The Effect of Nebivolol on Endothelial Dysfunction in African Americans With Hypertension

• Sponsor: Emory University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01049009
• Collaborator: Forest Laboratories (Industry)
• Enrollment: 91
• Location: 1
• Arms: 2
• Duration (Months): 30
• Patients Per Site Per Month: 3

Study Details

Study Description

Brief Summary

High blood pressure (hypertension) is called the "silent killer" because many people do not know they have it, and do not know when it is well controlled. Unfortunately, over time uncontrolled hypertension can cause irreversible organ damage that can lead to heart attack, stroke, heart failure, and kidney failure. If a person cannot control their blood pressure with diet and exercise, doctors often prescribe medications to help control the blood pressure. Nebivolol is a medication that has been recently approved by the FDA for the treatment of hypertension. Our study will investigate whether treatment with nebivolol, as compared to another medication called metoprolol, in African Americans with hypertension will be more effective in protecting blood vessels against the harmful effects of high blood pressure.

Over time high blood pressure causes hardening of the arteries (atherosclerosis) which leads to narrowing of the blood vessels and reduces blood flow to our organs. Arteries also relax and contract naturally, which further changes the blood supply. When arteries are narrowed, exercise can bring on a condition in which the blood supply is inadequate, and this might result in the sensation of pain.

Cells lining our blood vessels produce a variety of substances that normally cause arteries to relax. Two of these substances are called nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). We are trying to determine the nature of these substances in African Americans with high blood pressure and how it is affected by nebivolol and metoprolol. One way to determine this is to inject drugs such as L-NMMA (N(G)-monomethyl-L-arginine) or TEA (tetraethylammonium chloride), which block the production of NO and EDHF respectively, and then study what happens to the blood flow at rest and during exercise. It is our thought that nebivolol, in comparison to metoprolol, will increase the substances that naturally cause arteries to relax and improve blood supply.

Condition or Disease	Intervention/Treatment	Phase
High Blood Pressure	Drug: Nebivolol; Drug: Metoprolol XL	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 91 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: The Effect of Nebivolol on Endothelial Dysfunction in African Americans With Hypertension
• Study Start Date: Dec 1, 2009
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Nebivolol followed by Metoprolol XL Subjects are randomized to Nebivolol 5mg and titrate to Nebivolol 10mg two weeks after drug initiation. Ten weeks after titration subjects will cross over to Metoprolol XL 50mg and titrate to Metoprolol XL 100mg two weeks after cross over.	Drug: Nebivolol; Subjects will be randomized to either nebivolol or metoprolol xl, and remain on the study drug for 10 weeks. They will then "cross over" to take 10 weeks of the comparator drug.; Drug: Metoprolol XL; Subjects will be randomized to either nebivolol or metoprolol xl, and remain on the study drug for 10 weeks. They will then "cross over" to take 10 weeks of the comparator drug.
Active Comparator: Metoprolol XL followed by Nebivolol Subjects are randomized to Metoprolol XL 50mg and titrate to Metoprolol XL 100mg two weeks after drug initiation. Ten weeks after titration subjects will cross over to Nebivolol 5mg and titrate to Nebivolol 10mg two weeks after cross over.	Drug: Nebivolol; Subjects will be randomized to either nebivolol or metoprolol xl, and remain on the study drug for 10 weeks. They will then "cross over" to take 10 weeks of the comparator drug.; Drug: Metoprolol XL; Subjects will be randomized to either nebivolol or metoprolol xl, and remain on the study drug for 10 weeks. They will then "cross over" to take 10 weeks of the comparator drug.

Outcome Measures

Primary Outcome Measures

1. Endothelial Function Measured by Forearm Blood Flow (FBF) at 12 Weeks [12 weeks]

   Forearm blood flow measured by venous occlusion plethysmography at rest, after administration of N(G)-monomethyl-L-arginine (L-NMMA) and tetraethylammonium chloride (TEA), after administration of L-NMMA, TEA, and acetylcholine, and after administration of L-NMMA, TEA, and exercise. Unit of Measure refers to volume of blood (mL) per 100 mL of forearm tissue per minute.

2. Endothelial Function Measured by Forearm Blood Flow (FBF) at 24 Weeks [24 weeks]

   Forearm blood flow measured by venous occlusion plethysmography at rest, after administration of N(G)-monomethyl-L-arginine (L-NMMA) and tetraethylammonium chloride (TEA), after administration of L-NMMA, TEA, and acetylcholine, and after administration of L-NMMA, TEA, and exercise. Unit of Measure refers to volume of blood (mL) per 100 mL of forearm tissue per minute.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or post-menopausal females aged 18-80 years.

• Subjects self-identified as black or African-American.

• Diagnosis of hypertension.

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

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

• Concomitant therapy: Patients will be allowed to be on concomitant therapy with aspirin, statins, thiazide diuretics, calcium antagonists (for treatment of hypertension), clonidine, or vasodilators. 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:

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

• Inability to return to Emory for follow-up testing

• Age < 21 or >80 years

• Premenopausal females with potential for pregnancy

• Acute infection in previous 2 weeks

• On angiotensin antagonists (ACE inhibitors or ARBs)

• History of substance abuse

• Current neoplasm

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

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

• Known aortic stenosis, hypertrophic cardiomyopathy.

• Inability to give informed consent

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

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Arshed A. Quyyumi, Professor, Emory University
• ClinicalTrials.gov Identifier: NCT01049009
• Other Study ID Numbers: IRB00017946
• First Posted: Jan 14, 2010
• Last Update Posted: Apr 11, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by Arshed A. Quyyumi, Professor, Emory University: Nitric Oxide; Adrenergic beta-Antagonists; Antihypertensive Agents; Vasodilator Agents; Anti-Arrhythmia Agents; Sympatholytics; Vascular Resistance; Neurotransmitter Agents; Cardiovascular Diseases; Metoprolol succinate; Therapeutic Uses; Metoprolol; Vascular Diseases; Nebivolol; Cardiovascular Agents; Endothelium-Dependent Relaxing Factors
• Additional relevant MeSH terms: Hypertension; Metoprolol; Nebivolol

Study Results

Participant Flow

Recruitment Details	Subjects recruited from the general medical clinics of The Emory Clinic, Emory University Hospital, and Grady Memorial Hospital between January 2010 through January 2012.
Pre-assignment Detail	91 subjects were enrolled but 47 subjects were withdrawn prior to group assignment due to various factors, which included eligibility criteria, lost to follow-up, and withdrawal by subject.

Arm/Group Title	Nebivolol/Metoprolol XL	Metoprolol XL/Nebivolol
Arm/Group Description	Subjects are randomized to Nebivolol 5mg and titrate to Nebivolol 10mg two weeks after drug initiation. Ten weeks after titration subjects will cross over to Metoprolol XL 50mg and titrate to Metoprolol XL 100mg two weeks after cross over.	Subjects are randomized to Metoprolol XL 50mg and titrate to Metoprolol XL 100mg two weeks after drug initiation. Ten weeks after titration subjects will cross over to Nebivolol 5mg and titrate to Nebivolol 10mg two weeks after cross over.
Period Title: Treatment Period 1 (12 Weeks)
STARTED	23	21
COMPLETED	21	18
NOT COMPLETED	2	3
Period Title: Treatment Period 1 (12 Weeks)
STARTED	21	18
COMPLETED	11	8
NOT COMPLETED	10	10

Baseline Characteristics

Arm/Group Title	Nebivolol/Metoprolol XL	Metoprolol XL/Nebivolol	Total
Arm/Group Description	Subjects were randomized to Nebivolol 5mg and titrated to Nebivolol 10mg two weeks after drug initiation. Ten weeks after titration, subjects crossed over to Metoprolol XL 50mg and titrated to Metoprolol XL 100mg two weeks after cross over.	Subjects were randomized to Metoprolol XL 50mg and titrated to Metoprolol XL 100mg two weeks after drug initiation. Ten weeks after titration, subjects crossed over to Nebivolol 5mg and titrated to Nebivolol 10mg two weeks after cross over.	Total of all reporting groups
Overall Participants	11	8	19
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	11 100%	8 100%	19 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	4 36.4%	2 25%	6 31.6%
Male	7 63.6%	6 75%	13 68.4%

Outcome Measures

1. Primary Outcome

Title	Endothelial Function Measured by Forearm Blood Flow (FBF) at 12 Weeks
Description	Forearm blood flow measured by venous occlusion plethysmography at rest, after administration of N(G)-monomethyl-L-arginine (L-NMMA) and tetraethylammonium chloride (TEA), after administration of L-NMMA, TEA, and acetylcholine, and after administration of L-NMMA, TEA, and exercise. Unit of Measure refers to volume of blood (mL) per 100 mL of forearm tissue per minute.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nebivolol/Metoprolol XL	Metoprolol XL/Nebivolol
Arm/Group Description	Subjects were randomized to Nebivolol 5mg and titrated to Nebivolol 10mg two weeks after drug initiation. Ten weeks after titration, subjects crossed over to Metoprolol XL 50mg and titrated to Metoprolol XL 100mg two weeks after cross over.	Subjects were randomized to Metoprolol XL 50mg and titrated to Metoprolol XL 100mg two weeks after drug initiation. Ten weeks after titration, subjects crossed over to Nebivolol 5mg and titrated to Nebivolol 10mg two weeks after cross over.
Measure Participants	11	8
At rest	2.739 (1.365)	2.679 (.0901)
L-NMMA+TEA	1.963 (0.968)	2.221 (0.630)
L-NMMA+TEA+ACh	5.376 (3.362)	7.562 (4.358)
L-NMMA+TEA+exercise	7.377 (2.754)	11.574 (4.716)

2. Primary Outcome

Title	Endothelial Function Measured by Forearm Blood Flow (FBF) at 24 Weeks
Description	Forearm blood flow measured by venous occlusion plethysmography at rest, after administration of N(G)-monomethyl-L-arginine (L-NMMA) and tetraethylammonium chloride (TEA), after administration of L-NMMA, TEA, and acetylcholine, and after administration of L-NMMA, TEA, and exercise. Unit of Measure refers to volume of blood (mL) per 100 mL of forearm tissue per minute.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nebivolol/Metoprolol XL	Metoprolol XL/Nebivolol
Arm/Group Description	Subjects were randomized to Nebivolol 5mg and titrated to Nebivolol 10mg two weeks after drug initiation. Ten weeks after titration, subjects crossed over to Metoprolol XL 50mg and titrated to Metoprolol XL 100mg two weeks after cross over.	Subjects were randomized to Metoprolol XL 50mg and titrated to Metoprolol XL 100mg two weeks after drug initiation. Ten weeks after titration, subjects crossed over to Nebivolol 5mg and titrated to Nebivolol 10mg two weeks after cross over.
Measure Participants	11	8
At rest	3.066 (1.469)	2.968 (1.164)
L-NMMA+TEA	2.457 (1.549)	2.287 (0.693)
L-NMMA+TEA+ACh	7.158 (4.875)	7.534 (4.523)
L-NMMA+TEA+exercise	9.589 (3.550)	10.395 (2.687)

Adverse Events

Adverse Event Reporting Description	Only subjects that were randomized into an arm with drug were included in the "at-risk participant" fields.
Arm/Group Title	Nebivolol/Metoprolol XL		Metoprolol XL/Nebivolol
Arm/Group Description	Subjects were randomized to Nebivolol 5mg and titrated to Nebivolol 10mg two weeks after drug initiation. Ten weeks after titration, subjects crossed over to Metoprolol XL 50mg and titrated to Metoprolol XL 100mg two weeks after cross over.		Subjects were randomized to Metoprolol XL 50mg and titrated to Metoprolol XL 100mg two weeks after drug initiation. Ten weeks after titration, subjects crossed over to Nebivolol 5mg and titrated to Nebivolol 10mg two weeks after cross over.
All Cause Mortality
	Nebivolol/Metoprolol XL		Metoprolol XL/Nebivolol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Nebivolol/Metoprolol XL		Metoprolol XL/Nebivolol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/21 (0%)
Other (Not Including Serious) Adverse Events
	Nebivolol/Metoprolol XL		Metoprolol XL/Nebivolol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/21 (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.