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

NCT ID: NCT01522950

Last Updated: 2020-07-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 76 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-05-31
• Study Completion Date: 2016-10-31

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.

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.

Conditions

Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Nebivolol

Intervention Type: DRUG

5 mg daily or 10 mg daily

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.

Group Type: ACTIVE_COMPARATOR

atenolol

Intervention Type: DRUG

25 mg daily or 50 mg daily

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.

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

one tablet daily

Interventions

Nebivolol

5 mg daily or 10 mg daily

Intervention Type: DRUG

atenolol

25 mg daily or 50 mg daily

Intervention Type: DRUG

placebo

one tablet daily

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Forest Laboratories

INDUSTRY

Sponsor Role: collaborator

University of Minnesota

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jay N Cohn, MD

Role: PRINCIPAL_INVESTIGATOR

University of Minnesota Medical Center

Locations

University of Minnesota

Minneapolis, Minnesota, United States

Countries

United States

References

Duprez DA, Florea N, Duval S, Koukol C, Cohn JN. Effect of nebivolol or atenolol vs. placebo on cardiovascular health in subjects with borderline blood pressure: the EVIDENCE study. J Hum Hypertens. 2017 Dec;32(1):20-25. doi: 10.1038/s41371-017-0019-9. Epub 2017 Nov 28.

Reference Type: DERIVED

PMID: 29184167 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

CV-2014-20226

Identifier Type: -

Identifier Source: org_study_id