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

NCT01157234 | Completed Phase 4 Results

• 1 other identifier: BYS-MD-42
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

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. 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. 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. 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.

Conditions

Hypertension

Keywords

Hypertension; Kidney transplantation; Renal function; Nitric Oxide; Nebivolol

Outcome Measures

Primary Outcomes (1)

• Plasma Nitric Oxide Level Change From Baseline to Month 12 Between the Groups.

  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.

  Change in Baseline, Month-12

Secondary Outcomes (7)

• Estimated Glomerular Filtration Rate (ml/Minute) Change From Baseline to Month-12 Between the Groups

  Change in Baseline, Month-12

• Systolic Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 of Treatment Between the Groups

  Change in Baseline, Month-12

• Diastolic Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 Between the Groups

  Change in Baseline, Month-12

• Mean Arterial Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 Between the Groups

  Change in Baseline, Month-12

• Number of Antihypertensive Drug Classes Change From Baseline to Month-12 Between the Groups.

  Change in Baseline, Month-12

Other Outcomes (1)

• Plasma Nitric Oxide Level (Nmol/L) at Month-12 Between the Groups.

  12 Months

Study Arms (2)

Nebivolol

ACTIVE COMPARATOR

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

Metoprolol

ACTIVE COMPARATOR

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

Interventions

Nebivolol DRUG

Nebivolol 5 mg once daily, titrated to a maximum total daily dose of 40 mg to achieve a blood pressure of \< 140/ 90.

Also known as: Bystolic

Nebivolol

Metoprolol DRUG

Metoprolol 25 mg twice daily, titrated to a maximum total daily dose of 400 mg to achieve a blood pressure \< 140/90.

Also known as: Lopressor

Metoprolol

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Florida: lead
• Forest Laboratories: collaborator

Study Sites (1)

University of Florida

Gainesville, Florida, 32610, United States

Location

Related Publications (19)

• 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.

  PMID: 10330062 BACKGROUND

• 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. doi: 10.25011/cim.v31i1.3135.

  PMID: 18312743 BACKGROUND

• Passauer J, Bussemaker 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. doi: 10.1097/01.TP.0000065739.19681.93.

  PMID: 12811255 BACKGROUND

• 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.

  PMID: 19411743 BACKGROUND

• Schwenger V, Zeier M, Ritz E. Hypertension after renal transplantation. Ann Transplant. 2001;6(4):25-30.

  PMID: 12035455 BACKGROUND

• 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. doi: 10.1046/j.1523-1755.1998.00744.x.

  PMID: 9453022 BACKGROUND

• 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. doi: 10.1016/s0002-9343(88)80331-0.

  PMID: 3041828 BACKGROUND

• Koomans HA, Ligtenberg G. Mechanisms and consequences of arterial hypertension after renal transplantation. Transplantation. 2001 Sep 27;72(6 Suppl):S9-12. doi: 10.1097/00007890-200109271-00004.

  PMID: 11585243 BACKGROUND

• Ojo AO. Cardiovascular complications after renal transplantation and their prevention. Transplantation. 2006 Sep 15;82(5):603-11. doi: 10.1097/01.tp.0000235527.81917.fe.

  PMID: 16969281 BACKGROUND

• 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.

  PMID: 19393838 BACKGROUND

• 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.

  PMID: 15587107 BACKGROUND

• 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. doi: 10.1016/s0002-9149(03)00645-3.

  PMID: 12888152 BACKGROUND

• Brehm BR, Wolf SC, Bertsch D, Klaussner M, Wesselborg S, Schuler 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. doi: 10.1016/s0008-6363(00)00253-4.

  PMID: 11164853 BACKGROUND

• 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.

  PMID: 18925533 BACKGROUND

• 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. doi: 10.1016/j.ejphar.2004.11.043. Epub 2005 Jan 7.

  PMID: 15680267 BACKGROUND

• 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. doi: 10.1161/01.hyp.33.1.467.

  PMID: 9931149 BACKGROUND

• Pires MJ, Rodriguez-Pena AB, Arevalo M, Cenador B, Evangelista S, Esteller A, Sanchez-Rodriguez A, Colaco A, Lopez-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. doi: 10.1097/HJH.0b013e3282efeecb.

  PMID: 17984671 BACKGROUND

• 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. doi: 10.1111/j.1600-6143.2004.00515.x.

  PMID: 15268730 BACKGROUND

• Natale P, Mooi PK, Palmer SC, Cross NB, Cooper TE, Webster AC, Masson P, Craig JC, Strippoli GF. Antihypertensive treatment for kidney transplant recipients. Cochrane Database Syst Rev. 2024 Jul 31;7(7):CD003598. doi: 10.1002/14651858.CD003598.pub3.

  PMID: 39082471 DERIVED

MeSH Terms

Conditions

Hypertension

Interventions

Nebivolol; Metoprolol

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Phenoxypropanolamines; Propanolamines; Propanols

Limitations and Caveats

Small numbers of subjects analyzed in a single center limits precision and generalizability of results. Technical limitations prevented measurements of asymmetric dimethyl-arginine and arginine leading to absence of analysis for these outcomes.

Results Point of Contact

• Title: Alfonso H. Santos Jr, M,D,
• Organization: University of Florida

Alfonso.santos@medicine.ufl.edu

352-273-6374

Study Officials

• Alfonso Santos, MD

  University of Florida

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restriction Type: OTHER

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 2, 2010
• First Posted: July 5, 2010
• Study Start: July 1, 2010
• Primary Completion: July 1, 2014
• Study Completion: July 1, 2014
• Last Updated: November 6, 2024
• Results First Posted: March 24, 2016

Record last verified: 2024-11

Locations

US (1)