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

• Sponsor: University of Florida (Other)
• Overall Status: Completed
• CT.gov ID: NCT01157234
• Collaborator: Forest Laboratories (Industry)
• Enrollment: 32
• Location: 1
• Arms: 2
• Duration (Months): 48
• Patients Per Site Per Month: 0.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hypertension	Drug: Nebivolol; Drug: Metoprolol	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Nebivolol Effect on Nitric Oxide Levels, Blood Pressure, and Renal Function in Kidney Transplant Patients
• Study Start Date: Jul 1, 2010
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: Jul 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
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 Names: 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 Names: Lopressor

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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

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

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

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

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

6. Plasma Asymmetric Dimethylarginine (ADMA) Change From Baseline to Month 12 Between the Groups [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.

7. Plasma Arginine (ARG) Level Change From Baseline to Month-12 Between Groups [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

Other Outcome Measures

1. Plasma Nitric Oxide Level (Nmol/L) at Month-12 Between the Groups. [12 Months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Koomans HA, Ligtenberg G. Mechanisms and consequences of arterial hypertension after renal transplantation. Transplantation. 2001 Sep 27;72(6 Suppl):S9-12. Review.
• 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.
• Ojo AO. Cardiovascular complications after renal transplantation and their prevention. Transplantation. 2006 Sep 15;82(5):603-11. 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.
• 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.
• 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.
• 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.
• Schwenger V, Zeier M, Ritz E. Hypertension after renal transplantation. Ann Transplant. 2001;6(4):25-30. Review.
• 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.
• 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.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT01157234
• Other Study ID Numbers: BYS-MD-42
• First Posted: Jul 5, 2010
• Last Update Posted: Mar 24, 2016
• Last Verified: Feb 1, 2016

• Keywords provided by University of Florida: Hypertension; Kidney transplantation; Renal function; Nitric Oxide; Nebivolol
• Additional relevant MeSH terms: Hypertension; Metoprolol; Nebivolol

Study Results

Participant Flow

Recruitment Details	The trial was conducted at the University of Florida and Shands Renal Transplant Clinic. The first patient was randomized on July 8, 2010 and the follow up of the last patient ended on July 21, 2014.
Pre-assignment Detail	32 participants were screened, 2 failed screening and 30 met the eligibility criteria and randomized to either the arm with nebivolol or the arm with metoprolol.

Arm/Group Title	Nebivolol	Metoprolol
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	15	15
COMPLETED	14	15
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Nebivolol	Metoprolol	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	15	15	30
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53 (15.9)	46.4 (13.8)	49.7 (14.8)
Sex: Female, Male (Count of Participants)
Female	5 33.3%	4 26.7%	9 30%
Male	10 66.7%	11 73.3%	21 70%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	8 53.3%	5 33.3%	13 43.3%
White	7 46.7%	10 66.7%	17 56.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	15 100%	15 100%	30 100%
Plasma Nitric Oxide (nmol/l) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [nmol/l]	52.93 (21.09)	48.23 (15.37)	50.53 (17.99)
Estimated Glomerular Filtration Rate (milliliter/minute) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milliliter/minute]	53.13 (14.15)	54.47 (14.65)	53.80 (13.67)
Systolic Blood Pressure (millimeter, mercury) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [millimeter, mercury]	132.93 (15.79)	131.33 (18.14)	132.13 (16.73)
Diastolic Blood Pressure (millimeter, mercury) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [millimeter, mercury]	84.07 (8.59)	86.33 (8.62)	85.20 (8.53)
Mean Arterial Blood Pressure (millimeter, mercury) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [millimeter, mercury]	100.20 (8.06)	101.47 (10.76)	100.83 (9.36)
Number of Antihypertensive Drug Classes Being Used (Antihypertensive Drug Classes) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Antihypertensive Drug Classes]	2.00 (0.84)	1.80 (0.68)	1.90 (0.89)

Outcome Measures

1. Primary Outcome

Title	Plasma Nitric Oxide Level Change From Baseline to Month 12 Between the Groups.
Description	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.
Time Frame	Change in Baseline, Month-12

Outcome Measure Data

Analysis Population Description

Full analysis set included all participants who signed informed consent and received at least one dose of study drug.

Arm/Group Title	Nebivolol	Metoprolol
Arm/Group Description	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.	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.
Measure Participants	15	15
Least Squares Mean (Standard Error) [percent change]	11.47 (9.20)	-17.27 (9.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	28.73
	Confidence Interval	(2-Sided) 95.00%; 1.93 to 55.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Estimated Glomerular Filtration Rate (ml/Minute) Change From Baseline to Month-12 Between the Groups
Description	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.
Time Frame	Change in Baseline, Month-12

Outcome Measure Data

Analysis Population Description

Full analysis set included all participants who signed inform consent and received at least one dose of study drug.

Arm/Group Title	Nebivolol	Metoprolol
Arm/Group Description	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.	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.
Measure Participants	15	15
Least Squares Mean (Standard Error) [percent change]	2.16 (7.16)	10.43 (7.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	8.27
	Confidence Interval	(2-Sided) 95%; -12.58 to 29.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Systolic Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 of Treatment Between the Groups
Description	Absolute change in Systolic Blood Pressure (SBP), (millimeter, Mercury)=Month-12 sitting trough SBP level minus baseline sitting trough SBP level
Time Frame	Change in Baseline, Month-12

Outcome Measure Data

Analysis Population Description

Full analysis set included all participants who signed inform consent and received at least one dose of study drug.

Arm/Group Title	Nebivolol	Metoprolol
Arm/Group Description	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.	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.
Measure Participants	15	15
Least Squares Mean (Standard Error) [millimeter, Mercury]	-2.65 (2.73)	-3.88 (2.73)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	1.23
	Confidence Interval	(2-Sided) 95%; -6.74 to 9.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.87
	Estimation Comments

4. Secondary Outcome

Title	Diastolic Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 Between the Groups
Description	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).
Time Frame	Change in Baseline, Month-12

Outcome Measure Data

Analysis Population Description

Full analysis set included all participants who signed inform consent and received at least one dose of study drug.

Arm/Group Title	Nebivolol	Metoprolol
Arm/Group Description	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.	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.
Measure Participants	15	15
Least Squares Mean (Standard Error) [millimeter, mercury]	-0.66 (1.91)	-2.35 (1.91)

5. Secondary Outcome

Title	Mean Arterial Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 Between the Groups
Description	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
Time Frame	Change in Baseline, Month-12

Outcome Measure Data

Analysis Population Description

Full analysis set included all participants who signed inform consent and received at least one dose of study drug.

Arm/Group Title	Nebivolol	Metoprolol
Arm/Group Description	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.	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.
Measure Participants	15	15
Least Squares Mean (Standard Error) [millimeter, Mercury]	-1.07 (2.11)	-3.19 (2.11)

6. Secondary Outcome

Title	Number of Antihypertensive Drug Classes Change From Baseline to Month-12 Between the Groups.
Description	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.
Time Frame	Change in Baseline, Month-12

Outcome Measure Data

Analysis Population Description

Percent change

Arm/Group Title	Nebivolol	Metoprolol
Arm/Group Description	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.	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.
Measure Participants	15	15
Least Squares Mean (Standard Error) [percent change]	-8.14 (11.58)	8.70 (11.58)

7. Other Pre-specified Outcome

Title	Plasma Nitric Oxide Level (Nmol/L) at Month-12 Between the Groups.
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

Full analysis set included all participants who signed inform consent and received at least one dose of study drug

Arm/Group Title	Nebivolol	Metoprolol
Arm/Group Description	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.	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.
Measure Participants	15	15
Least Squares Mean (Standard Error) [nmol/L]	50.07 (3.93)	38.13 (3.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	11.94
	Confidence Interval	(2-Sided) 95.00%; 0.48 to 23.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Post-Hoc Outcome

Title	Percent Change in Plasma Nitric Oxide Level From Baseline to Month-12 of Treatment With Nebivolol in Transplant Recipients <50 Years Old Compared With Metoprolol in Transplant Recipients >/= 50 Years Old.
Time Frame	Baseline and Month-12

Outcome Measure Data

Analysis Population Description

Nebivolol and metoprolol groups were subdivided into <50 years old and >50 years old subgroups and differences between subgroups were analyzed.

Arm/Group Title	Nebivolol <50 Year Old	Metoprolol >/= 50 Year Old
Arm/Group Description	Hypertensive kidney transplant recipients less than 50 years of age treated with 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	Hypertensive kidney transplant recipients age 50 years or higher treated with Metoprolol 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
Measure Participants	6	7
Least Squares Mean (Standard Error) [percent change]	51.55 (14.55)	-17.99 (13.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	69.54
	Confidence Interval	(2-Sided) 99.7%; 12.71 to 126.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 19.83
	Estimation Comments

9. Post-Hoc Outcome

Title	Percent Change in Plasma Nitric Oxide Level From Baseline to Month-12 of Treatment With Nebivolol in Transplant Recipients < 50 Years Old Compared With Metoprolol in Transplant Recipients < 50 Years Old
Time Frame	Change in Baseline, Month-12

Outcome Measure Data

Analysis Population Description

Nebivolol and metoprolol groups were subdivided into <50 years old and >50 years old subgroups and differences between subgroups were analyzed.

Arm/Group Title	Nebivolol < 50 Years Old	Metoprolol <50 Years Old
Arm/Group Description	Hypertensive kidney transplant recipients less than 50 years of age treated with 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.	Hypertensive kidney transplant recipients less than 50 years of age treated with 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.
Measure Participants	6	8
Least Squares Mean (Standard Error) [percent change]	51.55 (14.55)	-16.64 (12.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	68.19
	Confidence Interval	(2-Sided) 99.17%; 13.02 to 123.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 19.24
	Estimation Comments

10. Post-Hoc Outcome

Title	Percent Change in Plasma Nitric Oxide Level From Baseline to Month-twelve of Treatment With Nebivolol in Transplant Recipients >/= 50 Years Old Compared With Nebivolol in Transplant Recipients < 50 Years Old.
Time Frame	Change in Baseline, Month-12

Outcome Measure Data

Analysis Population Description

Nebivolol and metoprolol groups were subdivided into <50 years old and >50 years old subgroups and differences between subgroups were analyzed.

Arm/Group Title	Nebivolol >/=50 Years Old	Metoprolol <50 Years Old
Arm/Group Description	Hypertensive kidney transplant recipients age 50 years or higher treated with 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.	Hypertensive kidney transplant recipients age less than 50 years treated with 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.
Measure Participants	9	8
Least Squares Mean (Standard Error) [percent change]	-15.25 (11.88)	-16.64 (12.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	1.39
	Confidence Interval	(2-Sided) 99.17%; -48.25 to 51.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.32
	Estimation Comments

11. Post-Hoc Outcome

Title	Percent Change in Plasma Nitric Oxide Level From Baseline to Month-12 of Treatment With Nebivolol in Transplant Recipients >/= 50 Years Old Compared With Metoprolol in Transplant Recipients Age >/= 50 Years Old.
Time Frame	Change in Baseline, Month-12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nebivolol >/=50 Years Old	Metoprolol >/=50 Years Old
Arm/Group Description	Hypertensive kidney transplant recipients age 50 years or higher treated with 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.	Hypertensive kidney transplant recipients age 50 years or higher treated with 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.
Measure Participants	9	7
Least Squares Mean (Standard Error) [percent change]	-15.25 (11.88)	-17.99 (13.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	2.74
	Confidence Interval	(2-Sided) 99.17%; -48.74 to 54.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.96
	Estimation Comments

12. Secondary Outcome

Title	Plasma Asymmetric Dimethylarginine (ADMA) Change From Baseline to Month 12 Between the Groups
Description	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.
Time Frame	Baseline, Month-12

Outcome Measure Data

Analysis Population Description

Technical limitations constrained measurements of Asymmetric Dimethylarginine (ADMA), resulting in no analysis for this outcome.

Arm/Group Title	Nebivolol	Metoprolol
Arm/Group Description	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.	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.
Measure Participants	0	0

13. Secondary Outcome

Title	Plasma Arginine (ARG) Level Change From Baseline to Month-12 Between Groups
Description	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
Time Frame	Baseline, Month-12

Outcome Measure Data

Analysis Population Description

Technical limitations constrained measurements of plasma Arginine, resulting in no analysis for this outcome.

Arm/Group Title	Nebivolol	Metoprolol
Arm/Group Description	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.	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.
Measure Participants	0	0

Adverse Events

Time Frame	4 years
Arm/Group Title	Nebivolol		Metoprolol
Arm/Group Description	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. Nebivolol: Nebivolol 5 mg once daily, titrated to a maximum total daily dose of 40 mg to achieve a blood pressure of < 140/ 90.		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. Metoprolol: Metoprolol 25 mg twice daily, titrated to a maximum total daily dose of 400 mg to achieve a blood pressure < 140/90.
All Cause Mortality
	Nebivolol		Metoprolol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Nebivolol		Metoprolol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/15 (26.7%)		5/15 (33.3%)
Gastrointestinal disorders
Vomiting	0/15 (0%)		1/15 (6.7%)
Infections and infestations
Urinary Tract Infection	1/15 (6.7%)		0/15 (0%)
Cytomegalovirus Infection	0/15 (0%)		1/15 (6.7%)
Injury, poisoning and procedural complications
Abdominal Hematoma	1/15 (6.7%)		0/15 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate Cancer	0/15 (0%)		1/15 (6.7%)
Renal and urinary disorders
Renal Insufficiency	2/15 (13.3%)		1/15 (6.7%)
Surgical and medical procedures
Herniorraphy	0/15 (0%)		1/15 (6.7%)
Other (Not Including Serious) Adverse Events
	Nebivolol		Metoprolol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/15 (60%)		13/15 (86.7%)
Blood and lymphatic system disorders
leukopenia	0/15 (0%)		1/15 (6.7%)
Ear and labyrinth disorders
Earache	1/15 (6.7%)		0/15 (0%)
Endocrine disorders
hyperglycemia	2/15 (13.3%)		3/15 (20%)
Eye disorders
Eye Irritation	1/15 (6.7%)		0/15 (0%)
Gastrointestinal disorders
Abdominal Pain	1/15 (6.7%)		1/15 (6.7%)
Constipation	1/15 (6.7%)		0/15 (0%)
Diarrhea	4/15 (26.7%)		2/15 (13.3%)
Dyspepsia	0/15 (0%)		1/15 (6.7%)
Nausea	2/15 (13.3%)		1/15 (6.7%)
Vomiting	2/15 (13.3%)		0/15 (0%)
General disorders
Chest Pain	1/15 (6.7%)		1/15 (6.7%)
Edema	1/15 (6.7%)		1/15 (6.7%)
Fatigue	1/15 (6.7%)		0/15 (0%)
Influenza-like Illness	1/15 (6.7%)		0/15 (0%)
Infections and infestations
Cytomegalovirus Infection	1/15 (6.7%)		0/15 (0%)
Urinary Tract Infection	2/15 (13.3%)		3/15 (20%)
Musculoskeletal and connective tissue disorders
Arm Pain	1/15 (6.7%)		0/15 (0%)
Low Back Pain	1/15 (6.7%)		0/15 (0%)
Nervous system disorders
Dizziness	0/15 (0%)		1/15 (6.7%)
Headache	2/15 (13.3%)		2/15 (13.3%)
Psychiatric disorders
Anxiety	0/15 (0%)		1/15 (6.7%)
Reproductive system and breast disorders
Hydrocele	0/15 (0%)		1/15 (6.7%)
Respiratory, thoracic and mediastinal disorders
Cough	4/15 (26.7%)		2/15 (13.3%)
Dyspnea	1/15 (6.7%)		0/15 (0%)
Nasal Congestion	3/15 (20%)		3/15 (20%)
Oropharyngeal Pain	0/15 (0%)		1/15 (6.7%)

Limitations/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.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.