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Nebivolol in the Supine Hypertension of Autonomic Failure

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ClinicalTrials.gov Identifier: NCT01044693
Recruitment Status : Completed
First Posted : January 8, 2010
Results First Posted : May 1, 2015
Last Update Posted : May 1, 2015
Sponsor:
Collaborator:
Forest Laboratories
Information provided by (Responsible Party):
Italo Biaggioni, Vanderbilt University

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Double (Participant, Investigator)
Conditions Hypertension
Pure Autonomic Failure
Multiple System Atrophy
Interventions Drug: Placebo
Drug: Nebivolol 5 mg
Drug: metoprolol tartrate 50 mg
Drug: Sildenafil25 mg
Enrollment 20
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Placebo Then Metoprolol Then Sildenafil Then Nebivolol Placebo Then Nebivolol Then Metoprolol Then Sildenafil Placebo Then Sildenafil Then Nebivolol Then Metoprolol Placebo Then Sildenafil Then Metoprolol Then Nebivolol Nebivolol Then Placebo Then Metoprolol Then Sildenafil Metoprolol Then Sildenafil Then Placebo Then Nebivolol Sildenafil Then Nebivolol Then Placebo Then Metoprolol Metoprolol Then Placebo Then Nebivolol Then Sildenafil Nebivolol Then Metoprolol Then Sildenafil Then Placebo Metoprolol Then Nebivolol Then Placebo Then Sildenafil Metoprolol Then Sildenafil Then Nebivolol Then Placebo Sildenafil Then Nebivolol Then Metoprolol Then Placebo Sildenafil Then Metoprolol Then Nebivolol Then Placebo Nebivolol Then Sildenafil Then Metoprolol Then Placebo Nebivolol Then Placebo Then Sildenafil Then Metoprolol Placebo Then Nebivolol Then Sildenafil Then Metoprolol
Hide Arm/Group Description Single oral dose of: metoprolol tartrate 50 mg, sildenafil 25 mg, nebivolol 5 mg Single oral dose of: metoprolol tartrate 50 mg, sildenafil 25 mg, nebivolol 5 mg Single oral dose of: metoprolol tartrate 50 mg, sildenafil 25 mg, nebivolol 5 mg Single oral dose of: metoprolol tartrate 50 mg, sildenafil 25 mg, nebivolol 5 mg Single oral dose of: metoprolol tartrate 50 mg, sildenafil 25 mg, nebivolol 5 mg Single oral dose of: metoprolol tartrate 50 mg, sildenafil 25 mg, nebivolol 5 mg Single oral dose of: metoprolol tartrate 50 mg, sildenafil 25 mg, nebivolol 5 mg Single oral dose of: metoprolol tartrate 50 mg, sildenafil 25 mg, nebivolol 5 mg Single oral dose of: metoprolol tartrate 50 mg, sildenafil 25 mg, nebivolol 5 mg Single oral dose of: metoprolol tartrate 50 mg, sildenafil 25 mg, nebivolol 5 mg Single oral dose of: metoprolol tartrate 50 mg, sildenafil 25 mg, nebivolol 5 mg Single oral dose of: metoprolol tartrate 50 mg, sildenafil 25 mg, nebivolol 5 mg Single oral dose of: metoprolol tartrate 50 mg, sildenafil 25 mg, nebivolol 5 mg Single oral dose of: metoprolol tartrate 50 mg, sildenafil 25 mg, nebivolol 5 mg Single oral dose of: metoprolol tartrate 50 mg, sildenafil 25 mg, nebivolol 5 mg Single oral dose of: metoprolol tartrate 50 mg, sildenafil 25 mg, nebivolol 5 mg
Period Title: Overall Study
Started 3 1 1 1 1 2 1 1 1 1 1 1 2 1 1 1
Completed 3 1 1 1 1 2 1 1 1 1 1 1 2 1 1 1
Not Completed 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Arm/Group Title All Study Participants
Hide Arm/Group Description Participants who were randomized to receive placebo, metoprolol, sildenafil and nebivolol in any order
Overall Number of Baseline Participants 20
Hide Baseline Analysis Population Description
Patients with primary forms of autonomic failure and supine hypertension
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 20 participants
69  (8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants
Female
6
  30.0%
Male
14
  70.0%
BMI  
Mean (Standard Deviation)
Unit of measure:  Kg/m2
Number Analyzed 20 participants
25.6  (3.2)
Duration of disease  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 20 participants
8  (6)
Diagnosis  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 20 participants
Pure autonomic failure 10
Parkinson Disease with autonomic failure 4
Multiple System Atrophy 6
Medical history of essential hypertension  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 20 participants
yes 4
No 16
Systolic BP, supine  
Mean (Standard Deviation)
Unit of measure:  Mm Hg
Number Analyzed 20 participants
169  (24)
Systolic BP, upright  
Mean (Standard Deviation)
Unit of measure:  Mm Hg
Number Analyzed 20 participants
83  (25)
Heart rate, supine  
Mean (Standard Deviation)
Unit of measure:  Bpm
Number Analyzed 20 participants
68  (10)
Heart rate, upright  
Mean (Standard Deviation)
Unit of measure:  Bpm
Number Analyzed 20 participants
83  (15)
Plasma norepinephrine, supine  
Mean (Standard Deviation)
Unit of measure:  pg/mL
Number Analyzed 20 participants
136  (98)
Plasma norepinephrine, upright  
Mean (Standard Deviation)
Unit of measure:  pg/mL
Number Analyzed 20 participants
253  (209)
1.Primary Outcome
Title Change in Systolic Blood Pressure During the Night
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants who completed the 4 treatment arms
Arm/Group Title Placebo Capsule Nebivolol 5 mg Metoprolol Tartrate 50 mg Sildenafil 25 mg
Hide Arm/Group Description:

Placebo capsule

Placebo: Placebo capsule

Nebivolol 5 mg capsule

Nebivolol 5 mg: Nebivolol 5mg single oral dose

Metoprolol tartrate 50 mg single oral dose

metoprolol tartrate 50 mg: metoprolol tartrate 50 mg single oral dose

Sildenafil 25 mg single oral dose

Sildenafil25 mg: Sildenafil 25 mg single oral dose

Overall Number of Participants Analyzed 20 20 20 20
Mean (Standard Error)
Unit of Measure: mm Hg
Baseline supine at 8 pm 154  (7) 162  (5) 157  (5) 158  (6)
Change in systolic BP 1  (7) -24  (9) -7  (6) -20  (6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Capsule, Nebivolol 5 mg
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.036
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo Capsule, Sildenafil 25 mg
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo Capsule, Metoprolol Tartrate 50 mg
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.05
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
2.Secondary Outcome
Title Nocturnal Urinary Sodium Excretion
Hide Description Nocturnal sodium excretion was defined as the ratio of urinary sodium to urinary creatinine.
Time Frame 8 pm - 8 am
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants with complete urine collections during the 4 study nights
Arm/Group Title Placebo Capsule Nebivolol 5 mg Metoprolol Tartrate 50 mg Sildenafil 25 mg
Hide Arm/Group Description:

Placebo capsule

Placebo: Placebo capsule

Nebivolol 5 mg capsule

Nebivolol 5 mg: Nebivolol 5mg single oral dose

Metoprolol tartrate 50 mg single oral dose

metoprolol tartrate 50 mg: metoprolol tartrate 50 mg single oral dose

Sildenafil 25 mg single oral dose

Sildenafil25 mg: Sildenafil 25 mg single oral dose

Overall Number of Participants Analyzed 14 14 14 14
Mean (Standard Error)
Unit of Measure: mEq/mg
0.145  (0.015) 0.127  (0.011) 0.139  (0.019) 0.125  (0.018)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Capsule, Nebivolol 5 mg, Metoprolol Tartrate 50 mg, Sildenafil 25 mg
Comments The main comparisons were between the active treatment groups versus placebo.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.607
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
3.Secondary Outcome
Title Orthostatic Tolerance the Following Morning
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Comparisons were made only for patients who could stand after all treatment groups
Arm/Group Title Placebo Capsule Nebivolol 5 mg Metoprolol Tartrate 50 mg Sildenafil 25 mg
Hide Arm/Group Description:

Placebo capsule

Placebo: Placebo capsule

Nebivolol 5 mg capsule

Nebivolol 5 mg: Nebivolol 5mg single oral dose

Metoprolol tartrate 50 mg single oral dose

metoprolol tartrate 50 mg: metoprolol tartrate 50 mg single oral dose

Sildenafil 25 mg single oral dose

Sildenafil25 mg: Sildenafil 25 mg single oral dose

Overall Number of Participants Analyzed 11 11 11 11
Mean (Standard Error)
Unit of Measure: mm Hg*min
594  (108) 675  (113) 696  (128) 575  (106)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Capsule, Nebivolol 5 mg, Metoprolol Tartrate 50 mg, Sildenafil 25 mg
Comments The main comparisons were between the active treatment groups versus placebo.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.597
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
4.Secondary Outcome
Title Change in Heart Rate During the Night
Hide Description Change from baseline (8 pm) in heart rate at the time of maximal BP-lowering effect
Time Frame 8 pm - 8 am
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants who completed the 4 treatment arms
Arm/Group Title Placebo Capsule Nebivolol 5 mg Metoprolol Tartrate 50 mg Sildenafil 25 mg
Hide Arm/Group Description:

Placebo capsule

Placebo: Placebo capsule

Nebivolol 5 mg capsule

Nebivolol 5 mg: Nebivolol 5mg single oral dose

Metoprolol tartrate 50 mg single oral dose

metoprolol tartrate 50 mg: metoprolol tartrate 50 mg single oral dose

Sildenafil 25 mg single oral dose

Sildenafil25 mg: Sildenafil 25 mg single oral dose

Overall Number of Participants Analyzed 20 20 20 20
Mean (Standard Error)
Unit of Measure: bpm
-3  (2) -6  (2) -6  (2) 0  (2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nebivolol 5 mg, Metoprolol Tartrate 50 mg
Comments The main comparisons were between the negative chronotropic effect of nebivolol and metoprolol at the time when BP-lowering effects were maximal.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.996
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Time Frame 1 day for each intervention
Adverse Event Reporting Description Safety population included all participants
 
Arm/Group Title Placebo Capsule Nebivolol 5 mg Metoprolol Tartrate 50 mg Sildenafil 25 mg
Hide Arm/Group Description

Placebo capsule

Placebo: Placebo capsule

Nebivolol 5 mg capsule

Nebivolol 5 mg: Nebivolol 5mg single oral dose

Metoprolol tartrate 50 mg single oral dose

metoprolol tartrate 50 mg: metoprolol tartrate 50 mg single oral dose

Sildenafil 25 mg single oral dose

Sildenafil25 mg: Sildenafil 25 mg single oral dose

All-Cause Mortality
Placebo Capsule Nebivolol 5 mg Metoprolol Tartrate 50 mg Sildenafil 25 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Capsule Nebivolol 5 mg Metoprolol Tartrate 50 mg Sildenafil 25 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/20 (0.00%)      0/20 (0.00%)      0/20 (0.00%)      0/20 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Placebo Capsule Nebivolol 5 mg Metoprolol Tartrate 50 mg Sildenafil 25 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/20 (0.00%)      0/20 (0.00%)      0/20 (0.00%)      2/20 (10.00%)    
Nervous system disorders         
fall [1]  0/20 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 1/20 (5.00%)  1
Renal and urinary disorders         
Urinary Tract Infection and diarrhea [2]  0/20 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 1/20 (5.00%)  1
[1]
Participant got up on his own to go to the bathroom during the night, partly falling and injuring his right 5th finger (dislocated).
[2]
During study participation, it was found that she had a urinary tract infection (UTI), which contributed to the worsening of hypotension. Subject was taken off the study and treatment for UTI started. She was discharged without further incident.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Italo Biaggioni MD
Organization: Vanderbilt University
Phone: 615-936-3420
Responsible Party: Italo Biaggioni, Vanderbilt University
ClinicalTrials.gov Identifier: NCT01044693     History of Changes
Other Study ID Numbers: 091252
First Submitted: January 6, 2010
First Posted: January 8, 2010
Results First Submitted: April 14, 2015
Results First Posted: May 1, 2015
Last Update Posted: May 1, 2015