Nebivolol and Endothelial Regulation of Fibrinolysis (NERF)

• Sponsor: University of Colorado, Boulder (Other)
• Overall Status: Completed
• CT.gov ID: NCT01595516
• Collaborator: Forest Laboratories (Industry)
• Enrollment: 44
• Location: 1
• Arms: 6
• Duration (Months): 68
• Patients Per Site Per Month: 0.6

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Prehypertension; Hypertension	Drug: Nebivolol; Drug: Metoprolol; Drug: Placebo; Other: Bradykinin; Other: Saline; Other: Vitamin C	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Nebivolol and Endothelial Regulation of Fibrinolysis
• Study Start Date: Feb 1, 2012
• Actual Primary Completion Date: Oct 1, 2017
• Actual Study Completion Date: Oct 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Nebivolol	Drug: Nebivolol; 5 mg tablet to be taken by mouth once per day for 12 weeks; Other Names: Bystolic
Active Comparator: Metoprolol	Drug: Metoprolol; 100 mg tablet to be taken by mouth once per day for 12 weeks; Other Names: Toprol-XL
Placebo Comparator: Placebo	Drug: Placebo; Gelatin capsule to be taken by mouth once per day for 12 weeks
Other: Bradykinin	Drug: Nebivolol; 5 mg tablet to be taken by mouth once per day for 12 weeks; Other Names: Bystolic ; Drug: Metoprolol; 100 mg tablet to be taken by mouth once per day for 12 weeks; Other Names: Toprol-XL ; Drug: Placebo; Gelatin capsule to be taken by mouth once per day for 12 weeks; Other: Bradykinin; 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.; Other Names: BDK
Other: Saline	Drug: Nebivolol; 5 mg tablet to be taken by mouth once per day for 12 weeks; Other Names: Bystolic ; Drug: Metoprolol; 100 mg tablet to be taken by mouth once per day for 12 weeks; Other Names: Toprol-XL ; Drug: Placebo; Gelatin capsule to be taken by mouth once per day for 12 weeks; Other: Bradykinin; 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.; Other Names: BDK ; Other: Saline; 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.; Other: Vitamin C; 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.
Other: Vitamin C	Drug: Nebivolol; 5 mg tablet to be taken by mouth once per day for 12 weeks; Other Names: Bystolic ; Drug: Metoprolol; 100 mg tablet to be taken by mouth once per day for 12 weeks; Other Names: Toprol-XL ; Other: Bradykinin; 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.; Other Names: BDK ; Other: Saline; 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.; Other: Vitamin C; 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.

Outcome Measures

Primary Outcome Measures

1. Heart Rate [Heart rate was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.]

   Resting heart rate in the seated position

2. 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.]

3. 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.]

4. Endothelial t-PA Release in Response to Bradykinin (BDK) Before and After the 12 Week Intervention [t-PA release was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo 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.

5. Endothelial t-PA Release in Response to Bradykinin (BDK) and Bradykinin+Vitamin C (BDK+C) Before and After 12 Weeks of Nebivolol Therapy. [t-PA release was measured before the 12 week drug intervention and after the 12 week drug intervention.]

   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.

6. Endothelial t-PA Release in Response to BDK and BDK+C Before and After 12 Weeks of Metoprolol Therapy. [t-PA release was measured before the 12 week drug intervention and after the 12 week drug intervention.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UC-Boulder Clinical and Translational Research Center	Boulder	Colorado	United States	80309

Sponsors and Collaborators

• University of Colorado, Boulder
• Forest Laboratories

Investigators

• Principal Investigator: Christopher DeSouza, Ph.D., University of Colorado at Boulder

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 25, 2015

More Information

Publications

None provided.

• Responsible Party: Christopher DeSouza, Professor, University of Colorado, Boulder
• ClinicalTrials.gov Identifier: NCT01595516
• Other Study ID Numbers: BYS-MD-72
• First Posted: May 10, 2012
• Last Update Posted: Jun 25, 2019
• Last Verified: Jun 1, 2019

• Additional relevant MeSH terms: Prehypertension; Ascorbic Acid; Metoprolol; Nebivolol; Bradykinin; Kininogens

Study Results

Participant Flow

Arm/Group Title	Nebivolol	Metoprolol	Placebo
Arm/Group Description	Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks	Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks	Placebo: Gelatin capsule to be taken by mouth once per day for 12 weeks
Period Title: Overall Study
STARTED	16	16	12
COMPLETED	16	16	12
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Nebivolol	Metoprolol	Placebo	Total
Arm/Group Description	Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks	Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks	Placebo: Gelatin capsule to be taken by mouth once per day for 12 weeks	Total of all reporting groups
Overall Participants	16	16	12	44
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58 (5)	58 (6)	57 (6)	58 (6)
Sex: Female, Male (Count of Participants)
Female	6 37.5%	6 37.5%	4 33.3%	16 36.4%
Male	10 62.5%	10 62.5%	8 66.7%	28 63.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 6.3%	2 12.5%	1 8.3%	4 9.1%
Not Hispanic or Latino	15 93.8%	14 87.5%	11 91.7%	40 90.9%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	1 6.3%	1 6.3%	0 0%	2 4.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	1 6.3%	1 6.3%	1 8.3%	3 6.8%
White	14 87.5%	14 87.5%	11 91.7%	39 88.6%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	16 100%	16 100%	12 100%	44 100%

Outcome Measures

1. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nebivolol	Metoprolol	Placebo
Arm/Group Description	Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks	Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks	Placebo: Gelatin capsule to be taken by mouth once per day for 12 weeks
Measure Participants	16	16	12
Before Intervention	64 (1)	71 (1)	69 (2)
After Intervention	58 (2)	64 (3)	72 (2)

2. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nebivolol	Metoprolol	Placebo
Arm/Group Description	Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks	Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks	Placebo: Gelatin capsule to be taken by mouth once per day for 12 weeks
Measure Participants	16	16	12
Before Intervention	140 (2)	138 (2)	138 (2)
After Intervention	125 (2)	125 (3)	135 (3)

3. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nebivolol	Metoprolol	Placebo
Arm/Group Description	Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks	Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks	Placebo: Gelatin capsule to be taken by mouth once per day for 12 weeks
Measure Participants	16	16	12
Before Intervention	85 (2)	87 (2)	85 (3)
After Intervention	78 (2)	79 (2)	81 (2)

4. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Before Nebivolol	After Nebivolol	Before Metoprolol	After Metoprolol	Before Placebo	After Placebo
Arm/Group Description	Before randomization to nebivolol	Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks	Before randomization to metoprolol	Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks	Before randomization to placebo	Placebo: Gelatin capsule to be taken by mouth once per day for 12 weeks
Measure Participants	16	16	16	16	12	12
Amount of t-PA release to Saline	-1.2 (0.8)	-1.8 (0.9)	-1.2 (1.2)	-1.9 (1.1)	-0.2 (1.2)	-0.9 (1.5)
Amount of t-PA release to BDK 12.5	15.7 (2.9)	25.2 (4.1)	14.4 (3.3)	16.6 (3.3)	18.1 (3.1)	17.6 (2.8)
Amount of t-PA release to BDK 25.0	29.1 (3.9)	46.4 (6.5)	27.5 (3.3)	31.2 (2.4)	28.3 (3.8)	32.7 (5.6)
Amount of t-PA release to BDK 50.0	47.2 (4.3)	72.8 (5.7)	48.2 (5.9)	52.7 (4.6)	51.1 (5.0)	52.9 (4.3)

5. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Before Nebivolol: Saline	Before Nebivolol: Vitamin C	After Nebivolol: Saline	After Nebivolol: Vitamin C
Arm/Group Description	Net t-PA antigen release in response to BDK before 12 weeks of nebivolol therapy.	Net t-PA antigen release in response to BDK+C before 12 weeks of nebivolol therapy.	Net t-PA antigen release in response to BDK after 12 weeks of nebivolol therapy.	Net t-PA antigen release in response to BDK+C after 12 weeks of nebivolol therapy.
Measure Participants	10	10	10	10
Amount of t-PA release to saline	-2.4 (1.1)	-1.4 (0.8)	-1.5 (1.3)	-3.8 (2.6)
Amount of t-PA release to BDK 12.5	14.3 (3.2)	31.3 (5.5)	28.2 (6.2)	38.1 (7.3)
Amount of t-PA release to BDK 25.0	27.6 (5.0)	52.7 (6.6)	49.1 (9.1)	54.2 (7.9)
Amount of t-PA release to BDK 50.0	47.2 (5.0)	80.5 (6.2)	67.5 (7.1)	79.9 (7.6)

6. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Before Metoprolol: Saline	Before Metoprolol: Vitamin C	After Metoprolol: Saline	After Metoprolol: Vitamin C
Arm/Group Description	Net t-PA antigen release in response to BDK before 12 weeks of nebivolol therapy.	Net t-PA antigen release in response to BDK+C before 12 weeks of nebivolol therapy.	Net t-PA antigen release in response to BDK after 12 weeks of nebivolol therapy.	Net t-PA antigen release in response to BDK+C after 12 weeks of nebivolol therapy.
Measure Participants	10	10	10	10
Amount of t-PA release to Saline	-2.7 (0.9)	-2.5 (0.8)	-1.3 (1.4)	-2.7 (1.1)
Amount of t-PA release to BDK 12.5	10.1 (3.9)	31.1 (5.0)	16.4 (5.0)	30.0 (4.4)
Amount of t-PA release to BDK 25.0	24.5 (3.8)	47.1 (7.3)	31.3 (3.3)	46.4 (6.3)
Amount of t-PA release to BDK 50.0	45.0 (5.5)	82.4 (10.2)	49.9 (5.7)	73.8 (7.4)

Adverse Events

Time Frame	Adverse event data for each participant was assessed every 2 weeks during their check-in visits at the CU-Boulder CTRC over the 12 weeks.
Arm/Group Title	Nebivolol		Metoprolol		Placebo
Arm/Group Description	Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks		Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks		Placebo: Gelatin capsule to be taken by mouth once per day for 12 weeks
All Cause Mortality
	Nebivolol		Metoprolol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)		0/12 (0%)
Serious Adverse Events
	Nebivolol		Metoprolol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Nebivolol		Metoprolol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)		0/12 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.