Nebivolol, Lifestyle Modification and Arterial Stiffness

• Sponsor: Virginia Polytechnic Institute and State University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01920282
• Collaborator: Forest Laboratories (Industry)
• Enrollment: 45
• Arms: 3
• Duration (Months): 31

Study Details

Study Description

Brief Summary

Numerous anti-hypertensive drugs have been reported to be efficacious in reducing central arterial stiffness and these effects may contribute to improved outcomes in hypertensive patients. However, the results of several studies suggest that beta-blockers may actually increase arterial stiffness. In contrast, there is limited evidence to suggest that nebivolol, a third generation beta-blocker that augments release of vascular nitric oxide, reduces central arterial stiffness in hypertensive individuals. Unfortunately, only a few studies have addressed this issue and all of these studies relied on indirect, blood pressure dependent measures of arterial stiffness. In addition, none of these studies focused on middle-aged and older, obese hypertensives, a population with accelerated arterial stiffening and at risk for cardiovascular diseases. Thus, the potential utility of nebivolol as a therapy to reduce large artery stiffness, particularly among the latter population, remains unclear.

Condition or Disease	Intervention/Treatment	Phase
Hypertension	Drug: Nebivolol; Other: Lifestyle Modification; Other: Nebivolol plus Lifestyle Modification	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effect of Nebivolol and Lifestyle Modification on Large Artery Stiffness in Middle-Aged and Older Hypertensive Adults
• Study Start Date: Jan 1, 2010
• Actual Primary Completion Date: Aug 1, 2012
• Actual Study Completion Date: Aug 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Nebivolol Subjects will be provided with daily 5 mg of nebivolol for the first 2 weeks. Subjects receive additional daily doses of 10 mg nebivolol for the remainder of the study period. The dose remains at 5 mg per day, however, if BP falls below 110/70 during the first 2 weeks. Subjects will continue taking the drug during the 2-week follow-up period.	Drug: Nebivolol; Other Names: Bystolic
Active Comparator: Lifestyle Modification Subjects will receive weekly lifestyle counseling by a registered dietitian to ensure adequate progress and compliance. Sample menus, 14-days of meal plans, and grocery shopping lists are provided to each individual. Individuals were instructed to reduce their daily caloric intake by 500-1000 calories and to perform a minimum of 150 minutes per week of moderate-intensity physical activity or 3000 steps/day above baseline levels. The diet plan conformed to the Dietary Approach to Stop Hypertension dietary guidelines emphasizing low fat dairy products, fruits and vegetable and contained 55% calories as carbohydrates, 30% calories as fat, and 15% calories as protein. Sodium consumption was set at 2,400 mg/day for all subjects.	Other: Lifestyle Modification; Other Names: Weight loss Sodium restriction Physical activity
Experimental: Nebivolol plus Lifestyle Modification Subjects begin with 5 mg/day of nebivolol and increase to 10 mg/day if brachial blood pressure is greater than 120/80 mmHg during the first 2 weeks of therapy. Subjects also receive weekly lifestyle counseling by a registered dietitian to ensure adequate progress and compliance. Sample menus, 14-days of meal plans, and grocery shopping lists are provided to each individual. Individuals will be instructed to reduce their daily caloric intake by 500-1000 calories and to perform a minimum of 150 min/wk of moderate-intensity physical activity or 3000 steps/day above baseline levels. The diet plan conforms to the Dietary Approaches to Stop Hypertension dietary guidelines emphasizing low fat dairy products, fruits and vegetable and contains 55% calories as carbohydrates, 30% calories as fat, and 15% calories as protein with sodium consumption set at 2,400 mg/day for all subjects.	Other: Nebivolol plus Lifestyle Modification; Other Names: Bsytolic Weight Loss Sodium restriction Physical activity

Outcome Measures

Primary Outcome Measures

1. Beta-stiffness Index [12 weeks]

   Longitudinal B-mode images of the left common carotid artery diameter (1-2 cm proximal to the carotid bulb) were obtained over 15 consecutive cardiac cycles. Brachial blood pressure was measured via an automated sphygmomanometer. Quantification of systolic and diastolic carotid artery diameters were analyzed with the Vascular Research Tools 5 software program. Beta-stiffness index was calculated as: Beta = ln(P1/P0)/((D1-D0)/D0), where D0 represents the minimal diameter recorded during diastole, D1 represents the maximal diameter recorded during systole, P0 represents the pressure measured during diastole, and P1 represents the pressure measured during systole.

Secondary Outcome Measures

1. Insulin Sensitivity (HOMA-IR) [12 weeks]

   The HOMA index was calculated as the product of plasma blood glucose and insulin divided by 22.5.

Other Outcome Measures

1. Oxidized LDL Concentration [12 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Stage 1 hypertension

• 40-75 years

• Weight stable (+/-2 kg)

• Sedentary to recreationally active

• Willing to be randomized to one of three arms

• Verbal and written consent

• Approval by medical director

Exclusion Criteria:

• Blood pressure outside stated range

• Diabetes or taking diabetes medications

• Total cholesterol >6.2 mmol/L; triglycerides >4.5 mmol/L

• Past or current ischemic heart disease, stroke, respiratory disease, endocrine or metabolic disease, neurological disease, or hematological-oncological disease

• Medications (including but not limited to antihypertensives, statins or other with anti-inflammatory actions) or antioxidant vitamins or supplements

• Known allergy or hypersensitivity to nebivolol or any of its components

• Inability to perform regular physical activity or participate in other components of lifestyle modification

• Pregnant or planning to become pregnant

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Virginia Polytechnic Institute and State University
• Forest Laboratories

Investigators

• Principal Investigator: Kevin P Davy, Ph.D., Virginia Polytechnic Institute and State University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Kevin Davy, Professor, Virginia Polytechnic Institute and State University
• ClinicalTrials.gov Identifier: NCT01920282
• Other Study ID Numbers: nebstiff
• First Posted: Aug 9, 2013
• Last Update Posted: Feb 23, 2018
• Last Verified: Jan 1, 2018

• Additional relevant MeSH terms: Hypertension; Nebivolol

Study Results

Participant Flow

Arm/Group Title	Nebivolol	Lifestyle Modification	Nebivolol Plus Lifestyle Modification
Arm/Group Description	Subjects will be provided with daily 5 mg of nebivolol for the first 2 weeks. Subjects receive additional daily doses of 10 mg nebivolol for the remainder of the study period. The dose remains at 5 mg per day, however, if BP falls below 110/70 during the first 2 weeks. Subjects will continue taking the drug during the 2-week follow-up period. Nebivolol	Subjects will receive weekly lifestyle counseling by a registered dietitian to ensure adequate progress and compliance. Sample menus, 14-days of meal plans, and grocery shopping lists were provided to each individual. Individuals were instructed to reduce their daily caloric intake by 500-1000 calories and to perform a minimum of 150 minutes per week of moderate-intensity physical activity or 3000 steps/day above baseline levels. The diet plan conformed to the Dietary Approach to Stop Hypertension dietary guidelines emphasizing low fat dairy products, fruits and vegetable and contained 55% calories as carbohydrates, 30% calories as fat, and 15% calories as protein21. Sodium consumption was set at 2,400 mg/day for all subjects. Lifestyle Modification	Subjects began with 5 mg/day of nebivolol and increased to 10 mg/day if brachial blood pressure was greater than 120/80 mmHg during the first two weeks of therapy. Subjects also received weekly lifestyle counseling by a registered dietitian to ensure adequate progress and compliance. Sample menus, 14-days of meal plans, and grocery shopping lists were provided to each individual. Individuals were instructed to reduce their daily caloric intake by 500-1000 calories and to perform a minimum of 150 minutes per week of moderate-intensity physical activity or 3000 steps/day above baseline levels. The diet plan conformed to the Dietary Approaches to Stop Hypertension dietary guidelines emphasizing low fat dairy products, fruits and vegetable and contained 55% calories as carbohydrates, 30% calories as fat, and 15% calories as protein21. Sodium consumption was set at 2,400 mg/day for all subjects. Nebivolol plus Lifestyle Modification
Period Title: Overall Study
STARTED	15	15	15
COMPLETED	15	15	15
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Nebivolol	Lifestyle Modification	Nebivolol Plus Lifestyle Modification	Total
Arm/Group Description	Subjects will be provided with daily 5 mg of nebivolol for the first 2 weeks. Subjects receive additional daily doses of 10 mg nebivolol for the remainder of the study period. The dose remains at 5 mg per day, however, if BP falls below 110/70 during the first 2 weeks. Subjects will continue taking the drug during the 2-week follow-up period. Nebivolol	Subjects will receive weekly lifestyle counseling by a registered dietitian to ensure adequate progress and compliance. Sample menus, 14-days of meal plans, and grocery shopping lists were provided to each individual. Individuals were instructed to reduce their daily caloric intake by 500-1000 calories and to perform a minimum of 150 minutes per week of moderate-intensity physical activity or 3000 steps/day above baseline levels. The diet plan conformed to the Dietary Approach to Stop Hypertension dietary guidelines emphasizing low fat dairy products, fruits and vegetable and contained 55% calories as carbohydrates, 30% calories as fat, and 15% calories as protein21. Sodium consumption was set at 2,400 mg/day for all subjects. Lifestyle Modification	Subjects began with 5 mg/day of nebivolol and increased to 10 mg/day if brachial blood pressure was greater than 120/80 mmHg during the first two weeks of therapy. Subjects also received weekly lifestyle counseling by a registered dietitian to ensure adequate progress and compliance. Sample menus, 14-days of meal plans, and grocery shopping lists were provided to each individual. Individuals were instructed to reduce their daily caloric intake by 500-1000 calories and to perform a minimum of 150 minutes per week of moderate-intensity physical activity or 3000 steps/day above baseline levels. The diet plan conformed to the Dietary Approaches to Stop Hypertension dietary guidelines emphasizing low fat dairy products, fruits and vegetable and contained 55% calories as carbohydrates, 30% calories as fat, and 15% calories as protein21. Sodium consumption was set at 2,400 mg/day for all subjects. Nebivolol plus Lifestyle Modification	Total of all reporting groups
Overall Participants	15	15	15	45
Age (yr) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [yr]	57.7 (3.1)	52.7 (2.2)	58.4 (2.2)	56.3 (2.5)
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	14 93.3%	10 66.7%	12 80%	36 80%
>=65 years	1 6.7%	5 33.3%	3 20%	9 20%
Sex: Female, Male (Count of Participants)
Female	7 46.7%	8 53.3%	8 53.3%	23 51.1%
Male	8 53.3%	7 46.7%	7 46.7%	22 48.9%
Region of Enrollment (participants) [Number]
United States	15 100%	15 100%	15 100%	45 100%
Supine blood pressure (mmHg) (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	146 (1.4)	138 (3.1)	142 (2.6)	142 (2.37)
Supine heart rate (bpm) (bpm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [bpm]	64 (1)	67 (3)	66 (2)	66 (2)

Outcome Measures

1. Primary Outcome

Title	Beta-stiffness Index
Description	Longitudinal B-mode images of the left common carotid artery diameter (1-2 cm proximal to the carotid bulb) were obtained over 15 consecutive cardiac cycles. Brachial blood pressure was measured via an automated sphygmomanometer. Quantification of systolic and diastolic carotid artery diameters were analyzed with the Vascular Research Tools 5 software program. Beta-stiffness index was calculated as: Beta = ln(P1/P0)/((D1-D0)/D0), where D0 represents the minimal diameter recorded during diastole, D1 represents the maximal diameter recorded during systole, P0 represents the pressure measured during diastole, and P1 represents the pressure measured during systole.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nebivolol	Lifestyle Modification	Nebivolol Plus Lifestyle Modification
Arm/Group Description	Subjects will be provided with daily 5 mg of nebivolol for the first 2 weeks. Subjects receive additional daily doses of 10 mg nebivolol for the remainder of the study period. The dose remains at 5 mg per day, however, if BP falls below 110/70 during the first 2 weeks. Subjects will continue taking the drug during the 2-week follow-up period. Nebivolol	Subjects will receive weekly lifestyle counseling by a registered dietitian to ensure adequate progress and compliance. Sample menus, 14-days of meal plans, and grocery shopping lists were provided to each individual. Individuals were instructed to reduce their daily caloric intake by 500-1000 calories and to perform a minimum of 150 minutes per week of moderate-intensity physical activity or 3000 steps/day above baseline levels. The diet plan conformed to the Dietary Approach to Stop Hypertension dietary guidelines emphasizing low fat dairy products, fruits and vegetable and contained 55% calories as carbohydrates, 30% calories as fat, and 15% calories as protein21. Sodium consumption was set at 2,400 mg/day for all subjects. Lifestyle Modification	Subjects began with 5 mg/day of nebivolol and increased to 10 mg/day if brachial blood pressure was greater than 120/80 mmHg during the first two weeks of therapy. Subjects also received weekly lifestyle counseling by a registered dietitian to ensure adequate progress and compliance. Sample menus, 14-days of meal plans, and grocery shopping lists were provided to each individual. Individuals were instructed to reduce their daily caloric intake by 500-1000 calories and to perform a minimum of 150 minutes per week of moderate-intensity physical activity or 3000 steps/day above baseline levels. The diet plan conformed to the Dietary Approaches to Stop Hypertension dietary guidelines emphasizing low fat dairy products, fruits and vegetable and contained 55% calories as carbohydrates, 30% calories as fat, and 15% calories as protein21. Sodium consumption was set at 2,400 mg/day for all subjects. Nebivolol plus Lifestyle Modification
Measure Participants	15	15	15
Mean (Standard Error) [Arbitrary units]	-2.03 (0.6)	-1.87 (0.83)	-2.51 (0.9)

2. Secondary Outcome

Title	Insulin Sensitivity (HOMA-IR)
Description	The HOMA index was calculated as the product of plasma blood glucose and insulin divided by 22.5.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nebivolol	Lifestyle Modification	Nebivolol Plus Lifestyle Modification
Arm/Group Description	Subjects will be provided with daily 5 mg of nebivolol for the first 2 weeks. Subjects receive additional daily doses of 10 mg nebivolol for the remainder of the study period. The dose remains at 5 mg per day, however, if BP falls below 110/70 during the first 2 weeks. Subjects will continue taking the drug during the 2-week follow-up period. Nebivolol	Subjects will receive weekly lifestyle counseling by a registered dietitian to ensure adequate progress and compliance. Sample menus, 14-days of meal plans, and grocery shopping lists were provided to each individual. Individuals were instructed to reduce their daily caloric intake by 500-1000 calories and to perform a minimum of 150 minutes per week of moderate-intensity physical activity or 3000 steps/day above baseline levels. The diet plan conformed to the Dietary Approach to Stop Hypertension dietary guidelines emphasizing low fat dairy products, fruits and vegetable and contained 55% calories as carbohydrates, 30% calories as fat, and 15% calories as protein21. Sodium consumption was set at 2,400 mg/day for all subjects. Lifestyle Modification	Subjects began with 5 mg/day of nebivolol and increased to 10 mg/day if brachial blood pressure was greater than 120/80 mmHg during the first two weeks of therapy. Subjects also received weekly lifestyle counseling by a registered dietitian to ensure adequate progress and compliance. Sample menus, 14-days of meal plans, and grocery shopping lists were provided to each individual. Individuals were instructed to reduce their daily caloric intake by 500-1000 calories and to perform a minimum of 150 minutes per week of moderate-intensity physical activity or 3000 steps/day above baseline levels. The diet plan conformed to the Dietary Approaches to Stop Hypertension dietary guidelines emphasizing low fat dairy products, fruits and vegetable and contained 55% calories as carbohydrates, 30% calories as fat, and 15% calories as protein21. Sodium consumption was set at 2,400 mg/day for all subjects. Nebivolol plus Lifestyle Modification
Measure Participants	15	15	15
Mean (Standard Error) [Arbitrary units]	-0.36 (0.33)	-1.98 (1.43)	-2.12 (0.73)

3. Other Pre-specified Outcome

Title	Oxidized LDL Concentration
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Nebivolol		Lifestyle Modification		Nebivolol Plus Lifestyle Modification
Arm/Group Description	Subjects will be provided with daily 5 mg of nebivolol for the first 2 weeks. Subjects receive additional daily doses of 10 mg nebivolol for the remainder of the study period. The dose remains at 5 mg per day, however, if BP falls below 110/70 during the first 2 weeks. Subjects will continue taking the drug during the 2-week follow-up period. Nebivolol		Subjects will receive weekly lifestyle counseling by a registered dietitian to ensure adequate progress and compliance. Sample menus, 14-days of meal plans, and grocery shopping lists were provided to each individual. Individuals were instructed to reduce their daily caloric intake by 500-1000 calories and to perform a minimum of 150 minutes per week of moderate-intensity physical activity or 3000 steps/day above baseline levels. The diet plan conformed to the Dietary Approach to Stop Hypertension dietary guidelines emphasizing low fat dairy products, fruits and vegetable and contained 55% calories as carbohydrates, 30% calories as fat, and 15% calories as protein21. Sodium consumption was set at 2,400 mg/day for all subjects. Lifestyle Modification		Subjects began with 5 mg/day of nebivolol and increased to 10 mg/day if brachial blood pressure was greater than 120/80 mmHg during the first two weeks of therapy. Subjects also received weekly lifestyle counseling by a registered dietitian to ensure adequate progress and compliance. Sample menus, 14-days of meal plans, and grocery shopping lists were provided to each individual. Individuals were instructed to reduce their daily caloric intake by 500-1000 calories and to perform a minimum of 150 minutes per week of moderate-intensity physical activity or 3000 steps/day above baseline levels. The diet plan conformed to the Dietary Approaches to Stop Hypertension dietary guidelines emphasizing low fat dairy products, fruits and vegetable and contained 55% calories as carbohydrates, 30% calories as fat, and 15% calories as protein21. Sodium consumption was set at 2,400 mg/day for all subjects. Nebivolol plus Lifestyle Modification
All Cause Mortality
	Nebivolol		Lifestyle Modification		Nebivolol Plus Lifestyle Modification
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Nebivolol		Lifestyle Modification		Nebivolol Plus Lifestyle Modification
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Nebivolol		Lifestyle Modification		Nebivolol Plus Lifestyle Modification
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)		0/15 (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.