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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Forest Laboratories
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:
NCT01522950
First received: January 17, 2012
Last updated: September 10, 2014
Last verified: September 2014
  Purpose

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 Intervention Phase
Hypertension
Drug: Nebivolol
Drug: atenolol
Drug: placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:


Further study details as provided by University of Minnesota - Clinical and Translational Science Institute:

Primary Outcome Measures:
  • Comparing effects of nebivolol against atenolol and placebo on endothelial function [ Time Frame: 9 months ] [ Designated as safety issue: No ]
    Change in small artery elasticity (a marker for endothelial function) from baseline to 9 months after intervention initiation.


Secondary Outcome Measures:
  • Evaluate effects of nebivolol as compared to atenolol and placebo [ Time Frame: 9 months ] [ Designated as safety issue: No ]

    Change in RDS from 0 to 3 and 9 months. Each test is scored 0/normal, 1/borderline, and 2/abnormal. The ten CV tests provide total score 0 to 20.

    Change in each of the CDS components as measured from baseline to 3 and 9 months.

    Change in risk factors and biomarkers.

    Difference in endothelial function quantification and sensitivity of pulse contour analysis and flow-mediated dilation.



Estimated Enrollment: 75
Study Start Date: May 2010
Estimated Study Completion Date: May 2015
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01522950

Locations
United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
Sponsors and Collaborators
University of Minnesota - Clinical and Translational Science Institute
Forest Laboratories
Investigators
Principal Investigator: Jay N Cohn, MD University of Minnesota Medical Center
  More Information

No publications provided

Responsible Party: University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT01522950     History of Changes
Other Study ID Numbers: 1004M81135
Study First Received: January 17, 2012
Last Updated: September 10, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by University of Minnesota - Clinical and Translational Science Institute:
hypertension
prevention
endothelial function

Additional relevant MeSH terms:
Hypertension
Vascular Diseases
Cardiovascular Diseases
Nebivolol
Atenolol
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Vasodilator Agents
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on September 16, 2014