EVIDENCE: A Study Examining the Effects of Nebivolol Compared to Atenolol on Endothelial Function

• Sponsor: University of Minnesota (Other)
• Overall Status: Completed
• CT.gov ID: NCT01522950
• Collaborator: Forest Laboratories (Industry)
• Enrollment: 76
• Location: 1
• Arms: 3
• Duration (Months): 77
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

This is a randomized, double-blind, placebo-controlled study comparing the efficacy of nebivolol and atenolol at improving small artery elasticity and reducing cardiovascular disease risk in subjects with early vascular disease. Approximately 75 subjects with borderline/elevated blood pressures and impaired endothelial function, as measured by arterial elasticity scores, will be recruited and assigned to treatment groups using a block randomization scheme. Patients will be randomly allocated to nebivolol, atenolol or placebo, and then followed for 9 months.

Condition or Disease	Intervention/Treatment	Phase
Hypertension	Drug: Nebivolol; Drug: atenolol; Drug: placebo	Phase 2

Detailed Description

The Rasmussen Disease Score (RDS) test panel is the chosen methodology for this study. The 10 parameters of the RDS were selected because of their ability to quantify early structural and functional abnormalities in the vasculature and left ventricle which appear long before cardiovascular disease is present.

The RDS tests include: large and small artery elasticity (measured by pulse contour analysis), resting blood pressure, mild treadmill exercise test, carotid IMT, left ventricle mass, ECG, retinal vasculature evaluation, as well as quantification of serum NT-proBNP, and microalbuminuria. Quantitative results from these tests are converted into categorical classifications based on values stratified by age and gender when appropriate. The categorical data is scored as follows: normal = 0 points, borderline = 1 point, abnormal = 2 points. Point values from all parameters are summed to create the RDS, with values ranging from 0-20. Scores of 0-2 are classified as normal, 3-5 as early disease, and 6+ as advanced disease. Previous research has shown that the RDS is a powerful predictor of future cardiovascular events.

The small artery elasticity (C2) parameter is of particular interest as it is responsive to changes in NO levels and is an effective and reliable predictor of future hypertension and other cardiovascular events. Changes in C2 will serve as the primary outcome of this study. Similar studies using anti-hypertensive or lipid-lowering interventions have found significant improvements in C2 values.

Brachial artery flow-mediated dilation (FMD) measurements will also be measured as an index of endothelial function, although this method appears to be less sensitive to functional changes related to NO bioavailability than C2. Utilizing both FMD and C2 will allow comparison with previous studies and take advantage of a large sample size to further examine the relative sensitivity of each method for reliably measuring endothelial dysfunction.

The duration of intervention for this study is 9 months which is the minimum time to adequately detect improvement in left ventricle (LV) mass values. LV mass measurements are a critical component of a comprehensive assessment of cardiovascular health and have improved within this temporal window as a result of anti-hypertensive intervention.

Study Design

• Study Type: Interventional
• Actual Enrollment: 76 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-blind, Placebo-controlled, Randomized Study Examining the Effects of Nebivolol Compared to Atenolol on Endothelial Function and Cardiovascular Risk in Patients With Early Vascular Disease
• Study Start Date: May 1, 2010
• Actual Primary Completion Date: Oct 1, 2016
• Actual Study Completion Date: Oct 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Nebivolol 5 mg, continue for 1 month; dose titration to 10 mg, continue for 8 months. Dose may be returned to initiation levels if side effects occur.	Drug: Nebivolol; 5 mg daily or 10 mg daily
Active Comparator: Atenolol 25 mg, continue for 1 month; dose titration to 50 mg, continue for 8 months. Dose may be returned to initiation levels if side effects occur.	Drug: atenolol; 25 mg daily or 50 mg daily
Placebo Comparator: Placebo Continue for 1 month; dose titration to "high dose" placebo, continue for 8 months. Dose may be returned to initiation levels if side effects occur.	Drug: placebo; one tablet daily

Outcome Measures

Primary Outcome Measures

1. Change in Small Artery Elasticity [baseline, 9 months]

   Change in small artery elasticity (a marker for endothelial function) from baseline to 9 months after intervention initiation.

Secondary Outcome Measures

1. Change in Large Artery Elasticity [baseline, 9 months]

   Change in large artery elasticity (a marker for endothelial function) from baseline to 9 months after intervention initiation.

2. Change in Systolic Blood Pressure [baseline, 9 months]

   Change in systolic blood pressure as measured by sphygmomanometer from baseline to 9 months after intervention initiation.

3. Change in Diastolic Blood Pressure [baseline, 9 months]

   Change in diastolic blood pressure as measured by sphygmomanometer from baseline to 9 months after intervention initiation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• borderline blood pressure (120-145/80-90 mm Hg);

• borderline or abnormal small artery elasticity (C2) as measured by pulse contour analysis;

• treatment-naive for all blood pressure medications including diuretics for at least 30 days prior to baseline visit;

• able to walk on a treadmill for 3 minutes;

• female patients with reproductive potential must use an approved contraceptive method if appropriate (for example, intrauterine device [IUD], birth control pills, or barrier device during and for 1 month after the last dose of study drug;

• voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.

Exclusion Criteria:

• history of intolerance to beta-blockers or clear contraindications to their use; current pharmaceutical treatment of blood pressure;

• known history of cardiovascular disease (myocardial infarction, coronary artery bypass graft, unstable angina, uncontrolled arrhythmias, stroke, etc.);

• known history of diabetes; known history of hepatic, renal or gastrointestinal disorder;

• known history of any illness that may cause additional risk (as determined by study investigator);

• pregnant or lactating women [when used during pregnancy, beta-blockers may cause fetal harm];

• participation in a concomitant clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Minnesota	Minneapolis	Minnesota	United States	55455

Sponsors and Collaborators

• University of Minnesota
• Forest Laboratories

Investigators

• Principal Investigator: Jay N Cohn, MD, University of Minnesota Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 14, 2014

More Information

Publications

None provided.

• Responsible Party: University of Minnesota
• ClinicalTrials.gov Identifier: NCT01522950
• Other Study ID Numbers: CV-2014-20226
• First Posted: Feb 1, 2012
• Last Update Posted: Jul 17, 2020
• Last Verified: Jul 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by University of Minnesota: hypertension; prevention; endothelial function
• Additional relevant MeSH terms: Hypertension; Atenolol; Nebivolol

Study Results

Participant Flow

Arm/Group Title	Nebivolol	Atenolol	Placebo
Arm/Group Description	5 mg, continue for 1 month; dose titration to 10 mg, continue for 8 months. Dose may be returned to initiation levels if side effects occur. Nebivolol: 5 mg daily or 10 mg daily	25 mg, continue for 1 month; dose titration to 50 mg, continue for 8 months. Dose may be returned to initiation levels if side effects occur. atenolol: 25 mg daily or 50 mg daily	Continue for 1 month; dose titration to "high dose" placebo, continue for 8 months. Dose may be returned to initiation levels if side effects occur. placebo: one tablet daily
Period Title: Overall Study
STARTED	26	23	27
COMPLETED	20	18	22
NOT COMPLETED	6	5	5

Baseline Characteristics

Arm/Group Title	Nebivolol	Atenolol	Placebo	Total
Arm/Group Description	5 mg, continue for 1 month; dose titration to 10 mg, continue for 8 months. Dose may be returned to initiation levels if side effects occur. Nebivolol: 5 mg daily or 10 mg daily	25 mg, continue for 1 month; dose titration to 50 mg, continue for 8 months. Dose may be returned to initiation levels if side effects occur. atenolol: 25 mg daily or 50 mg daily	Continue for 1 month; dose titration to "high dose" placebo, continue for 8 months. Dose may be returned to initiation levels if side effects occur. placebo: one tablet daily	Total of all reporting groups
Overall Participants	20	18	22	60
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	18 90%	16 88.9%	16 72.7%	50 83.3%
>=65 years	2 10%	2 11.1%	6 27.3%	10 16.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.1 (14.5)	50.8 (14)	54 (9)	50.7 (13.2)
Sex: Female, Male (Count of Participants)
Female	9 45%	4 22.2%	13 59.1%	26 43.3%
Male	11 55%	14 77.8%	9 40.9%	34 56.7%
Region of Enrollment (participants) [Number]
United States	20 100%	18 100%	22 100%	60 100%

Outcome Measures

1. Primary Outcome

Title	Change in Small Artery Elasticity
Description	Change in small artery elasticity (a marker for endothelial function) from baseline to 9 months after intervention initiation.
Time Frame	baseline, 9 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nebivolol	Atenolol	Placebo
Arm/Group Description	5 mg, continue for 1 month; dose titration to 10 mg, continue for 8 months. Dose may be returned to initiation levels if side effects occur. Nebivolol: 5 mg daily or 10 mg daily	25 mg, continue for 1 month; dose titration to 50 mg, continue for 8 months. Dose may be returned to initiation levels if side effects occur. atenolol: 25 mg daily or 50 mg daily	Continue for 1 month; dose titration to "high dose" placebo, continue for 8 months. Dose may be returned to initiation levels if side effects occur. placebo: one tablet daily
Measure Participants	20	18	22
Mean (Standard Deviation) [(ml/mmHg × 100)]	2.4 (2.1)	1.0 (2.1)	0.4 (1.7)

2. Secondary Outcome

Title	Change in Large Artery Elasticity
Description	Change in large artery elasticity (a marker for endothelial function) from baseline to 9 months after intervention initiation.
Time Frame	baseline, 9 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nebivolol	Atenolol	Placebo
Arm/Group Description	5 mg, continue for 1 month; dose titration to 10 mg, continue for 8 months. Dose may be returned to initiation levels if side effects occur. Nebivolol: 5 mg daily or 10 mg daily	25 mg, continue for 1 month; dose titration to 50 mg, continue for 8 months. Dose may be returned to initiation levels if side effects occur. atenolol: 25 mg daily or 50 mg daily	Continue for 1 month; dose titration to "high dose" placebo, continue for 8 months. Dose may be returned to initiation levels if side effects occur. placebo: one tablet daily
Measure Participants	20	18	22
Mean (Standard Deviation) [(ml/mmHg × 10)]	3.2 (5.4)	2.9 (3.4)	0.2 (2.6)

3. Secondary Outcome

Title	Change in Systolic Blood Pressure
Description	Change in systolic blood pressure as measured by sphygmomanometer from baseline to 9 months after intervention initiation.
Time Frame	baseline, 9 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nebivolol	Atenolol	Placebo
Arm/Group Description	5 mg, continue for 1 month; dose titration to 10 mg, continue for 8 months. Dose may be returned to initiation levels if side effects occur. Nebivolol: 5 mg daily or 10 mg daily	25 mg, continue for 1 month; dose titration to 50 mg, continue for 8 months. Dose may be returned to initiation levels if side effects occur. atenolol: 25 mg daily or 50 mg daily	Continue for 1 month; dose titration to "high dose" placebo, continue for 8 months. Dose may be returned to initiation levels if side effects occur. placebo: one tablet daily
Measure Participants	20	18	22
Mean (Standard Deviation) [mmHg]	-9 (12.9)	-13 (10.6)	-3.2 (12.4)

4. Secondary Outcome

Title	Change in Diastolic Blood Pressure
Description	Change in diastolic blood pressure as measured by sphygmomanometer from baseline to 9 months after intervention initiation.
Time Frame	baseline, 9 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nebivolol	Atenolol	Placebo
Arm/Group Description	5 mg, continue for 1 month; dose titration to 10 mg, continue for 8 months. Dose may be returned to initiation levels if side effects occur. Nebivolol: 5 mg daily or 10 mg daily	25 mg, continue for 1 month; dose titration to 50 mg, continue for 8 months. Dose may be returned to initiation levels if side effects occur. atenolol: 25 mg daily or 50 mg daily	Continue for 1 month; dose titration to "high dose" placebo, continue for 8 months. Dose may be returned to initiation levels if side effects occur. placebo: one tablet daily
Measure Participants	20	18	22
Mean (Standard Deviation) [mmHg]	-8.5 (10.1)	-8.5 (8.9)	-2.9 (6.7)

Adverse Events

Arm/Group Title	Nebivolol		Atenolol		Placebo
Arm/Group Description	5 mg, continue for 1 month; dose titration to 10 mg, continue for 8 months. Dose may be returned to initiation levels if side effects occur. Nebivolol: 5 mg daily or 10 mg daily		25 mg, continue for 1 month; dose titration to 50 mg, continue for 8 months. Dose may be returned to initiation levels if side effects occur. atenolol: 25 mg daily or 50 mg daily		Continue for 1 month; dose titration to "high dose" placebo, continue for 8 months. Dose may be returned to initiation levels if side effects occur. placebo: one tablet daily
All Cause Mortality
	Nebivolol		Atenolol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		1/18 (5.6%)		1/22 (4.5%)
Serious Adverse Events
	Nebivolol		Atenolol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/18 (0%)		0/22 (0%)
Other (Not Including Serious) Adverse Events
	Nebivolol		Atenolol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/20 (30%)		4/18 (22.2%)		7/22 (31.8%)
Gastrointestinal disorders
Nausea	1/20 (5%)		2/18 (11.1%)		1/22 (4.5%)
General disorders
Fatigue	5/20 (25%)		2/18 (11.1%)		2/22 (9.1%)
Headache	0/20 (0%)		0/18 (0%)		1/22 (4.5%)
Dizziness	0/20 (0%)		0/18 (0%)		1/22 (4.5%)
Pruritus	0/20 (0%)		0/18 (0%)		1/22 (4.5%)
Hypertension	0/20 (0%)		0/18 (0%)		1/22 (4.5%)

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.