Nebivolol and Endothelial Regulation of Fibrinolysis (NERF)

NCT01595516 | Completed Phase 4 Results DMC

• 1 other identifier: BYS-MD-72
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

The investigators hypothesize that nebivolol will improve endothelial t-PA release in adult humans with elevated blood pressure to a greater extent than either metoprolol or placebo. The investigators further hypothesize that the improvement in the capacity of the vascular endothelium to release t-PA with nebivolol is mediated, in part, by the compound's antioxidant properties.

Conditions

Prehypertension; Hypertension

Outcome Measures

Primary Outcomes (6)

• Heart Rate

  Resting heart rate in the seated position

  Heart rate was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.

• Systolic Blood Pressure

  Systolic blood pressure was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.

• Diastolic Blood Pressure

  Diastolic blood pressure was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.

• Endothelial t-PA Release in Response to Bradykinin (BDK) Before and After the 12 Week Intervention

  Net endothelial release of t-PA antigen in response to bradykinin (BDK) was calculated using the following equation: Net Release of t-PA Antigen=(Cv-Ca) x (FBF x \[101-hematocrit/100\]) where Cv and Ca represent the concentration of t-PA in the vein and artery respectively. A positive difference indicates a net release and a negative difference net uptake. Arterial and venous blood samples are collected simultaneously at baseline and each dose of the drug (BDK). t-PA concentration were determined by enzyme immunoassay. Hematocrit was measured in triplicate using the standard microhematocrit technique and corrected for trapped plasma volume within the trapped red blood cells.

  t-PA release was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.

• Endothelial t-PA Release in Response to Bradykinin (BDK) and Bradykinin+Vitamin C (BDK+C) Before and After 12 Weeks of Nebivolol Therapy.

  Net endothelial release of t-PA antigen in response to bradykinin (BDK) and bradykinin+vitamin C (BDK+C) was calculated using the following equation: Net Release of t-PA Antigen=(Cv-Ca) x (FBF x \[101-hematocrit/100\]) where Cv and Ca represent the concentration of t-PA in the vein and artery respectively. A positive difference indicates a net release and a negative difference net uptake. Arterial and venous blood samples are collected simultaneously at baseline and each dose of the drug (BDK) and BDK+Vit C. t-PA concentration were determined by enzyme immunoassay. Hematocrit was measured in triplicate using the standard microhematocrit technique and corrected for trapped plasma volume within the trapped red blood cells.

  t-PA release was measured before the 12 week drug intervention and after the 12 week drug intervention.

• Endothelial t-PA Release in Response to BDK and BDK+C Before and After 12 Weeks of Metoprolol Therapy.

  Net endothelial release of t-PA antigen in response to BDK and BDK+C was calculated using the following equation: Net Release of t-PA Antigen=(Cv-Ca) x (FBF x \[101-hematocrit/100\]) where Cv and Ca represent the concentration of t-PA in the vein and artery respectively. A positive difference indicates a net release and a negative difference net uptake. Arterial and venous blood samples are collected simultaneously at baseline and each dose of the drug (BDK) and BDK+Vit C. t-PA concentration were determined by enzyme immunoassay. Hematocrit was measured in triplicate using the standard microhematocrit technique and corrected for trapped plasma volume within the trapped red blood cells.

  t-PA release was measured before the 12 week drug intervention and after the 12 week drug intervention.

Study Arms (6)

Nebivolol

ACTIVE COMPARATOR

Drug: Nebivolol

Metoprolol

ACTIVE COMPARATOR

Drug: Metoprolol

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Bradykinin

OTHER

Drug: Nebivolol; Drug: Metoprolol; Drug: Placebo; Other: Bradykinin

Saline

OTHER

Drug: Nebivolol; Drug: Metoprolol; Drug: Placebo; Other: Bradykinin; Other: Saline; Other: Vitamin C

Vitamin C

OTHER

Drug: Nebivolol; Drug: Metoprolol; Other: Bradykinin; Other: Saline; Other: Vitamin C

Interventions

Nebivolol DRUG

5 mg tablet to be taken by mouth once per day for 12 weeks

Also known as: Bystolic

Bradykinin; Nebivolol; Saline; Vitamin C

Metoprolol DRUG

100 mg tablet to be taken by mouth once per day for 12 weeks

Also known as: Toprol-XL

Bradykinin; Metoprolol; Saline; Vitamin C

Placebo DRUG

Gelatin capsule to be taken by mouth once per day for 12 weeks

Bradykinin; Placebo; Saline

Bradykinin OTHER

Bradykinin is infused into the brachial artery at doses of 12.5, 25.0 and 50.0 ng/100 mL of forearm tissue /min. BDK stimulates the endothelial cells to release tissue type plasminogen activator (t-PA). Blood flow in mL/100 mL tissue/min is also measured to BDK.

Also known as: BDK

Bradykinin; Saline; Vitamin C

Saline OTHER

Baseline or resting forearm blood flow is measured in response to saline for 5 minutes before each drug infusion. t-PA release in response to the saline is also measured.

Saline; Vitamin C

Vitamin C OTHER

The acute effects of into-arterial vitamin C on the ability of the endothelium to release t-PA was determined before and after the nebivolol and metoprolol intervention. After allowing sufficient time (\~20 minutes) for FBF and plasma t-PA concentrations to return to baseline following the initial infusion of BDK, vitamin C (24 mg/min) was infused at a constant rate while the BDK dose-response curves were repeated. t-PA and FBF were measured.

Saline; Vitamin C

Eligibility Criteria

• Age: 45 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects will be men and women of all races and ethnic backgrounds aged 45-65 years.
• Subjects will be prehypertensive/hypertensive defined as resting systolic blood pressure \>125 mmHg and \<160 mmHg and/or diastolic \>80 mmHg and \<100 mmHg.
• All of the women in the study will be postmenopausal and not receiving hormone replacement therapy (HRT) currently or in the preceding 3-year period.
• Candidates will be sedentary as determined from the Stanford Physical Activity Questionnaire (\<35 kcal/wk) and will not have engaged in any program of regular physical activity for at least 1 year prior to the study.

You may not qualify if:

• Candidates who smoke (currently or in the past 7 years), report more than low-risk alcohol consumption as defined as no more than 14 standard drinks/wk and no more than 4 standard drinks/day for men and 7 standard drinks/wk and 3 standard drinks/day for women (a standard drink is defined as 12 ounces of beer, 5 ounces of wine, 1½ ounces of 80-proof distilled spirits).
• Potential candidates who are taking cardiovascular-acting (i.e. statins, blood pressure medication and aspirin) medications will not be eligible.
• Fasting plasma glucose \>126 mg/dL.
• Potential candidates with a resting heart rate of \< 50 beats/minute will be excluded.
• Use of hormone replacement therapy.
• In hypertensive subjects, a seated systolic blood pressure \>160 mmHg or a seated diastolic blood pressure \>100 mmHg will be excluded.

Sponsors & Collaborators

• University of Colorado, Boulder: lead
• Forest Laboratories: collaborator

Study Sites (1)

UC-Boulder Clinical and Translational Research Center

Boulder, Colorado, 80309, United States

Location

Related Publications (1)

• Stauffer BL, Dow CA, Diehl KJ, Bammert TD, Greiner JJ, DeSouza CA. Nebivolol, But Not Metoprolol, Treatment Improves Endothelial Fibrinolytic Capacity in Adults With Elevated Blood Pressure. J Am Heart Assoc. 2017 Nov 9;6(11):e007437. doi: 10.1161/JAHA.117.007437.

  PMID: 29122812 DERIVED

MeSH Terms

Conditions

Prehypertension; Hypertension

Interventions

Nebivolol; Metoprolol; Bradykinin; Sodium Chloride; Ascorbic Acid

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Phenoxypropanolamines; Propanolamines; Propanols; Kinins; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Neuropeptides; Oligopeptides; Proteins; Nerve Tissue Proteins; Autacoids; Inflammation Mediators; Biological Factors; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Sugar Acids; Acids, Acyclic; Carboxylic Acids; Hydroxy Acids; Carbohydrates

Results Point of Contact

• Title: Dr. Christopher DeSouza
• Organization: University of Colorado

desouzac@colorado.edu

303-492-2988

Study Officials

• Christopher DeSouza, Ph.D.

  University of Colorado at Boulder

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: March 5, 2012
• First Posted: May 10, 2012
• Study Start: February 1, 2012
• Primary Completion: October 1, 2017
• Study Completion: October 1, 2017
• Last Updated: June 25, 2019
• Results First Posted: June 25, 2019

Record last verified: 2019-06

Locations

US (1)