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Effects of Nebivolol on Skeletal Muscle During Exercise in Hypertensive Patients

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ClinicalTrials.gov Identifier: NCT01501929
Recruitment Status : Completed
First Posted : December 30, 2011
Results First Posted : November 6, 2018
Last Update Posted : November 6, 2018
Sponsor:
Collaborator:
Forest Laboratories
Information provided by (Responsible Party):
Wanpen Vongpatanasin, University of Texas Southwestern Medical Center

Tracking Information
First Submitted Date  ICMJE November 29, 2011
First Posted Date  ICMJE December 30, 2011
Results First Submitted Date  ICMJE May 11, 2018
Results First Posted Date  ICMJE November 6, 2018
Last Update Posted Date November 6, 2018
Study Start Date  ICMJE August 2010
Actual Primary Completion Date December 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 9, 2018)
  • Endothelial Cell Protein Expression p47phox From Endothelial Cell Collection [ Time Frame: 12 weeks ]
    Endothelial cell (EC) was collected after a 20-guage angiocatheter was inserted into the contralateral forearm vein under sterile conditions. Three J-shaped vascular guidewires (St. Jude, St. Paul, MN) were advanced sequentially into the vein up to 10 cm. Endothelial cells were collected by gentle abrasion and placed into a dissociation buffer (0.5% bovine serum albumin, 2mM EDTA, and 100 ug/ml heparin in PBS). Endothelial cells were recovered from the tips of guide wires by repeated washing into collection tubes and subsequent centrifugation. EC were incubated with monoclonal antibodies against the polyclonal antibodies against NADPH oxidase p47 subunit. The intensity of staining was measured using fluorescence microscopy.
  • Microvascular Blood Flow [ Time Frame: 12 weeks ]
    Microvascular perfusion of skeletal muscle were measured during handgrip at 20 cycle per minute after 12 weeks of metoprolol, and after 12 weeks of nebivolol
Original Primary Outcome Measures  ICMJE
 (submitted: December 29, 2011)
  • Endothelial cell protein expression [ Time Frame: 12 weeks after initiation of metoprolol ]
  • Endothelial cell protein expression [ Time Frame: 12 weeks after initiation of nebivolol ]
  • Microvascular Blood Flow [ Time Frame: 12 weeks after initiation of metoprolol ]
  • Microvascular blood flow [ Time Frame: 12 weeks after initiation of nebivolol ]
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: December 29, 2011)
  • Flow mediated dilation (FMD) [ Time Frame: 12 weeks after initiation of metoprolol ]
  • Flow mediated dilation (FMD) [ 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 Effects of Nebivolol on Skeletal Muscle During Exercise in Hypertensive Patients
Official Title  ICMJE Effects of Nebivolol on Microvascular Perfusion in the Skeletal Muscles During Exercise in Hypertensive Patients
Brief Summary The purpose of this study is to determine if Nebivolol improves microvascular perfusion in skeletal muscle during exercise in hypertensive patients and whether this improvement is accompanied by reduction in vascular oxidative stress or increased endothelial nitric oxide synthase (eNOS) expression in humans.
Detailed Description

In 32 untreated stage 1 hypertensive subjects, the investigators will measure blood pressure; noninvasive cardiac output by thoracic electrical bioimpedance (Bioz, Cardio Dynamics); forearm mediated vasodilation (FMD), which is a non-invasive assessment of endothelial function; collect venous endothelial cells; and measure microvascular perfusion using an Octafluoropropane microbubble contrast agent (Definity).

To obtain FMD, the brachial artery will be imaged using ultrasound. After a clear picture has been obtained, the cuff on the same arm will be inflated until it is tight for five minutes. During and following this, the subject's arm will continue to be imaged to monitor maximal increase in the brachial artery diameter.

To collect endothelial cells, a thin wire will be inserted in the vein to collect cells from the inner lining of the vein. The cells collected will be processed and stained for several proteins involved in endothelial cell function, using immunofluorescent technique.

To assess the microvascular perfusion in the skeletal muscle, a contrast agent (Definity) will be administered at baseline and after 5 minutes of rhythmic hand grip exercise at 30% of maximal voluntary contraction.

The investigators will then randomize our subjects to receive 12 weeks of Metoprolol or Nebivolol, using a cross over design. There will be a 4 week washout period between the two treatments. During the washout period, subjects will be followed after 2 weeks of drug withdrawal. Subjects found to have BP > 140/90 mmHg then, will be started on hydrochlorothiazide (HCTZ) at 25 mg once daily. Then subjects will be asked to return in 2 weeks. At that time HCTZ will be stopped if started in the earlier visit, and subject will be switched to the remaining treatment (Nebivolol or Metoprolol). Then, the investigators will assess microvascular perfusion in the skeletal muscle at rest and during handgrip exercise, endothelial function (FMD), and changes in endothelial cell protein expression after 12 weeks of Nebivolol and after 12 weeks of Metoprolol treatment 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: Non-invasive measurement of Cardiac Output (CO)
    Cardiac Output (CO) will be measured non-invasively at rest and during exercise by thoracic electrical bioimpedance. Stroke volume will be derived from change in impedance/time measured during electrical systole. Cardiac output will be determined as the product of stroke volume and heart rate.
    Other Names:
    • Cardiac output by thoracic electrical bioimpedance
    • Bioz, Cardio Dynamics International Corporation
  • Procedure: Endothelial cell collection
    We will collect endothelial cells from a superficial vein, usually in the arm. Following insertion of a peripheral intravenous (IV) catheter, we will collect cells from the inner lining of the vein using a thin, flexible J-tipped wire. The wire will be inserted through the IV into the vein and then removed, along with a sampling of endothelial cells. The cells collected will be processed and stained for several proteins involved in endothelial cell function, using immunofluorescent technique.
    Other Name: Endocell collection
  • Procedure: Microvascular perfusion assessment using Definity
    Using high-resolution ultrasound, we will measure skeletal muscle blood flow during infusion of a solution containing the octafluoropropane microbubble contrast agent, Definity. The solution will be a dilution of 1 vial of Definity to 30 cc of normal saline. The ultrasound probe will be placed over the forearm to obtain images while octafluoropropane microbubbles (Definity) are infused intravenously at the rate of 0.20 to 0.27 ml/min, not to exceed a maximum dose of 2 vials per study subject per day or visit. The microvascular perfusion assessment using Definity be performed at rest as well as during slow and fast handgrip exercises.
Study Arms  ICMJE
  • Active Comparator: Initial treatment with metoprolol
    The subject will be started on metoprolol succinate (Toprol XL) 100-300mg daily, which he/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. If necessary, 2 weeks after drug withdrawal, subjects will be started on HCTZ if BP > 140/90 mmHg and will continue HCTZ for a 2-week period, after which the subject will be transitioned to 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: Non-invasive measurement of Cardiac Output (CO)
    • Procedure: Endothelial cell collection
    • Procedure: Microvascular perfusion assessment using Definity
  • 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. If necessary, 2 weeks after drug withdrawal, subject will be started on HCTZ if BP > 140/90 mmHg and will continue HCTZ for a 2-week period, after which the subject will be transitioned to 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: Non-invasive measurement of Cardiac Output (CO)
    • Procedure: Endothelial cell collection
    • Procedure: Microvascular perfusion assessment using Definity
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: December 29, 2011)
32
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE December 2015
Actual Primary Completion Date December 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Men and women with stage I primary untreated hypertension (BP between 140-159/90-99 mmHg)
  • Age 18-65

Exclusion Criteria:

  • Congestive heart failure
  • Coronary artery disease
  • Left ventricular hypertrophy by echocardiography or ECG
  • History of stroke
  • Average blood pressure >159/99 mmHg
  • Bradycardia with a resting heart rate <55 bpm
  • Chronic kidney disease with a serum creatinine > 1.4 mg/dL
  • Asthma or chronic obstructive pulmonary disease
  • Women who are pregnant or planning to become pregnant
  • Hypersensitivity to beta blockers, hydrochlorothiazide, or Definity
  • Any history of substance abuse (other than tobacco)
  • Concomitant drug treatment which raises endogenous nitric oxide levels, including nitrates or phosphodiesterase V inhibitors (Viagra, Levitra)
  • History of symptomatic bradycardia or heart block
  • Patients with Right-to-left, bidirectional, or transient right-to-left cardiac shunts
  • Hypersensitivity to perflutren, blood, blood products or albumin.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
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 NCT01501929
Other Study ID Numbers  ICMJE Bystolic MD52
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Wanpen Vongpatanasin, 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 May 2018

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