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

This study has been completed.
Sponsor:
Collaborator:
Forest Laboratories
Information provided by (Responsible Party):
University of Florida
ClinicalTrials.gov Identifier:
NCT01157234
First received: July 2, 2010
Last updated: February 23, 2016
Last verified: February 2016
  Purpose

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.

Condition Intervention Phase
Hypertension
Drug: Nebivolol
Drug: Metoprolol
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Nebivolol Effect on Nitric Oxide Levels, Blood Pressure, and Renal Function in Kidney Transplant Patients

Resource links provided by NLM:


Further study details as provided by University of Florida:

Primary Outcome Measures:
  • Plasma Nitric Oxide Level Change From Baseline to Month 12 Between the Groups. [ Time Frame: Change in Baseline, Month-12 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Estimated Glomerular Filtration Rate (ml/Minute) Change From Baseline to Month-12 Between the Groups [ Time Frame: Change in Baseline, Month-12 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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


Other Outcome Measures:
  • Plasma Nitric Oxide Level (Nmol/L) at Month-12 Between the Groups. [ Time Frame: 12 Months ] [ Designated as safety issue: No ]

Enrollment: 32
Study Start Date: July 2010
Study Completion Date: July 2014
Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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
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.
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  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: NCT01157234

Locations
United States, Florida
University of Florida
Gainesville, Florida, United States, 32610
Sponsors and Collaborators
University of Florida
Forest Laboratories
Investigators
Principal Investigator: Alfonso Santos, MD University of Florida
  More Information

Publications:

Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT01157234     History of Changes
Other Study ID Numbers: BYS-MD-42 
Study First Received: July 2, 2010
Results First Received: January 25, 2016
Last Updated: February 23, 2016
Health Authority: United States: Institutional Review Board

Keywords provided by University of Florida:
Hypertension
Kidney transplantation
Renal function
Nitric Oxide
Nebivolol

Additional relevant MeSH terms:
Hypertension
Vascular Diseases
Cardiovascular Diseases
Nitric Oxide
Metoprolol
Nebivolol
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Endothelium-Dependent Relaxing Factors
Vasodilator Agents
Gasotransmitters
Protective Agents
Anti-Arrhythmia Agents
Antihypertensive Agents
Sympatholytics
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Adrenergic beta-1 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists

ClinicalTrials.gov processed this record on July 25, 2016