Hypertension, Multiple System Atrophy, Pure Autonomic Failure
Conditions
Keywords
supine Hypertension, autonomic failure, nitric oxide, nebivolol
Brief summary
The purpose of this study is to evaluate the effect of the antihypertensive drug, nebivolol (Bystolic), compared to metoprolol (Lopressor) and sildenafil (Viagra) on blood pressure in patients with autonomic failure and supine hypertension.
Detailed description
Nebivolol is distinct among beta-blockers by its ability to increase nitric oxide (NO) bioactivity. The contribution of this effect to the pharmacological actions of the drug, however, is difficult to ascertain in normal subjects because of the confounding contribution of the autonomic nervous system. Autonomic failure patients provide a unique model of hypertension devoid of autonomic modulation but sensitive to NO mechanisms. We propose to determine the effect of nebivolol on blood pressure in this patient population. A decrease in blood pressure will imply increased bioactivity of NO. Comparisons will be made with placebo, metoprolol (as a negative control) and sildenafil (as a positive control).
Interventions
DRUGPlacebo
Placebo capsule
DRUGNebivolol 5 mg
Nebivolol 5mg single oral dose
DRUGmetoprolol tartrate 50 mg
metoprolol tartrate 50 mg single oral dose
DRUGSildenafil25 mg
Sildenafil 25 mg single oral dose
Sponsors
Forest Laboratories
Vanderbilt University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Male or female and aged 18 years or over. * Clinical diagnosis of orthostatic hypotension associated with Primary Autonomic Failure (Parkinson Disease, Multiple System Atrophy and Pure Autonomic Failure). * A documented fall in systolic blood pressure of at least 20 mmHg, or in diastolic blood pressure of at least 10 mmHg, within 3 minutes after standing. * Supine hypertension, defined as a systolic blood pressure \>150 mm Hg or diastolic blood pressure \> 90 mm Hg. * Provide written informed consent to participate in the study and understand that they may withdraw their consent at any time without prejudice to their future medical care.
Exclusion criteria
* Have changed dose, frequency and or type of prescribed medication, within two weeks of study start. * Women of childbearing potential who are not using a medically accepted contraception. * Have, in the investigator's opinion, any significant cardiac, systemic, hepatic, or renal illness. * Diabetes mellitus or insipidus. * In the investigator's opinion, have clinically significant abnormalities on clinical examination or laboratory testing. * In the investigator's opinion, are unable to adequately co-operate because of individual or family situation. * In the investigator's opinion, are suffering from a mental disorder that interferes with the diagnosis and/or with the conduct of the study, e.g. schizophrenia, major depression, dementia. * Are not able or willing to comply with the study requirements for the duration of the study. * Persons on drugs with beta-blocking potential (e.g., amiodarone), persons taking scheduled or as needed nitrates and persons on drugs with alpha-blocking potential (e.g. tamsulosin).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Systolic Blood Pressure During the Night | 8 pm - 8 am | Maximal change from baseline in systolic blood pressure, measured from 8 pm to 8 am, after a single dose of the intervention |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Nocturnal Urinary Sodium Excretion | 8 pm - 8 am | Nocturnal sodium excretion was defined as the ratio of urinary sodium to urinary creatinine. |
| Orthostatic Tolerance the Following Morning | 10 min standing | Orthostatic tolerance was defined as the area under the curve of standing systolic blood pressure calculated by the trapezoidal rule (upright systolic blood pressure multiplied by standing time) during a 10-minute standing test |
| Change in Heart Rate During the Night | 8 pm - 8 am | Change from baseline (8 pm) in heart rate at the time of maximal BP-lowering effect |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Participants who were randomized to receive placebo, metoprolol, sildenafil and nebivolol in any order | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 69 years STANDARD_DEVIATION 8 |
| BMI | 25.6 kg/m2 STANDARD_DEVIATION 3.2 |
| Diagnosis Multiple System Atrophy | 6 participants |
| Diagnosis Parkinson Disease with autonomic failure | 4 participants |
| Diagnosis Pure autonomic failure | 10 participants |
| Duration of disease | 8 years STANDARD_DEVIATION 6 |
| Heart rate, supine | 68 bpm STANDARD_DEVIATION 10 |
| Heart rate, upright | 83 bpm STANDARD_DEVIATION 15 |
| Medical history of essential hypertension No | 16 participants |
| Medical history of essential hypertension yes | 4 participants |
| Plasma norepinephrine, supine | 136 pg/mL STANDARD_DEVIATION 98 |
| Plasma norepinephrine, upright | 253 pg/mL STANDARD_DEVIATION 209 |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 14 Participants |
| Systolic BP, supine | 169 mm Hg STANDARD_DEVIATION 24 |
| Systolic BP, upright | 83 mm Hg STANDARD_DEVIATION 25 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 20 | 0 / 20 | 0 / 20 | 2 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 | 0 / 20 | 0 / 20 |
Outcome results
Primary
Change in Systolic Blood Pressure During the Night
Maximal change from baseline in systolic blood pressure, measured from 8 pm to 8 am, after a single dose of the intervention
Time frame: 8 pm - 8 am
Population: Participants who completed the 4 treatment arms
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Capsule | Change in Systolic Blood Pressure During the Night | Baseline supine at 8 pm | 154 mm Hg | Standard Error 7 |
| Placebo Capsule | Change in Systolic Blood Pressure During the Night | Change in systolic BP | 1 mm Hg | Standard Error 7 |
| Nebivolol 5 mg | Change in Systolic Blood Pressure During the Night | Change in systolic BP | -24 mm Hg | Standard Error 9 |
| Nebivolol 5 mg | Change in Systolic Blood Pressure During the Night | Baseline supine at 8 pm | 162 mm Hg | Standard Error 5 |
| Metoprolol Tartrate 50 mg | Change in Systolic Blood Pressure During the Night | Baseline supine at 8 pm | 157 mm Hg | Standard Error 5 |
| Metoprolol Tartrate 50 mg | Change in Systolic Blood Pressure During the Night | Change in systolic BP | -7 mm Hg | Standard Error 6 |
| Sildenafil 25 mg | Change in Systolic Blood Pressure During the Night | Baseline supine at 8 pm | 158 mm Hg | Standard Error 6 |
| Sildenafil 25 mg | Change in Systolic Blood Pressure During the Night | Change in systolic BP | -20 mm Hg | Standard Error 6 |
Comparison: The main comparisons were between the active treatment groups versus placebo. We hypothesized that if NO-mediated vasodilation contributes to the BP-lowering effect of nebivolol then BP will be lowered by nebivolol and sildenafil, but not by metoprolol in autonomic failure patients.p-value: 0.036Mixed Models Analysis
Comparison: The main comparisons were between the active treatment groups versus placebo. We hypothesized that if NO-mediated vasodilation contributes to the BP-lowering effect of nebivolol then BP will be lowered by nebivolol and sildenafil, but not by metoprolol in autonomic failure patients.p-value: <0.001Mixed Models Analysis
Comparison: The main comparisons were between the active treatment groups versus placebo. We hypothesized that if NO-mediated vasodilation contributes to the BP-lowering effect of nebivolol then BP will be lowered by nebivolol and sildenafil, but not by metoprolol in autonomic failure patients.p-value: >0.05Mixed Models Analysis
Secondary
Change in Heart Rate During the Night
Change from baseline (8 pm) in heart rate at the time of maximal BP-lowering effect
Time frame: 8 pm - 8 am
Population: Participants who completed the 4 treatment arms
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Capsule | Change in Heart Rate During the Night | -3 bpm | Standard Error 2 |
| Nebivolol 5 mg | Change in Heart Rate During the Night | -6 bpm | Standard Error 2 |
| Metoprolol Tartrate 50 mg | Change in Heart Rate During the Night | -6 bpm | Standard Error 2 |
| Sildenafil 25 mg | Change in Heart Rate During the Night | 0 bpm | Standard Error 2 |
Comparison: The main comparisons were between the negative chronotropic effect of nebivolol and metoprolol at the time when BP-lowering effects were maximal.p-value: 0.996Wilcoxon (Mann-Whitney)
Secondary
Nocturnal Urinary Sodium Excretion
Nocturnal sodium excretion was defined as the ratio of urinary sodium to urinary creatinine.
Time frame: 8 pm - 8 am
Population: Participants with complete urine collections during the 4 study nights
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Capsule | Nocturnal Urinary Sodium Excretion | 0.145 mEq/mg | Standard Error 0.015 |
| Nebivolol 5 mg | Nocturnal Urinary Sodium Excretion | 0.127 mEq/mg | Standard Error 0.011 |
| Metoprolol Tartrate 50 mg | Nocturnal Urinary Sodium Excretion | 0.139 mEq/mg | Standard Error 0.019 |
| Sildenafil 25 mg | Nocturnal Urinary Sodium Excretion | 0.125 mEq/mg | Standard Error 0.018 |
Comparison: The main comparisons were between the active treatment groups versus placebo.p-value: 0.607ANOVA
Secondary
Orthostatic Tolerance the Following Morning
Orthostatic tolerance was defined as the area under the curve of standing systolic blood pressure calculated by the trapezoidal rule (upright systolic blood pressure multiplied by standing time) during a 10-minute standing test
Time frame: 10 min standing
Population: Comparisons were made only for patients who could stand after all treatment groups
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Capsule | Orthostatic Tolerance the Following Morning | 594 mm Hg*min | Standard Error 108 |
| Nebivolol 5 mg | Orthostatic Tolerance the Following Morning | 675 mm Hg*min | Standard Error 113 |
| Metoprolol Tartrate 50 mg | Orthostatic Tolerance the Following Morning | 696 mm Hg*min | Standard Error 128 |
| Sildenafil 25 mg | Orthostatic Tolerance the Following Morning | 575 mm Hg*min | Standard Error 106 |
Comparison: The main comparisons were between the active treatment groups versus placebo.p-value: 0.597ANOVA