Hypertension
Conditions
Keywords
Hypertension, Kidney transplantation, Renal function, Nitric Oxide, Nebivolol
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.
Interventions
DRUGNebivolol
Nebivolol 5 mg once daily, titrated to a maximum total daily dose of 40 mg to achieve a blood pressure of \< 140/ 90.
DRUGMetoprolol
Metoprolol 25 mg twice daily, titrated to a maximum total daily dose of 400 mg to achieve a blood pressure \< 140/90.
Sponsors
Forest Laboratories
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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). |
| 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. |
| 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. |
| 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 |
| 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 |
Other
| Measure | Time frame |
|---|---|
| Plasma Nitric Oxide Level (Nmol/L) at Month-12 Between the Groups. | 12 Months |
Countries
United States
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 15 |
| 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. | 15 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Nebivolol | Metoprolol | Total |
|---|---|---|---|
| Age, Continuous | 53 years STANDARD_DEVIATION 15.9 | 46.4 years STANDARD_DEVIATION 13.8 | 49.7 years STANDARD_DEVIATION 14.8 |
| Diastolic Blood Pressure | 84.07 millimeter, mercury STANDARD_DEVIATION 8.59 | 86.33 millimeter, mercury STANDARD_DEVIATION 8.62 | 85.20 millimeter, mercury STANDARD_DEVIATION 8.53 |
| Estimated Glomerular Filtration Rate | 53.13 milliliter/minute STANDARD_DEVIATION 14.15 | 54.47 milliliter/minute STANDARD_DEVIATION 14.65 | 53.80 milliliter/minute STANDARD_DEVIATION 13.67 |
| Mean Arterial Blood Pressure | 100.20 millimeter, mercury STANDARD_DEVIATION 8.06 | 101.47 millimeter, mercury STANDARD_DEVIATION 10.76 | 100.83 millimeter, mercury STANDARD_DEVIATION 9.36 |
| Number of Antihypertensive Drug Classes Being Used | 2.00 Antihypertensive Drug Classes STANDARD_DEVIATION 0.84 | 1.80 Antihypertensive Drug Classes STANDARD_DEVIATION 0.68 | 1.90 Antihypertensive Drug Classes STANDARD_DEVIATION 0.89 |
| Plasma Nitric Oxide | 52.93 nmol/l STANDARD_DEVIATION 21.09 | 48.23 nmol/l STANDARD_DEVIATION 15.37 | 50.53 nmol/l STANDARD_DEVIATION 17.99 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 5 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 10 Participants | 17 Participants |
| Region of Enrollment United States | 15 participants | 15 participants | 30 participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Male | 10 Participants | 11 Participants | 21 Participants |
| Systolic Blood Pressure | 132.93 millimeter, mercury STANDARD_DEVIATION 15.79 | 131.33 millimeter, mercury STANDARD_DEVIATION 18.14 | 132.13 millimeter, mercury STANDARD_DEVIATION 16.73 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 15 | 13 / 15 |
| serious Total, serious adverse events | 4 / 15 | 5 / 15 |
Outcome results
Primary
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.
Time frame: Change in Baseline, Month-12
Population: Full analysis set included all participants who signed informed consent and received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Plasma Nitric Oxide Level Change From Baseline to Month 12 Between the Groups. | 11.47 percent change | Standard Error 9.2 |
| Metoprolol | Plasma Nitric Oxide Level Change From Baseline to Month 12 Between the Groups. | -17.27 percent change | Standard Error 9.2 |
95% CI: [1.93, 55.53]
Secondary
Diastolic Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 Between the Groups
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
Population: Full analysis set included all participants who signed inform consent and received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Diastolic Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 Between the Groups | -0.66 millimeter, mercury | Standard Error 1.91 |
| Metoprolol | Diastolic Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 Between the Groups | -2.35 millimeter, mercury | Standard Error 1.91 |
Secondary
Estimated Glomerular Filtration Rate (ml/Minute) Change From Baseline to Month-12 Between the Groups
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
Population: Full analysis set included all participants who signed inform consent and received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Estimated Glomerular Filtration Rate (ml/Minute) Change From Baseline to Month-12 Between the Groups | 2.16 percent change | Standard Error 7.16 |
| Metoprolol | Estimated Glomerular Filtration Rate (ml/Minute) Change From Baseline to Month-12 Between the Groups | 10.43 percent change | Standard Error 7.16 |
95% CI: [-12.58, 29.12]
Secondary
Mean Arterial Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 Between the Groups
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
Population: Full analysis set included all participants who signed inform consent and received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Mean Arterial Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 Between the Groups | -1.07 millimeter, Mercury | Standard Error 2.11 |
| Metoprolol | Mean Arterial Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 Between the Groups | -3.19 millimeter, Mercury | Standard Error 2.11 |
Secondary
Number of Antihypertensive Drug Classes Change From Baseline to Month-12 Between the Groups.
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
Population: Percent change
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Number of Antihypertensive Drug Classes Change From Baseline to Month-12 Between the Groups. | -8.14 percent change | Standard Error 11.58 |
| Metoprolol | Number of Antihypertensive Drug Classes Change From Baseline to Month-12 Between the Groups. | 8.70 percent change | Standard Error 11.58 |
Secondary
Plasma Arginine (ARG) Level Change From Baseline to Month-12 Between Groups
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
Population: Technical limitations constrained measurements of plasma Arginine, resulting in no analysis for this outcome.
Secondary
Plasma Asymmetric Dimethylarginine (ADMA) Change From Baseline to Month 12 Between the Groups
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
Population: Technical limitations constrained measurements of Asymmetric Dimethylarginine (ADMA), resulting in no analysis for this outcome.
Secondary
Systolic Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 of Treatment Between the Groups
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
Population: Full analysis set included all participants who signed inform consent and received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Systolic Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 of Treatment Between the Groups | -2.65 millimeter, Mercury | Standard Error 2.73 |
| Metoprolol | Systolic Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 of Treatment Between the Groups | -3.88 millimeter, Mercury | Standard Error 2.73 |
95% CI: [-6.74, 9.2]
Post Hoc
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
Population: Nebivolol and metoprolol groups were subdivided into \<50 years old and \>50 years old subgroups and differences between subgroups were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | 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 | 51.55 percent change | Standard Error 14.55 |
| Metoprolol | 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 | -16.64 percent change | Standard Error 12.6 |
99.17% CI: [13.02, 123.36]
Post Hoc
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
Population: Nebivolol and metoprolol groups were subdivided into \<50 years old and \>50 years old subgroups and differences between subgroups were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | 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. | 51.55 percent change | Standard Error 14.55 |
| Metoprolol | 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. | -17.99 percent change | Standard Error 13.47 |
99.7% CI: [12.71, 126.37]
Post Hoc
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
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | 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. | -15.25 percent change | Standard Error 11.88 |
| Metoprolol | 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. | -17.99 percent change | Standard Error 13.47 |
99.17% CI: [-48.74, 54.22]
Post Hoc
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
Population: Nebivolol and metoprolol groups were subdivided into \<50 years old and \>50 years old subgroups and differences between subgroups were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | 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. | -15.25 percent change | Standard Error 11.88 |
| Metoprolol | 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. | -16.64 percent change | Standard Error 12.6 |
99.17% CI: [-48.25, 51.03]
Other Pre-specified
Plasma Nitric Oxide Level (Nmol/L) at Month-12 Between the Groups.
Time frame: 12 Months
Population: Full analysis set included all participants who signed inform consent and received at least one dose of study drug
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Plasma Nitric Oxide Level (Nmol/L) at Month-12 Between the Groups. | 50.07 nmol/L | Standard Error 3.93 |
| Metoprolol | Plasma Nitric Oxide Level (Nmol/L) at Month-12 Between the Groups. | 38.13 nmol/L | Standard Error 3.93 |
95% CI: [0.48, 23.4]