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

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hypertension
• Interventions: Drug: Nebivolol; Drug: Metoprolol
• Enrollment: 32

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 Details	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
Reason Not Completed
Withdrawal by Subject	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 Number of Baseline Participants		15	15	30
Baseline Analysis Population Description		Full analysis set included all participants who signed informed consent and received at least one dose of study drug
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	15 participants	15 participants	30 participants
		53 (15.9)	46.4 (13.8)	49.7 (14.8)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	15 participants	15 participants	30 participants
	Female	5 33.3%	4 26.7%	9 30.0%
	Male	10 66.7%	11 73.3%	21 70.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	15 participants	15 participants	30 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	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%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	15 participants	15 participants	30 participants
		15	15	30
Plasma Nitric Oxide [1]; Mean (Standard Deviation); Unit of measure: Nmol/l
	Number Analyzed	15 participants	15 participants	30 participants
		52.93 (21.09)	48.23 (15.37)	50.53 (17.99)
		[1] Measure Description: Full analysis included all participants who signed informed consent and received at least one dose of study drug.
Estimated Glomerular Filtration Rate [1]; Mean (Standard Deviation); Unit of measure: Milliliter/minute
	Number Analyzed	15 participants	15 participants	30 participants
		53.13 (14.15)	54.47 (14.65)	53.80 (13.67)
		[1] Measure Description: Estimated glomerular filtration rate is calculated according to the modification of diet in renal disease equation using age, gender and race in calculating kidney function. Full analysis included all participants who signed informed consent and received at least one dose of study drug
Systolic Blood Pressure [1]; Mean (Standard Deviation); Unit of measure: Millimeter, mercury
	Number Analyzed	15 participants	15 participants	30 participants
		132.93 (15.79)	131.33 (18.14)	132.13 (16.73)
		[1] Measure Description: Full analysis included all participants who signed informed consent and received at least one dose of study drug.
Diastolic Blood Pressure [1]; Mean (Standard Deviation); Unit of measure: Millimeter, mercury
	Number Analyzed	15 participants	15 participants	30 participants
		84.07 (8.59)	86.33 (8.62)	85.20 (8.53)
		[1] Measure Description: Full analysis included all participants who signed informed consent and received at least one dose of study drug
Mean Arterial Blood Pressure [1]; Mean (Standard Deviation); Unit of measure: Millimeter, mercury
	Number Analyzed	15 participants	15 participants	30 participants
		100.20 (8.06)	101.47 (10.76)	100.83 (9.36)
		[1] Measure Description: Full analysis included all participants who signed informed consent and received at least one dose of study drug
Number of Antihypertensive Drug Classes Being Used [1]; Mean (Standard Deviation); Unit of measure: Antihypertensive Drug Classes
	Number Analyzed	15 participants	15 participants	30 participants
		2.00 (0.84)	1.80 (0.68)	1.90 (0.89)
		[1] Measure Description: Full analysis included all participants who signed informed consent and received at least one dose of study drug

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.
Overall Number of Participants Analyzed	15	15
Least Squares Mean (Standard Error); Unit of Measure: percent change
	11.47 (9.20)	-17.27 (9.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	28.73
	Confidence Interval	(2-Sided) 95.00%; 1.93 to 55.53
	Estimation Comments	[Not Specified]

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.
Overall Number of Participants Analyzed	15	15
Least Squares Mean (Standard Error); Unit of Measure: percent change
	2.16 (7.16)	10.43 (7.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	8.27
	Confidence Interval	(2-Sided) 95%; -12.58 to 29.12
	Estimation Comments	[Not Specified]

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.
Overall Number of Participants Analyzed	15	15
Least Squares Mean (Standard Error); Unit of Measure: millimeter, Mercury
	-2.65 (2.73)	-3.88 (2.73)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
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	[Not Specified]

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.
Overall Number of Participants Analyzed	15	15
Least Squares Mean (Standard Error); Unit of Measure: 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.
Overall Number of Participants Analyzed	15	15
Least Squares Mean (Standard Error); Unit of Measure: 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.
Overall Number of Participants Analyzed	15	15
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-8.14 (11.58)	8.70 (11.58)

7. 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.
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

8. 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.
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

9. Other Pre-specified Outcome

Title	Plasma Nitric Oxide Level (Nmol/L) at Month-12 Between the Groups.
Description	[Not Specified]
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.
Overall Number of Participants Analyzed	15	15
Least Squares Mean (Standard Error); Unit of Measure: nmol/L
	50.07 (3.93)	38.13 (3.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	11.94
	Confidence Interval	(2-Sided) 95.00%; 0.48 to 23.40
	Estimation Comments	[Not Specified]

10. 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.
Description	[Not Specified]
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
Overall Number of Participants Analyzed	6	7
Least Squares Mean (Standard Error); Unit of Measure: percent change
	51.55 (14.55)	-17.99 (13.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol <50 Year Old, Metoprolol >/= 50 Year Old
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
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	[Not Specified]

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 < 50 Years Old
Description	[Not Specified]
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.
Overall Number of Participants Analyzed	6	8
Least Squares Mean (Standard Error); Unit of Measure: percent change
	51.55 (14.55)	-16.64 (12.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol < 50 Years Old, Metoprolol <50 Years Old
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
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	[Not Specified]

12. 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.
Description	[Not Specified]
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.
Overall Number of Participants Analyzed	9	8
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-15.25 (11.88)	-16.64 (12.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol >/=50 Years Old, Metoprolol <50 Years Old
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
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	[Not Specified]

13. 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.
Description	[Not Specified]
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.
Overall Number of Participants Analyzed	9	7
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-15.25 (11.88)	-17.99 (13.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol >/=50 Years Old, Metoprolol >/=50 Years Old
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
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	[Not Specified]

Adverse Events

Time Frame	4 years
Adverse Event Reporting Description	[Not Specified]
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 (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Nebivolol	Metoprolol
	Affected / at Risk (%)	Affected / at Risk (%)
Total	4/15 (26.67%)	5/15 (33.33%)
Gastrointestinal disorders
Vomiting †	0/15 (0.00%)	1/15 (6.67%)
Infections and infestations
Urinary Tract Infection †	1/15 (6.67%)	0/15 (0.00%)
Cytomegalovirus Infection †	0/15 (0.00%)	1/15 (6.67%)
Injury, poisoning and procedural complications
Abdominal Hematoma †	1/15 (6.67%)	0/15 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate Cancer †	0/15 (0.00%)	1/15 (6.67%)
Renal and urinary disorders
Renal Insufficiency †	2/15 (13.33%)	1/15 (6.67%)
Surgical and medical procedures
Herniorraphy †	0/15 (0.00%)	1/15 (6.67%)
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Nebivolol	Metoprolol
	Affected / at Risk (%)	Affected / at Risk (%)
Total	9/15 (60.00%)	13/15 (86.67%)
Blood and lymphatic system disorders
leukopenia †	0/15 (0.00%)	1/15 (6.67%)
Ear and labyrinth disorders
Earache †	1/15 (6.67%)	0/15 (0.00%)
Endocrine disorders
hyperglycemia †	2/15 (13.33%)	3/15 (20.00%)
Eye disorders
Eye Irritation †	1/15 (6.67%)	0/15 (0.00%)
Gastrointestinal disorders
Abdominal Pain †	1/15 (6.67%)	1/15 (6.67%)
Constipation †	1/15 (6.67%)	0/15 (0.00%)
Diarrhea †	4/15 (26.67%)	2/15 (13.33%)
Dyspepsia †	0/15 (0.00%)	1/15 (6.67%)
Nausea †	2/15 (13.33%)	1/15 (6.67%)
Vomiting †	2/15 (13.33%)	0/15 (0.00%)
General disorders
Chest Pain †	1/15 (6.67%)	1/15 (6.67%)
Edema †	1/15 (6.67%)	1/15 (6.67%)
Fatigue †	1/15 (6.67%)	0/15 (0.00%)
Influenza-like Illness †	1/15 (6.67%)	0/15 (0.00%)
Infections and infestations
Cytomegalovirus Infection †	1/15 (6.67%)	0/15 (0.00%)
Urinary Tract Infection †	2/15 (13.33%)	3/15 (20.00%)
Musculoskeletal and connective tissue disorders
Arm Pain †	1/15 (6.67%)	0/15 (0.00%)
Low Back Pain †	1/15 (6.67%)	0/15 (0.00%)
Nervous system disorders
Dizziness †	0/15 (0.00%)	1/15 (6.67%)
Headache †	2/15 (13.33%)	2/15 (13.33%)
Psychiatric disorders
Anxiety †	0/15 (0.00%)	1/15 (6.67%)
Reproductive system and breast disorders
Hydrocele †	0/15 (0.00%)	1/15 (6.67%)
Respiratory, thoracic and mediastinal disorders
Cough †	4/15 (26.67%)	2/15 (13.33%)
Dyspnea †	1/15 (6.67%)	0/15 (0.00%)
Nasal Congestion †	3/15 (20.00%)	3/15 (20.00%)
Oropharyngeal Pain †	0/15 (0.00%)	1/15 (6.67%)
† Indicates events were collected by systematic assessment

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.

More Information

Certain Agreements

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

Results Point of Contact

• Name/Title: Alfonso H. Santos Jr, M,D,
• Organization: University of Florida
• Phone: 352-273-6374
• EMail: Alfonso.santos@medicine.ufl.edu

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.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT01157234
• Other Study ID Numbers: BYS-MD-42
• First Submitted: July 2, 2010
• First Posted: July 5, 2010
• Results First Submitted: January 25, 2016
• Results First Posted: March 24, 2016
• Last Update Posted: March 24, 2016