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Nebivolol and Endothelial Regulation of Fibrinolysis (NERF)

Primary Purpose

Prehypertension, Hypertension

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Nebivolol
Metoprolol
Placebo
Bradykinin
Saline
Vitamin C
Sponsored by
University of Colorado, Boulder
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Prehypertension

Eligibility Criteria

45 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.

Sites / Locations

  • UC-Boulder Clinical and Translational Research Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Active Comparator

Active Comparator

Placebo Comparator

Other

Other

Other

Arm Label

Nebivolol

Metoprolol

Placebo

Bradykinin

Saline

Vitamin C

Arm Description

Outcomes

Primary Outcome Measures

Heart Rate
Resting heart rate in the seated position
Systolic Blood Pressure
Diastolic Blood Pressure
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.
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.
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.

Secondary Outcome Measures

Full Information

First Posted
March 5, 2012
Last Updated
June 5, 2019
Sponsor
University of Colorado, Boulder
Collaborators
Forest Laboratories
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1. Study Identification

Unique Protocol Identification Number
NCT01595516
Brief Title
Nebivolol and Endothelial Regulation of Fibrinolysis (NERF)
Official Title
Nebivolol and Endothelial Regulation of Fibrinolysis
Study Type
Interventional

2. Study Status

Record Verification Date
June 2019
Overall Recruitment Status
Completed
Study Start Date
February 2012 (undefined)
Primary Completion Date
October 2017 (Actual)
Study Completion Date
October 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Colorado, Boulder
Collaborators
Forest Laboratories

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Prehypertension, Hypertension

7. Study Design

Primary Purpose
Other
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
44 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Nebivolol
Arm Type
Active Comparator
Arm Title
Metoprolol
Arm Type
Active Comparator
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Title
Bradykinin
Arm Type
Other
Arm Title
Saline
Arm Type
Other
Arm Title
Vitamin C
Arm Type
Other
Intervention Type
Drug
Intervention Name(s)
Nebivolol
Other Intervention Name(s)
Bystolic
Intervention Description
5 mg tablet to be taken by mouth once per day for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Metoprolol
Other Intervention Name(s)
Toprol-XL
Intervention Description
100 mg tablet to be taken by mouth once per day for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Gelatin capsule to be taken by mouth once per day for 12 weeks
Intervention Type
Other
Intervention Name(s)
Bradykinin
Other Intervention Name(s)
BDK
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Saline
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Vitamin C
Intervention Description
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.
Primary Outcome Measure Information:
Title
Heart Rate
Description
Resting heart rate in the seated position
Time Frame
Heart rate was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.
Title
Systolic Blood Pressure
Time Frame
Systolic blood pressure was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.
Title
Diastolic Blood Pressure
Time Frame
Diastolic blood pressure was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.
Title
Endothelial t-PA Release in Response to Bradykinin (BDK) Before and After the 12 Week Intervention
Description
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.
Time Frame
t-PA release was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.
Title
Endothelial t-PA Release in Response to Bradykinin (BDK) and Bradykinin+Vitamin C (BDK+C) Before and After 12 Weeks of Nebivolol Therapy.
Description
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.
Time Frame
t-PA release was measured before the 12 week drug intervention and after the 12 week drug intervention.
Title
Endothelial t-PA Release in Response to BDK and BDK+C Before and After 12 Weeks of Metoprolol Therapy.
Description
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.
Time Frame
t-PA release was measured before the 12 week drug intervention and after the 12 week drug intervention.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
45 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: 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. Exclusion Criteria: 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christopher DeSouza, Ph.D.
Organizational Affiliation
University of Colorado at Boulder
Official's Role
Principal Investigator
Facility Information:
Facility Name
UC-Boulder Clinical and Translational Research Center
City
Boulder
State/Province
Colorado
ZIP/Postal Code
80309
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
29122812
Citation
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.
Results Reference
derived

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Nebivolol and Endothelial Regulation of Fibrinolysis (NERF)

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