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Nebivolol Effect on Nitric Oxide Levels, Blood Pressure, and Renal Function in Kidney Transplant Patients

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ClinicalTrials.gov Identifier: NCT01157234
Recruitment Status : Completed
First Posted : July 5, 2010
Results First Posted : March 24, 2016
Last Update Posted : March 24, 2016
Sponsor:
Collaborator:
Forest Laboratories
Information provided by (Responsible Party):
University of Florida

Tracking Information
First Submitted Date  ICMJE July 2, 2010
First Posted Date  ICMJE July 5, 2010
Results First Submitted Date  ICMJE January 25, 2016
Results First Posted Date  ICMJE March 24, 2016
Last Update Posted Date March 24, 2016
Study Start Date  ICMJE July 2010
Actual Primary Completion Date July 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 23, 2016)
Plasma Nitric Oxide Level Change From Baseline to Month 12 Between the Groups. [ Time Frame: Change in Baseline, Month-12 ]
Percent change in Nitric Oxide (NO) blood level (nmol/L)=[Month-12 NO blood level minus baseline NO blood level] divided by [baseline NO blood level] multiplied by 100, where all levels are in nmol/L.
Original Primary Outcome Measures  ICMJE
 (submitted: July 2, 2010)
To determine the effect of nebivolol versus metoprolol on serum nitric oxide levels in hypertensive renal transplant patients [ Time Frame: one year ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 23, 2016)
  • Estimated Glomerular Filtration Rate (ml/Minute) Change From Baseline to Month-12 Between the Groups [ Time Frame: Change in Baseline, Month-12 ]
    The changed percentage in Estimated Glomerular Filtration Rate (eGFR), (based on the Modification of Diet in Renal Disease Equation)=[Month-12 GFR level minus baseline eGFR level] divided by [baseline eGFR level] multiplied by 100, where all levels are in ml/min.
  • Systolic Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 of Treatment Between the Groups [ Time Frame: Change in Baseline, Month-12 ]
    Absolute change in Systolic Blood Pressure (SBP), (millimeter, Mercury)=Month-12 sitting trough SBP level minus baseline sitting trough SBP level
  • Diastolic Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 Between the Groups [ Time Frame: Change in Baseline, Month-12 ]
    Absolute Change in Diastolic Blood Pressure (DBP), (millimeter, Mercury)= Month-12 sitting trough Diastolic Blood Pressure (millimeter, Mercury) level minus baseline sitting trough Diastolic Blood Pressure (millimeter, Mercury).
  • Mean Arterial Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 Between the Groups [ Time Frame: Change in Baseline, Month-12 ]
    Absolute change in Mean Arterial Blood Pressure, (MAP), (millimeter, Mercury= Month-12 sitting trough MAP minus baseline sitting trough MAP. Mean Arterial Pressure= 2/3 trough diastolic blood pressure + 1/3 trough systolic blood pressure
  • Number of Antihypertensive Drug Classes Change From Baseline to Month-12 Between the Groups. [ Time Frame: Change in Baseline, Month-12 ]
    Percent change in quantity of Anti-Hypertensive Drug Classes (AHDC)=[Month-12 absolute number of AHDC minus baseline absolute number of AHDC] divided by [baseline absolute number of AHDC] multiplied by 100.
  • Plasma Asymmetric Dimethylarginine (ADMA) Change From Baseline to Month 12 Between the Groups [ Time Frame: Baseline, Month-12 ]
    Percent change in plasma ADMA (umol/L)=[month-12 plasma ADMA level minus baseline plasma ADMA level] divided by [baseline plasma ADMA level] multiplied by 100, where all levels are in umol/L.
  • Plasma Arginine (ARG) Level Change From Baseline to Month-12 Between Groups [ Time Frame: Baseline, Month-12 ]
    Percent change in plasma Arginine (umol/L)=[month-12 plasma Arginine level minus baseline plasma Arginine level] divided by [baseline plasma Arginine level] multiplied by 100, where all levels are in umol/L
Original Secondary Outcome Measures  ICMJE
 (submitted: July 2, 2010)
  • To determine the effect of nebivolol versus metoprolol on markers for oxidative stress. [ Time Frame: One Year ]
  • To determine the effect of nebivolol versus metoprolol on renal function in hypertensive renal transplant patients. [ Time Frame: One Year ]
  • To determine the effect of nebivolol versus metoprolol on blood pressure control in hypertensive renal transplant patients. [ Time Frame: One Year ]
Current Other Pre-specified Outcome Measures
 (submitted: February 23, 2016)
Plasma Nitric Oxide Level (Nmol/L) at Month-12 Between the Groups. [ Time Frame: 12 Months ]
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Nebivolol Effect on Nitric Oxide Levels, Blood Pressure, and Renal Function in Kidney Transplant Patients
Official Title  ICMJE Nebivolol Effect on Nitric Oxide Levels, Blood Pressure, and Renal Function in Kidney Transplant Patients
Brief Summary

This study will investigate the blood pressure lowering efficacy of nebivolol among renal transplant recipients who are on calcineurin inhibitors which are believed to contribute to hypertension by sympathetic nervous system (SNS) activation and decreased prostaglandin and nitric oxide production. Hypotheses:

  1. There is a significant difference in the effect of 12 months of Nebivolol versus Metoprolol treatment on the plasma nitric oxide level of hypertensive renal transplant patients.
  2. There is a significant difference in the effect of 12 months of Nebivolol versus Metoprolol treatment on the estimated glomerular filtration rate of hypertensive renal transplant patients.
  3. There is a significant difference in the effect of 12 months of Nebivolol versus Metoprolol treatment on the systolic, diastolic and mean arterial blood pressures of hypertensive renal transplant patients.
Detailed Description

Nitric Oxide (NO) plays a plethora of functions in the kidney including vascular and hemodynamic regulation, fluid and electrolyte transport, and is an important component of pressure natriuresis and tubule-glomerular feedback.

Deficient NO levels have been associated with oxidative stress in conditions like hypertension, diabetes mellitus, and cardiovascular disease. NO deficiency has been identified in states of chronic progressive renal disease and altered NO production and/or decreased bioavailability is believed to characterize the endothelial dysfunction and resistant hypertension of renal failure.

It has been shown that kidney transplantation improves endothelium-dependent vasodilation in patients with end-stage renal disease (ESRD) and the NO activity significantly increases after transplantation. However, calcineurin inhibitor drugs used in the anti-rejection regimen can reduce endothelial NO production and aggravate hypertension through vascular and renal mechanisms. In turn, uncontrolled elevation in blood pressure has been associated with increased renal allograft failure and post-transplant mortality.

In the absence of randomized clinical trials of antihypertensive drugs and optimal blood pressure goals in kidney transplant recipients. There is no scientifically-robust consensus on the specific drugs to use among transplant patients. Nebivolol, is a third generation B1-selective B-blocker shown to have similar BP-lowering effect as other B-blockers, angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blocker (ARB) drugs, and calcium channel blockers. Nebivolol ameliorates hypertension by increasing NO release, promoting arterial and venous vasodilatation and beta-blockade. Nebivolol has beneficial effect on the kidney allograft. Studies in animal transplants have shown that nebivolol could reduce ischemia-induced reperfusion injury, alleviate renal perfusion pressure and increase NO release with associated vasodilation of the renal vasculature. These effects have not been seen with older generation B-blockers like propranolol or bisoprolol. Finally, in surgically reduced renal mass, nebivolol has been demonstrated to attenuate collagen type 1 expression with lessening of glomerular and interstitial fibrosis.

In this study, the effect of nebivolol and metoprolol on the change in NO level at baseline and at the 12th month of treatment will be compared. Similarly,the effects of the two drugs on the change in renal function, blood pressure, and blood pressure regimen from baseline to month-12 of treatment will also be compared.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hypertension
Intervention  ICMJE
  • Drug: Nebivolol
    Nebivolol 5 mg once daily, titrated to a maximum total daily dose of 40 mg to achieve a blood pressure of < 140/ 90.
    Other Name: Bystolic
  • Drug: Metoprolol
    Metoprolol 25 mg twice daily, titrated to a maximum total daily dose of 400 mg to achieve a blood pressure < 140/90.
    Other Name: Lopressor
Study Arms  ICMJE
  • Active Comparator: Nebivolol
    Nebivolol starting dose of 5 mg orally once daily, titrated to a maximum total daily dose of 40 mg daily to achieve a target blood pressure of <140/90 and continued until month-12 of the study.
    Intervention: Drug: Nebivolol
  • Active Comparator: Metoprolol
    Metoprolol starting dose of 25mg orally once twice daily, titrated to a maximum total daily dose of 400 mg to achieve a target blood pressure of <140/90 and continued until month-12 of the study.
    Intervention: Drug: Metoprolol
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: February 23, 2016)
32
Original Estimated Enrollment  ICMJE
 (submitted: July 2, 2010)
50
Actual Study Completion Date  ICMJE July 2014
Actual Primary Completion Date July 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Men or women at least 18 years of age who are recipients of - a solitary kidney or combined kidney-pancreas transplant within the last twenty four months
  • Current diagnosis of hypertension
  • Normal hepatic enzymes
  • Estimated creatinine clearance (by cockcroft-gault formula) >or= 30 ml/min

Exclusion Criteria:

  • Any contraindication to taking beta-blockers, specifically Nebivolol or Metoprolol. Conditions such as : (bradycardia heart rate (HR) <60 beats per minute , heart block > 1st degree, decompensated cardiac failure, sick sinus syndrome (unless permanent pacemaker in place), severe hepatic impairment( defined as elevation of aspartamine aminotransferase , alanine aminotransferase, or bilirubin levels to three times upper limit of normal reference range), severe peripheral arterial circulatory disorder, history of bronchospasm and /or asthma and /or regular medication with inhaled bronchodilators. or , or any medical condition that in the opinion of the investigator may interfere with the subject's ability to successfully complete the protocol.
  • Any medical condition which, in the opinion of the Principal Investigator, might compromise the safety of the subject in participating in the protocol such as hypotension or not requiring antihypertensive medications.
  • Any serious systemic disease that might complicate management and reduce life expectancy.
  • Uncontrolled hypertension defined as systolic blood pressure (SBP) > 210 or diastolic blood pressure (DBP) > 120 mm Hg.
  • Symptomatic hypotension
  • Previous intolerance to beta blockers
  • Cerebrovascular accident within 3 months of randomization
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (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 NCT01157234
Other Study ID Numbers  ICMJE BYS-MD-42
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Florida
Study Sponsor  ICMJE University of Florida
Collaborators  ICMJE Forest Laboratories
Investigators  ICMJE
Principal Investigator: Alfonso Santos, MD University of Florida
PRS Account University of Florida
Verification Date February 2016

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