Nebivolol and the Endothelin (ET)-1 System

NCT01395329 | Completed Phase 4 Results DMC

• 1 other identifier: BYS-MD-57
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief Summary

The investigators hypothesize that nebivolol will reduce ET-1-mediated vasoconstrictor tone in adult humans with elevated blood pressure to a greater extent than either metoprolol or placebo.

Conditions

Prehypertension; Hypertension

Outcome Measures

Primary Outcomes (7)

• Systolic Blood Pressure

  Systolic blood pressure was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.

• Diastolic Blood Pressure

  Diastolic blood pressure was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.

• Percent Change in Forearm Blood Flow (FBF) Response to BQ-123 (100 Nmol/Min)

  Forearm blood flow (FBF) was measured via strain-gauge venous occlusion plethysmography at rest and every 10 minutes thereafter for 60 minutes. The average percent change for before and after either drug or placebo was calculated as the FBF at (each time point-resting value)/resting value and multiplied by 100 to calculate the percent change. The baseline or resting value was measured before the start of each drug infusion.

  Forearm blood flow was measured at 0-60 minutes before the 12 week drug or placebo intervention and 0-60 minutes after the 12 week drug or placebo intervention.

• Percent Change in FBF Response to BQ-123 (100 Nmol/Min) + BQ-788 (50 Nmol/Min)

  Forearm blood flow (FBF) was measured via strain-gauge venous occlusion plethysmography at rest and every 10 minutes thereafter for 60 minutes. The average percent change for before and after either drug or placebo was calculated as the FBF at (each time point-resting value)/resting value and multiplied by 100 to calculate the percent change. The baseline or resting value was measured before the start of each drug infusion.

  Forearm blood flow was measured 0-120 minutes before the 12 week drug or placebo intervention and 0-120 minutes after the 12 week drug or placebo intervention.

• FBF Response to Acetylcholine (ACh)

  FBF was measured via strain-gauge occlusion plethysmography at rest and in response to ACh (4.0, 8.0 and 16.0 ug/100 mL tissue/min) for 5 minutes at each dose. Flows during the last minute of rest and each drug dose were measured and the mean value reported.

  Forearm blood flow was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.

• FBF Response to Sodium Nitroprusside

  FBF was measured via strain-gauge occlusion plethysmography at rest and in response to sodium nitroprusside (1.0, 2.0 and 4.0 ug/100 mL tissue/min) for 5 minutes at each dose. Flows during the last minute of rest and each drug dose were measured and the mean value reported.

  Forearm blood flow was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.

• FBF Response to ACh in the Absence or Presence of Nonselective Endothelin A/B Blockade (BQ-123+BQ-788)

  FBF was measured via strain-gauge occlusion plethysmography at rest and in response to BQ-123+BQ-788 +ACh (4.0, 8.0 and 16.0 ug/100 mL tissue/min) for 5 minutes at each dose. Flows during the last minute of rest and each drug dose were measured and the mean value reported.

  Forearm blood flow was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention.

Study Arms (3)

Nebivolol

ACTIVE COMPARATOR

Systolic and Diastolic blood pressure will be measured before and after randomization to12 weeks of Nebivolol. Forearm blood flow will be measured in response to 100 nmol/min of BQ-123, BQ-123+BQ788 (50 mol/min), Acetylcholine (4.0, 8.0, 16.0 ug/100 mL tissue/min), Sodium Nitroprusside (1.0, 2.0, 4.0 ug/100 mL tissue/min) and BQ-123+BQ-788+Acetylcholine (same doses as above) will be measured before and after the 12 weeks of nebivolol.

Drug: Nebivolol; Other: Forearm Blood Flow (FBF) response to BQ-123 (100 mol/min); Other: FBF response to BQ-123 (100 nmol/min)+BQ-788(50 nmol/min); Other: FBF response to Acetylcholine; Other: FBF response to Sodium Nitroprusside; Other: FBF response to BQ-123+BQ-788+ACh

Metoprolol

ACTIVE COMPARATOR

Systolic and Diastolic blood pressure will be measured before and after randomization to12 weeks of Metoprolol. Forearm blood flow will be measured in response to 100 nmol/min of BQ-123, BQ-123+BQ788 (50 mol/min), Acetylcholine (4.0, 8.0, 16.0 ug/100 mL tissue/min), Sodium Nitroprusside (1.0, 2.0, 4.0 ug/100 mL tissue/min) and BQ-123+BQ-788+Acetylcholine (same doses as above) will be measured before and after the 12 weeks of Metoprolol.

Drug: Metoprolol; Other: Forearm Blood Flow (FBF) response to BQ-123 (100 mol/min); Other: FBF response to BQ-123 (100 nmol/min)+BQ-788(50 nmol/min); Other: FBF response to Acetylcholine; Other: FBF response to Sodium Nitroprusside; Other: FBF response to BQ-123+BQ-788+ACh

Placebo

PLACEBO COMPARATOR

Systolic and Diastolic blood pressure will be measured before and after randomization to12 weeks of placebo. Forearm blood flow will be measured in response to 100 nmol/min of BQ-123, BQ-123+BQ788 (50 mol/min), Acetylcholine (4.0, 8.0, 16.0 ug/100 mL tissue/min), Sodium Nitroprusside (1.0, 2.0, 4.0 ug/100 mL tissue/min) and BQ-123+BQ-788+Acetylcholine (same doses as above) will be measured before and after the 12 weeks of placebo.

Drug: Placebo; Other: Forearm Blood Flow (FBF) response to BQ-123 (100 mol/min); Other: FBF response to BQ-123 (100 nmol/min)+BQ-788(50 nmol/min); Other: FBF response to Acetylcholine; Other: FBF response to Sodium Nitroprusside; Other: FBF response to BQ-123+BQ-788+ACh

Interventions

Nebivolol DRUG

5 mg tablet to be taken by mouth once per day for 12 weeks

Also known as: Bystolic

Nebivolol

Metoprolol DRUG

100 mg tablet to be taken by mouth once per day for 12 weeks

Also known as: Toprol-XL

Metoprolol

Placebo DRUG

gelatin capsule to be taken by mouth once per day for 12 weeks

Placebo

Forearm Blood Flow (FBF) response to BQ-123 (100 mol/min) OTHER

The forearm blood flow response to the endothelin (ET) -1 A receptor blocker BQ-123 (100 nmol/min) for 60 minutes at baseline and at 12 weeks.

Also known as: BQ-123

Metoprolol; Nebivolol; Placebo

FBF response to BQ-123 (100 nmol/min)+BQ-788(50 nmol/min) OTHER

The FBF response to the nonselective endothelin (ET) -1 receptor blockade BQ-123 (100 nmol/min) + BQ-788 (50 nmol/min)for 60 minutes at baseline and at 12 weeks.

Also known as: BQ-123+BQ-788

Metoprolol; Nebivolol; Placebo

FBF response to Acetylcholine OTHER

The FBF response to the endothelium-dependent vasodilator ACh (4, 8 and 16 ug/100 mL tissue/min) at baseline and at 12 weeks.

Also known as: ACh

Metoprolol; Nebivolol; Placebo

FBF response to Sodium Nitroprusside OTHER

The FBF response to the endothelium independent vasodilator NTP (1,2 and 4 ug/100 mL tissue/min) at baseline and at 12 weeks.

Also known as: NTP

Metoprolol; Nebivolol; Placebo

FBF response to BQ-123+BQ-788+ACh OTHER

The FBF response to the nonselective endothelin (ET) -1 receptor blockade BQ-123 (100 nmol/min) + BQ-788 (50 nmol/min)for 60 minutes at baseline and at 12 weeks.

Also known as: BQ-123+BQ-788+ACh

Metoprolol; Nebivolol; Placebo

Eligibility Criteria

• Age: 45 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects will be men and women of all races and ethnic backgrounds aged 45-65 years.
• Subjects will be prehypertensive/hypertensive defined as resting systolic blood pressure \>130 mmHg and \< 160 mm Hg and/or diastolic blood pressure \>80 mmHg and \< 100 mm Hg.
• All of the women in the study will be postmenopausal (at least 1 year from last menstrual cycle) and not receiving hormone replacement therapy (HRT) currently or in the preceding 3-year period.
• Lastly, candidates will be sedentary as determined from the Stanford Physical Activity Questionnaire (\<35 kcal/wk) and will not have engaged in any program of regular physical activity for at least 1 year prior to the study.

You may not qualify if:

• Candidates who smoke (currently or in the past 7 years), report more than low-risk alcohol consumption as defined as no more than 14 standard drinks/wk and no more than 4 standard drinks/day for men and 7 standard drinks/wk and 3 standard drinks/day for women (a standard drink is defined as 12 ounces of beer, 5 ounces of wine, 1½ ounces of 80-proof distilled spirits)
• Potential candidates who are taking cardiovascular-acting (i.e. statins, blood pressure medication an aspirin) medications will not be eligible.
• Fasting plasma glucose \>126 mg/dL.
• Potential candidates with a resting heart rate of \< 50 beats/minute will be excluded.
• Use of hormone replacement therapy.
• In hypertensive subjects, a seated systolic blood pressure greater than 160 mmHg or a seated diastolic blood pressure greater than 100 mmHg.

Sponsors & Collaborators

• University of Colorado, Boulder: lead
• Forest Laboratories: collaborator

Study Sites (1)

UC-Boulder Clinical and Translational Research Center

Boulder, Colorado, 80309, United States

Location

Related Publications (1)

• Diehl KJ, Stauffer BL, Dow CA, Bammert TD, Brunjes DL, Greiner JJ, DeSouza CA. Chronic Nebivolol Treatment Suppresses Endothelin-1-Mediated Vasoconstrictor Tone in Adults With Elevated Blood Pressure. Hypertension. 2016 Jun;67(6):1196-204. doi: 10.1161/HYPERTENSIONAHA.115.06979. Epub 2016 Apr 25.

  PMID: 27113048 DERIVED

MeSH Terms

Conditions

Prehypertension; Hypertension

Interventions

Nebivolol; Metoprolol; cyclo(Trp-Asp-Pro-Val-Leu); BQ 788

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Phenoxypropanolamines; Propanolamines; Propanols

Results Point of Contact

• Title: Dr. Christopher DeSouza
• Organization: University of Colorado

desouzac@colorado.edu

303-492-2988

Study Officials

• Christopher A DeSouza, Ph.D.

  University of Colorado at Boulder

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: June 9, 2011
• First Posted: July 15, 2011
• Study Start: May 1, 2011
• Primary Completion: November 1, 2016
• Study Completion: December 1, 2016
• Last Updated: January 2, 2019
• Results First Posted: December 6, 2018

Record last verified: 2018-12

Locations

US (1)