Clinical trial NCT00992056
Conditions: Hypertension
Sponsor: University of Miami
Start date: 2010-12-01; Completion date: 2012-05-01
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Research objectives

The objective of this randomized, placebo-controlled, 2 period crossover clinical trial is to determine the effects of nebivolol versus metoprolol on ambulatory blood pressure, the blood pressure response to dietary sodium loading, and renal handling of an acute sodium load in postmenopausal women with hypertension.

Hypothesis

Nebivolol will result in a blunted response of blood pressure to oral sodium administration and improved renal handling of an intravenous sodium load in comparison with metoprolol in hypertensive postmenopausal women.

Research plan

Study design

The study consisted of a randomized crossover trial of the effects on sodium sensitivity and renal sodium handling of nebivolol versus metoprolol. All study procedures were carried out under the direct supervision of the Principal Investigator in the outpatient and inpatient research unit of the University of Miami Division of Clinical Pharmacology.

Primary endpoint

Change in 24-hour mean systolic blood pressure determined by 24-hour ambulatory blood pressure monitor (ABPM) from the final day of low sodium to the final day of high sodium in nebivolol versus metoprolol

Detailed description:
This investigation consisted of a randomized, open-label, 2-Treatment Period (metoprolol versus nebivolol) crossover clinical trial conducted in postmenopausal women with stage 1 hypertension. Nineteen of 24 participants completed all phases of the protocol and had 4 technically adequate ABPM determinations.

Each randomized 4-week Treatment Period was with either nebivolol 5 mg daily titrated to 10 mg daily versus metoprolol 50 mg daily increased to 100 mg. Participants were randomly assigned in blocks of 2 to either arm of the crossover trial: Metoprolol/Nebivolol or Nebivolol/Metoprolol.

Participants returned at weekly (7 days ± 4 days) intervals during all outpatient study phases. On the day of a scheduled visit, participants were instructed not to take their medication at home, but to bring the medication with them to the visit. Participant visits were scheduled in the morning and all evaluations were performed at drug trough (24 ± 2 hours after the previous day's dose). Medications for that day were administered after all evaluations planned for that visit had been completed. At each visit participants were questioned directly about compliance and any missed or delayed doses. In addition pill counts were conducted at each visit.

Eleven-day Inpatient Confinement Period Both 4-week outpatient Treatment Periods were followed by an 11-day inpatient confinement period in the clinical pharmacology research unit (CPRU). During Days 1-5 participants received a diet designed to contain approximately 30 mmol Na and 50 mmol K. On Day 5 a determination of 24-hour ABPM was performed while continuing to receive this low sodium diet. During Days 6-10 participants received a diet designed to contain approximately 200 mmol Na and 50 mmol K. On Day 10 of this high sodium period ABPM was performed while the subjects continued to receive the 200 mmol Na and 50 mmol K diet. The response to increased dietary sodium was defined as the difference between the ABPM measurements conducted on Day 5 and Day 10. On day 11 a sodium handling study was performed to determine the effects of nebivolol versus metoprolol on sodium excretion (UnaV) following 1 liter 0.9% saline administered over 2 hours. All meals were designed with the supervision of a certified dietitian, provided by the University of Miami Hospital Food Service, and directly supervised by CPRU staff.

Renal sodium handling following a 1 L saline challenge. On Day 11 of the inpatient confinement period, while continuing to receive the 200 mmol Na 50 mmol K diet, an intravenous saline load test was performed. Beginning at approximately 0600, baseline urine for sodium, potassium, and creatinine was collected for two hours. At the midpoint of this 2-hour urine collection, blood was taken for sodium, potassium, and creatinine. At approximately 0800 1 L 0.9% normal saline was infused over 2 hours. Urine collections were performed hourly for six one-hour periods for sodium, potassium, and creatinine. Hour 1 and 2 collections were during the saline infusion. Hour 3-6 collections were post saline infusion. Blood pressure and heart rate were determined at baseline and at each hour during the collection period.

At hour 1 midpoint (30 minutes after the infusion was started), and the midpoint of each hourly urine collection for a total of 6 collection periods, blood was taken for creatinine, sodium, and potassium. Immediately following the 6 one-hour collection periods, the subject resumed the standard diet. Meals were identical and served at the same time on Day 11 for both periods. Urine was then collected and volume recorded at intervals of 6-8 hours, 8-12 hours and 12-24 hours. Aliquots were sent for creatinine, sodium, and potassium.

Nebivolol was provided in 5, 10 and 20 mg tablets by Forest Laboratories, New York, New York. Metoprolol ER was purchased as the generic product in 25, 50 and 100 mg tablets.

Arms: arm 1: Metoprolol/Nebivolol: Metoprolol 50 mg titrated to 100 mg then nebivolol 5 mg titrated to 10 mg arm 2: Metoprolol 50 mg titrated to 100 mg then Nebivolol 5 mg titrated to 10 mg
Interventions: intervention 1: nebivolol intervention 2: Metoprolol
Intervention descriptions: intervention 1: 5 mg titrated to 10 mg daily versus matching placebo intervention 2: Metoprolol 50 mg titrated to 100 mg

Protocol documents: