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

• 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: University of Florida
• Collaborator: Forest Laboratories
• Information provided by (Responsible Party): University of Florida

Tracking Information

• First Submitted Date: July 2, 2010
• First Posted Date: July 5, 2010
• Results First Submitted Date: January 25, 2016
• Results First Posted Date: March 24, 2016
• Last Update Posted Date: March 24, 2016
• Study Start Date: July 2010
• Actual Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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 ]

Current Secondary Outcome Measures (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 (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: Nebivolol Effect on Nitric Oxide Levels, Blood Pressure, and Renal Function in Kidney Transplant Patients
• Official Title: 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: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hypertension

Intervention

• 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

• 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 *

• Schmidt RJ, Yokota S, Tracy TS, Sorkin MI, Baylis C. Nitric oxide production is low in end-stage renal disease patients on peritoneal dialysis. Am J Physiol. 1999 May;276(5):F794-7. doi: 10.1152/ajprenal.1999.276.5.F794.
• Uzun H, Konukoglu D, Besler M, Erdenen F, Sezgin C, Muderrisoglu C. The effects of renal replacement therapy on plasma, asymmetric dimethylarginine, nitric oxide and C-reactive protein levels. Clin Invest Med. 2008;31(1):E1-7.
• Passauer J, Büssemaker E, Lassig G, Gross P. Kidney transplantation improves endothelium-dependent vasodilation in patients with endstage renal disease. Transplantation. 2003 Jun 15;75(11):1907-10.
• Zhang W, Zhou C, Xie J, Chen B, Chang L. Serum asymmetric dimethylarginine and endothelial function after renal transplantation. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2009 Apr;34(4):289-94.
• Schwenger V, Zeier M, Ritz E. Hypertension after renal transplantation. Ann Transplant. 2001;6(4):25-30. Review.
• Opelz G, Wujciak T, Ritz E. Association of chronic kidney graft failure with recipient blood pressure. Collaborative Transplant Study. Kidney Int. 1998 Jan;53(1):217-22.
• Curtis JJ, Luke RG, Jones P, Diethelm AG. Hypertension in cyclosporine-treated renal transplant recipients is sodium dependent. Am J Med. 1988 Aug;85(2):134-8.
• Koomans HA, Ligtenberg G. Mechanisms and consequences of arterial hypertension after renal transplantation. Transplantation. 2001 Sep 27;72(6 Suppl):S9-12. Review.
• Ojo AO. Cardiovascular complications after renal transplantation and their prevention. Transplantation. 2006 Sep 15;82(5):603-11. Review.
• Cheng JW. Nebivolol: a third-generation beta-blocker for hypertension. Clin Ther. 2009 Mar;31(3):447-62. doi: 10.1016/j.clinthera.2009.03.007. Review.
• Ignarro LJ. Experimental evidences of nitric oxide-dependent vasodilatory activity of nebivolol, a third-generation beta-blocker. Blood Press Suppl. 2004 Oct;1:2-16. Review.
• Kamp O, Sieswerda GT, Visser CA. Comparison of effects on systolic and diastolic left ventricular function of nebivolol versus atenolol in patients with uncomplicated essential hypertension. Am J Cardiol. 2003 Aug 1;92(3):344-8.
• Brehm BR, Wolf SC, Bertsch D, Klaussner M, Wesselborg S, Schüler S, Schulze-Osthoff K. Effects of nebivolol on proliferation and apoptosis of human coronary artery smooth muscle and endothelial cells. Cardiovasc Res. 2001 Feb 1;49(2):430-9.
• Gandhi C, Zalawadia R, Balaraman R. Nebivolol reduces experimentally induced warm renal ischemia reperfusion injury in rats. Ren Fail. 2008;30(9):921-30. doi: 10.1080/08860220802353900.
• Georgescu A, Pluteanu F, Flonta ML, Badila E, Dorobantu M, Popov D. The cellular mechanisms involved in the vasodilator effect of nebivolol on the renal artery. Eur J Pharmacol. 2005 Jan 31;508(1-3):159-66. Epub 2005 Jan 7.
• Kakoki M, Hirata Y, Hayakawa H, Nishimatsu H, Suzuki Y, Nagata D, Suzuki E, Kikuchi K, Nagano T, Omata M. Effects of vasodilatory beta-adrenoceptor antagonists on endothelium-derived nitric oxide release in rat kidney. Hypertension. 1999 Jan;33(1 Pt 2):467-71.
• Pires MJ, Rodríguez-Peña AB, Arévalo M, Cenador B, Evangelista S, Esteller A, Sánchez-Rodríguez A, Colaço A, López-Novoa JM. Long-term nebivolol administration reduces renal fibrosis and prevents endothelial dysfunction in rats with hypertension induced by renal mass reduction. J Hypertens. 2007 Dec;25(12):2486-96.
• Meier-Kriesche HU, Schold JD, Kaplan B. Long-term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant. 2004 Aug;4(8):1289-95.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 23, 2016): 32
• Original Estimated Enrollment (submitted: July 2, 2010): 50
• Actual Study Completion Date: July 2014
• Actual Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01157234
• Other Study ID Numbers: BYS-MD-42
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: University of Florida
• Study Sponsor: University of Florida
• Collaborators: Forest Laboratories

Investigators

• Principal Investigator: Alfonso Santos, MD; University of Florida

• PRS Account: University of Florida
• Verification Date: February 2016