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Comparison of Nebivolol and Metoprolol With Exercise and Angiotensin II in Hypertensive Patients

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ClinicalTrials.gov Identifier: NCT01502787
Recruitment Status : Completed
First Posted : January 2, 2012
Results First Posted : December 31, 2014
Last Update Posted : July 7, 2020
Sponsor:
Collaborator:
Forest Laboratories
Information provided by (Responsible Party):
University of Texas Southwestern Medical Center

Tracking Information
First Submitted Date  ICMJE November 1, 2011
First Posted Date  ICMJE January 2, 2012
Results First Submitted Date  ICMJE December 2, 2014
Results First Posted Date  ICMJE December 31, 2014
Last Update Posted Date July 7, 2020
Study Start Date  ICMJE April 2009
Actual Primary Completion Date June 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 8, 2018)
Forearm Blood Flow [ Time Frame: 12 weeks after each specified medication ]
Original Primary Outcome Measures  ICMJE
 (submitted: December 29, 2011)
  • Forearm Blood Flow [ Time Frame: 12 weeks after initiation of metoprolol ]
  • Forearm blood flow [ Time Frame: 12 weeks after initiation of nebivolol ]
  • Sympathetic Nerve Activity (SNA) During Exercise [ Time Frame: 12 weeks after initiation of metoprolol ]
  • Sympathetic Nerve Activity (SNA) During Exercise [ Time Frame: 12 weeks after initiation of nebivolol ]
  • Sympathetic Nerve Activity (SNA) During Angiotensin II Infusion [ Time Frame: 12 weeks after initiation of metoprolol ]
  • Sympathetic Nerve Activity (SNA) During Angiotensin II Infusion [ Time Frame: 12 weeks after initiation of nebivolol ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 8, 2018)
  • Blood Pressure During Exercise [ Time Frame: 12 weeks ]
  • Blood Pressure During Angiotensin II Infusion [ Time Frame: 12 weeks after initiation of metoprolol ]
Original Secondary Outcome Measures  ICMJE
 (submitted: December 29, 2011)
  • Blood Pressure During Exercise [ Time Frame: 12 weeks after initiation of metoprolol ]
  • Blood Pressure During Exercise [ Time Frame: 12 weeks after initiation of nebivolol ]
  • Blood Pressure During Angiotensin II Infusion [ Time Frame: 12 weeks after initiation of metoprolol ]
  • Blood Pressure During Angiotensin II Infusion [ Time Frame: 12 weeks after initiation of nebivolol ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Comparison of Nebivolol and Metoprolol With Exercise and Angiotensin II in Hypertensive Patients
Official Title  ICMJE Effects of Nebivolol Versus Metoprolol on Blood Flow Responses to Exercise and Angiotensin II in Hypertensive Patients
Brief Summary The purpose of this study is to determine if Nebivolol a) attenuates the angiotensin II (Ang II)-induced increase in oxidative stress, thereby attenuating Ang II-induced vasoconstriction; and b) attenuates sympathetic mediated vasoconstriction during exercise, thereby reducing functional skeletal muscle ischemia in hypertensive patients.
Detailed Description

In 40 untreated, stage I hypertensive subjects, Investigators will measure sympathetic nerve activity (microneurography); total forearm blood flow (high-resolution ultrasonography); skeletal muscle oxygenation (Near Infrared spectroscopy); plasma F2-isoprostanes; cardiac output (non-invasive impedance plethysmography); and blood pressure at baseline and after a) rhythmic handgrip exercise at 30% of maximal voluntary contraction alone for 3 minutes, b) rhythmic handgrip at the same intensity of exercise plus lower body negative pressure (LBNP) to activate sympathetic nerve activity (SNA) for 2 minutes, and c) during intravenous infusion of Angiotensin II at the dose of 1, 2, and 3 ng/kg/min for 15 minutes at each dose.

Each subject will then be randomized to receive 12 weeks of Nebivolol (Bystolic, 5-20 mg/day) or Metoprolol Succinate (Toprol XL, 100-300 mg/day), using a randomized crossover design. There will be a 2-week washout period between the two treatment periods. During drug treatment, blood pressure will be monitored every 4 weeks and the doses of Nebivolol and Metoprolol will be titrated to keep BP <140/90 mmHg. SNA, total forearm blood flow, skeletal muscle blood flow, muscle oxygenation, cardiac output, and blood pressure responses to Nebivolol will be compared to responses during Metoprolol in the same subjects.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Condition  ICMJE Hypertension
Intervention  ICMJE
  • Drug: Metoprolol succinate
    The subject will be started on metoprolol succinate (Toprol XL) 100-300mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.
    Other Name: Toprol XL
  • Drug: Nebivolol
    The subject will be started on nebivolol (Bystolic) 5-20mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.
    Other Name: Bystolic
  • Procedure: Forearm blood flow
    Using high-resolution ultrasound, investigators will measure skeletal muscle blood flow in the forearm at rest, following handgrip exercise (described below), and following Angiotensin II infusion (described below).
  • Procedure: Microneurography
    Investigators will measure sympathetic nerve activity from the peroneal nerve by inserting a tiny needle directly into the nerve in the leg. Investigators will localize the nerve by electrical stimulation over the skin using a blunt probe. With this stimulation, subject will notice either involuntary twitching or a tingling sensation, which may be annoying but not painful. Investigators will then introduce a tiny, sterile wire needle (an electrode) through the skin at the same location. When the tip of the needle enters the nerve, subjects may again notice involuntary muscle twitches or tingling in the leg. Investigators will then turn the electrical stimulator off and make minor adjustments in the position of the needle until investigators begin to record the nerve signals. The recording needle will remain in position throughout the study.
    Other Name: Assessment of sympathetic nerve activity (SNA)
  • Procedure: Rhythmic handgrip exercise
    Subjects will perform a rhythmic handgrip exercise at 30% of maximal voluntary contraction for 3 minutes. Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure, and sympathetic nerve activity (SNA) at baseline and following this handgrip exercise.
  • Procedure: Lower body negative pressure
    Lower body negative pressure increases sympathetic nerve activity. Therefore, investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure and sympathetic nerve activity at baseline and after rhythmic handgrip exercise plus lower body negative pressure (LBNP) for 2 minutes.
    Other Name: LBNP
  • Drug: Angiotensin II
    Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure and sympathetic nerve activity at baseline and during intravenous infusion of Angiotensin II at the dose of 1, 2, and 3 ng/kg/min for 15 minutes at each dose.
    Other Name: IND #103,935
Study Arms  ICMJE
  • Active Comparator: Initial treatment with metoprolol
    The subject will be started on metoprolol succinate (Toprol XL) 100-300mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued. There will be a 2-week washout period. Following washout, the subject will be started on nebivolol (Bystolic) 5-20mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.
    Interventions:
    • Drug: Metoprolol succinate
    • Drug: Nebivolol
    • Procedure: Forearm blood flow
    • Procedure: Microneurography
    • Procedure: Rhythmic handgrip exercise
    • Procedure: Lower body negative pressure
    • Drug: Angiotensin II
  • Active Comparator: Initial treatment with nebivolol
    The subject will be started on nebivolol (Bystolic) 5-20mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued. There will be a 2-week washout period. Following washout, the subject will be started on metoprolol succinate (Toprol XL) 100-300mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.
    Interventions:
    • Drug: Metoprolol succinate
    • Drug: Nebivolol
    • Procedure: Forearm blood flow
    • Procedure: Microneurography
    • Procedure: Rhythmic handgrip exercise
    • Procedure: Lower body negative pressure
    • Drug: Angiotensin II
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 27, 2014)
46
Original Estimated Enrollment  ICMJE
 (submitted: December 29, 2011)
40
Actual Study Completion Date  ICMJE June 2013
Actual Primary Completion Date June 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Stage I hypertension (140-159/90-99 mmHg)
  • Men and women age 18-65

Exclusion Criteria:

  • Congestive heart failure or coronary artery disease
  • Blood pressure averaging >159/99 mmHg or resting heart rate < 55 bpm
  • Serum creatinine > 1.4 mg/dL
  • Asthma or chronic obstructive pulmonary diseases
  • Left ventricular hypertrophy by echocardiography or ECG
  • Pregnancy
  • Hypersensitivity to beta blockers, microbubble contrast agents, or angiotensin
  • Any history of substance abuse (other than tobacco)
  • Concomitant drug treatment which raises endogenous nitric oxide levels such as nitrates or phosphodiesterase V inhibitors (Viagra, Levitra, or Cialis)
  • History of symptomatic bradycardia or heart block
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01502787
Other Study ID Numbers  ICMJE STU 062011-072
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Texas Southwestern Medical Center
Study Sponsor  ICMJE University of Texas Southwestern Medical Center
Collaborators  ICMJE Forest Laboratories
Investigators  ICMJE
Principal Investigator: Wanpen Vongpatanasin, MD UT Southwestern Medical Center
PRS Account University of Texas Southwestern Medical Center
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP