Effect of Nebivolol on Oxidative Stress and Endothelial Progenitor Cells

• Sponsor: Emory University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01041287
• Collaborator: Forest Laboratories (Industry)
• Enrollment: 96
• Location: 1
• Arms: 2
• Duration (Months): 48
• Patients Per Site Per Month: 2

Study Details

Study Description

Brief Summary

Hypertension, or high blood pressure, is a common disease that affects many Americans, and can lead to devastating consequences such as heart attack, stroke, and death if not treated. Nebivolol is a medication that has been recently approved by the FDA for the treatment of hypertension. Nebivolol has an unusual profile compared to other medications, in that its effects may be related to release of a substance called nitric oxide. Nitric oxide is released from the cells lining the blood vessels, and nebivolol may stimulate these cells to release more nitric oxide. Our study will investigate whether treatment with nebivolol, as compared to another medication called metoprolol, in hypertensive subjects will be more effective in protecting blood vessels against the harmful effects of high blood pressure. The mechanisms we will investigate include oxidative stress markers and circulating levels of endothelial progenitor cells.

Condition or Disease	Intervention/Treatment	Phase
Hypertension	Drug: Nebivolol; Drug: Metoprolol succinate	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 96 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Effect of Nebivolol on Oxidative Stress and Endothelial Progenitor Cells in Subjects With Hypertension
• Study Start Date: Dec 1, 2009
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Nebivolol/ Metoprolol Subjects were randomized to nebivolol for 3 months. They "crossed over" to take 3 months of metoprolol succinate. The initial 5 mg daily dose of nebivolol was titrated to 10 mg daily after 2 weeks if their BP remained >125/80, and subsequently titrated to 20 mg daily after another 2 weeks if the BP remained >125/80. Similarly, the initial 50 mg daily dose of metoprolol succinate was titrated to 100 mg daily after 2 weeks if BP remained >125/80, and further increased to 200 mg after 2 weeks if BP remained >125/80.	Drug: Nebivolol; Nebivolol 5 mg PO qday for 2 weeks, titrated up to Nebivolol 10 mg PO qday if BP is >125/80 for the 2 more weeks, and then titrated up to Nebivolol 20 mg PO qday if BP is >125/80 for the remaining 8 weeks; Other Names: Bystolic ; Drug: Metoprolol succinate; Metoprolol 50 mg PO qday for 2 weeks, titrated up to Metoprolol 100 mg PO qday if BP is >125/80 for the 2 more weeks, and then titrated up to Metoprolol 200 mg PO qday if BP is >125/80 for the remaining 8 weeks; Other Names: Toprol XL
Active Comparator: Metoprolol/Nebivolol Subjects were randomized to metoprolol succinate for 3 months. They "crossed over" to take 3 months of nebivolol. The initial 5 mg daily dose of nebivolol was titrated to 10 mg daily after 2 weeks if their BP remained >125/80, and subsequently titrated to 20 mg daily after another 2 weeks if the BP remained >125/80. Similarly, the initial 50 mg daily dose of metoprolol succinate was titrated to 100 mg daily after 2 weeks if BP remained >125/80, and further increased to 200 mg after 2 weeks if BP remained >125/80.	Drug: Nebivolol; Nebivolol 5 mg PO qday for 2 weeks, titrated up to Nebivolol 10 mg PO qday if BP is >125/80 for the 2 more weeks, and then titrated up to Nebivolol 20 mg PO qday if BP is >125/80 for the remaining 8 weeks; Other Names: Bystolic ; Drug: Metoprolol succinate; Metoprolol 50 mg PO qday for 2 weeks, titrated up to Metoprolol 100 mg PO qday if BP is >125/80 for the 2 more weeks, and then titrated up to Metoprolol 200 mg PO qday if BP is >125/80 for the remaining 8 weeks; Other Names: Toprol XL

Outcome Measures

Primary Outcome Measures

1. Pulse Wave Velocity (Measure of Arterial Stiffness) [Baseline]

   The pulse wave velocity (PWV) system measured the velocity of the blood pressure waveform between the carotid and femoral arteries using a single-lead electrocardiogram and tonometer to measure the pressure pulse waveform sequentially at the two peripheral artery sites. PWV is calculated as PWV=distance (d)/time (t) and the unit of measure is reported as meters per second (m/s).

2. Pulse Wave Velocity (Measure of Arterial Stiffness) [3 months]

   The pulse wave velocity (PWV) system measured the velocity of the blood pressure waveform between the carotid and femoral arteries using a single-lead electrocardiogram and tonometer to measure the pressure pulse waveform sequentially at the two peripheral artery sites. PWV is calculated as PWV=distance (d)/time (t) and the unit of measure is reported as meters per second (m/s).

3. Pulse Wave Velocity (Measure of Arterial Stiffness) [6 months]

   The pulse wave velocity (PWV) system measured the velocity of the blood pressure waveform between the carotid and femoral arteries using a single-lead electrocardiogram and tonometer to measure the pressure pulse waveform sequentially at the two peripheral artery sites. PWV is calculated as PWV=distance (d)/time (t) and the unit of measure is reported as meters per second (m/s).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Males or post-menopausal females aged 21-80 years.

2. Hypertensive patients (BP >135/85) will be eligible to participate.

3. Patients on current anti-hypertensive therapy that does not include beta blockade should have BP >135/85.

4. Patients on anti-hypertensive therapy including beta blockade will have their beta blockers discontinued gradually over 2 weeks before enrolment.

5. Concomitant therapy: Patients will be allowed to be on comcomitant therapy with aspirin, statins, thiazide diuretics, calcium antagonists (for treatment of hypertension), clonidine, vasodilators, or angiotensin antagonists. Patients will be on stable medical therapy for at least 2 months before recruitment. Patients with previous treatment with beta adrenergic blockers (metoprolol, propranolol, atenolol, and labetalol) will also be eligible to participate, but will be randomized to the study beta blocker.

Exclusion Criteria:

1. Age < 21 or >80 years

2. Initiation or change in dose of statin or anti-hypertensive therapy within 2 months before the study

3. Premenopausal females with potential for pregnancy

4. Acute infection in previous 2 weeks

5. History of substance abuse

6. Current neoplasm

7. Chronic renal failure [creatinine > 2.5 mg/dL] or liver failure (Liver enzymes >2X normal)

8. Acute coronary syndrome, Class IV heart failure, CVA, coronary intervention within 2 months

9. Known aortic stenosis, hypertrophic cardiomyopathy.

10. Inability to give informed consent

11. Inability to return to Emory for follow-up testing

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University	Atlanta	Georgia	United States	30322

Sponsors and Collaborators

• Emory University
• Forest Laboratories

Investigators

• Principal Investigator: Arshed Quyyumi, MD, Emory University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Arshed A. Quyyumi, Professor, Emory University
• ClinicalTrials.gov Identifier: NCT01041287
• Other Study ID Numbers: IRB00013262; BYD-MD-20
• First Posted: Dec 31, 2009
• Last Update Posted: Dec 19, 2014
• Last Verified: Dec 1, 2014

• Additional relevant MeSH terms: Hypertension; Metoprolol; Nebivolol

Study Results

Participant Flow

Recruitment Details	Patients recruited from clinic sites at Emory University Hospital and by advertisements between December 2009 through April 2012.
Pre-assignment Detail	There were 96 subjects enrolled. 58 of the subjects were withdrawn prior to group assignment. 39 subjects did not meet eligibility criteria and 19 subjects withdrew.

Arm/Group Title	Nebivolol/ Metoprolol	Metoprolol/Nebivolol
Arm/Group Description	Subjects were randomized to nebivolol for the first 3 months. Then they "crossed over" to take 3 months of metoprolol succinate. The initial 5 mg daily dose of nebivolol was titrated to 10 mg daily after 2 weeks if their BP remained >125/80, and subsequently titrated to 20 mg daily after another 2 weeks if the BP remained >125/80. Similarly, the initial 50 mg daily dose of metoprolol succinate was titrated to 100 mg daily after 2 weeks if BP remained >125/80, and further increased to 200 mg after 2 weeks if BP remained >125/80.	Subjects were randomized to metoprolol succinate for the first 3 months. Then they "crossed over" to take 3 months of nebivolol. The initial 5 mg daily dose of nebivolol was titrated to 10 mg daily after 2 weeks if their BP remained >125/80, and subsequently titrated to 20 mg daily after another 2 weeks if the BP remained >125/80. Similarly, the initial 50 mg daily dose of metoprolol succinate was titrated to 100 mg daily after 2 weeks if BP remained >125/80, and further increased to 200 mg after 2 weeks if BP remained >125/80.
Period Title: Treatment Period 1 (3 Months)
STARTED	19	19
COMPLETED	19	19
NOT COMPLETED	0	0
Period Title: Treatment Period 1 (3 Months)
STARTED	19	19
COMPLETED	16	14
NOT COMPLETED	3	5

Baseline Characteristics

Arm/Group Title	Nebivolol/ Metoprolol	Metoprolol/Nebivolol	Total
Arm/Group Description	Subjects were randomized to nebivolol for 3 months. They "crossed over" to take 3 months of metoprolol succinate. The initial 5 mg daily dose of nebivolol was titrated to 10 mg daily after 2 weeks if their BP remained >125/80, and subsequently titrated to 20 mg daily after another 2 weeks if the BP remained >125/80. Similarly, the initial 50 mg daily dose of metoprolol succinate was titrated to 100 mg daily after 2 weeks if BP remained >125/80, and further increased to 200 mg after 2 weeks if BP remained >125/80.	Subjects were randomized to metoprolol succinate for 3 months. They "crossed over" to take 3 months of nebivolol. The initial 5 mg daily dose of nebivolol was titrated to 10 mg daily after 2 weeks if their BP remained >125/80, and subsequently titrated to 20 mg daily after another 2 weeks if the BP remained >125/80. Similarly, the initial 50 mg daily dose of metoprolol succinate was titrated to 100 mg daily after 2 weeks if BP remained >125/80, and further increased to 200 mg after 2 weeks if BP remained >125/80.	Total of all reporting groups
Overall Participants	16	14	30
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	16 100%	12 85.7%	28 93.3%
>=65 years	0 0%	2 14.3%	2 6.7%
Sex: Female, Male (Count of Participants)
Female	8 50%	5 35.7%	13 43.3%
Male	8 50%	9 64.3%	17 56.7%

Outcome Measures

1. Primary Outcome

Title	Pulse Wave Velocity (Measure of Arterial Stiffness)
Description	The pulse wave velocity (PWV) system measured the velocity of the blood pressure waveform between the carotid and femoral arteries using a single-lead electrocardiogram and tonometer to measure the pressure pulse waveform sequentially at the two peripheral artery sites. PWV is calculated as PWV=distance (d)/time (t) and the unit of measure is reported as meters per second (m/s).
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nebivolol/ Metoprolol	Metoprolol/Nebivolol
Arm/Group Description	Subjects were randomized to nebivolol for the first 3 months. Then they "crossed over" to take 3 months of metoprolol succinate. The initial 5 mg daily dose of nebivolol was titrated to 10 mg daily after 2 weeks if their BP remained >125/80, and subsequently titrated to 20 mg daily after another 2 weeks if the BP remained >125/80. Similarly, the initial 50 mg daily dose of metoprolol succinate was titrated to 100 mg daily after 2 weeks if BP remained >125/80, and further increased to 200 mg after 2 weeks if BP remained >125/80.	Subjects were randomized to metoprolol succinate for the first 3 months. Then they "crossed over" to take 3 months of nebivolol. The initial 5 mg daily dose of nebivolol was titrated to 10 mg daily after 2 weeks if their BP remained >125/80, and subsequently titrated to 20 mg daily after another 2 weeks if the BP remained >125/80. Similarly, the initial 50 mg daily dose of metoprolol succinate was titrated to 100 mg daily after 2 weeks if BP remained >125/80, and further increased to 200 mg after 2 weeks if BP remained >125/80.
Measure Participants	16	14
Mean (Standard Deviation) [meters per second (m/s)]	9.4 (2.6)	8.9 (1.5)

2. Primary Outcome

Title	Pulse Wave Velocity (Measure of Arterial Stiffness)
Description	The pulse wave velocity (PWV) system measured the velocity of the blood pressure waveform between the carotid and femoral arteries using a single-lead electrocardiogram and tonometer to measure the pressure pulse waveform sequentially at the two peripheral artery sites. PWV is calculated as PWV=distance (d)/time (t) and the unit of measure is reported as meters per second (m/s).
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nebivolol/ Metoprolol	Metoprolol/Nebivolol
Arm/Group Description	Subjects were randomized to nebivolol for the first 3 months. Then they "crossed over" to take 3 months of metoprolol succinate. The initial 5 mg daily dose of nebivolol was titrated to 10 mg daily after 2 weeks if their BP remained >125/80, and subsequently titrated to 20 mg daily after another 2 weeks if the BP remained >125/80. Similarly, the initial 50 mg daily dose of metoprolol succinate was titrated to 100 mg daily after 2 weeks if BP remained >125/80, and further increased to 200 mg after 2 weeks if BP remained >125/80.	Subjects were randomized to metoprolol succinate for the first 3 months. Then they "crossed over" to take 3 months of nebivolol. The initial 5 mg daily dose of nebivolol was titrated to 10 mg daily after 2 weeks if their BP remained >125/80, and subsequently titrated to 20 mg daily after another 2 weeks if the BP remained >125/80. Similarly, the initial 50 mg daily dose of metoprolol succinate was titrated to 100 mg daily after 2 weeks if BP remained >125/80, and further increased to 200 mg after 2 weeks if BP remained >125/80.
Measure Participants	16	14
Mean (Standard Deviation) [meters per second (m/s)]	8.4 (2.4)	10.1 (1.4)

3. Primary Outcome

Title	Pulse Wave Velocity (Measure of Arterial Stiffness)
Description	The pulse wave velocity (PWV) system measured the velocity of the blood pressure waveform between the carotid and femoral arteries using a single-lead electrocardiogram and tonometer to measure the pressure pulse waveform sequentially at the two peripheral artery sites. PWV is calculated as PWV=distance (d)/time (t) and the unit of measure is reported as meters per second (m/s).
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nebivolol/ Metoprolol	Metoprolol/Nebivolol
Arm/Group Description	Subjects were randomized to nebivolol for the first 3 months. Then they "crossed over" to take 3 months of metoprolol succinate. The initial 5 mg daily dose of nebivolol was titrated to 10 mg daily after 2 weeks if their BP remained >125/80, and subsequently titrated to 20 mg daily after another 2 weeks if the BP remained >125/80. Similarly, the initial 50 mg daily dose of metoprolol succinate was titrated to 100 mg daily after 2 weeks if BP remained >125/80, and further increased to 200 mg after 2 weeks if BP remained >125/80.	Subjects were randomized to metoprolol succinate for the first 3 months. Then they "crossed over" to take 3 months of nebivolol. The initial 5 mg daily dose of nebivolol was titrated to 10 mg daily after 2 weeks if their BP remained >125/80, and subsequently titrated to 20 mg daily after another 2 weeks if the BP remained >125/80. Similarly, the initial 50 mg daily dose of metoprolol succinate was titrated to 100 mg daily after 2 weeks if BP remained >125/80, and further increased to 200 mg after 2 weeks if BP remained >125/80.
Measure Participants	16	16
Mean (Standard Deviation) [meters per second (m/s)]	9.1 (2.2)	9.8 (1.6)

Adverse Events

Adverse Event Reporting Description	58 subjects were withdrawn prior to randomization/group assignment (no intervention occurred), therefore they are not accounted for in the at-risk population for the adverse events.
Arm/Group Title	Nebivolol/ Metoprolol		Metoprolol/Nebivolol
Arm/Group Description	Subjects were randomized to nebivolol for the first 3 months. Then they "crossed over" to take 3 months of metoprolol succinate. The initial 5 mg daily dose of nebivolol was titrated to 10 mg daily after 2 weeks if their BP remained >125/80, and subsequently titrated to 20 mg daily after another 2 weeks if the BP remained >125/80. Similarly, the initial 50 mg daily dose of metoprolol succinate was titrated to 100 mg daily after 2 weeks if BP remained >125/80, and further increased to 200 mg after 2 weeks if BP remained >125/80.		Subjects were randomized to metoprolol succinate for the first 3 months. Then they "crossed over" to take 3 months of nebivolol. The initial 5 mg daily dose of nebivolol was titrated to 10 mg daily after 2 weeks if their BP remained >125/80, and subsequently titrated to 20 mg daily after another 2 weeks if the BP remained >125/80. Similarly, the initial 50 mg daily dose of metoprolol succinate was titrated to 100 mg daily after 2 weeks if BP remained >125/80, and further increased to 200 mg after 2 weeks if BP remained >125/80.
All Cause Mortality
	Nebivolol/ Metoprolol		Metoprolol/Nebivolol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Nebivolol/ Metoprolol		Metoprolol/Nebivolol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		2/19 (10.5%)
Cardiac disorders
Stroke	0/19 (0%)		2/19 (10.5%)
Other (Not Including Serious) Adverse Events
	Nebivolol/ Metoprolol		Metoprolol/Nebivolol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/19 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.