline (day 0) and at day 6 (post-treatment). Group comparisons will be based on the overall (24-hour) mean, the daytime mean, and the night-time mean.


Secondary Outcome Measures:
  • Renal function [ Time Frame: Baseline and after 7 days treatment ] [ Designated as safety issue: No ]
    The secondary endpoints will include renal function as assessed by calculated glomerular filtration rate (GFR) and cystatin-C, effects of SQ BNP on 24-hour sodium excretion.

  • Hormonal changes [ Time Frame: Baseline and after 7 days treatment ] [ Designated as safety issue: No ]
    The effects upon the endogenous NPs system determined by changes in ANP, NT-ANP, proBNP1-108, NT-proBNP, cyclic guanylate monophosphate (cGMP), and suppression of the renin-angiotensin-aldosterone system (RAAS) will also be assessed.


Estimated Enrollment: 75
Study Start Date: April 2012
Estimated Study Completion Date: November 2016
Estimated Primary Completion Date: November 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Nesiritide (BNP) doses
Patients will receive low, medium and high dose of subcutaneous (SQ) BNP to determine the feasibility, safety, and blood pressure lowering effect of BNP so as to identify the optimal dose.
Drug: Nesiritide (BNP)
This arm is designed to determine the optimal dose rage of nesiritide (BNP) to be used in the double blind trial (second arm of the study).
Other Name: Natrecor
Active Comparator: SQ Nesiritide (BNP)
Patients will receive SQ BNP bid at the optimal dose, as assessed in the dose finding arm, for seven consecutive days.
Drug: Nesiritide (BNP)
The optimal dose rage of nesiritide (BNP) to be used in the double blind trial will be determined in the first dose finding arm.
Other Name: Natrecor
Placebo Comparator: Placebo
Patients will receive SQ placebo bid for seven consecutive days.
Drug: Placebo
Placebo will be administered subcutaneously instead of active drug (nesiritide) in a blind fashion in the second arm of the study.
Other Name: saline solution

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. Our 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.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 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 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 GFR < 30 ml/min (Cockroft-Gault equation)
  • Serum sodium of < 125 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
  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: NCT01514357

Locations
United States, Minnesota
Mayo Clinic in Rochester
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
Investigators
Principal Investigator: Alessandro Cataliotti, MD, PhD Mayo Clinic
  More Information

No publications provided

Responsible Party: Alessandro Cataliotti, Associate Professor of Medicine, Mayo Clinic
ClinicalTrials.gov Identifier: NCT01514357     History of Changes
Other Study ID Numbers: 11-001372
Study First Received: January 12, 2012
Last Updated: November 8, 2013
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on July 26, 2014