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| Name | Class |
|---|---|
| Forest Laboratories | INDUSTRY |
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The investigators hypothesize that nebivolol will improve endothelial t-PA release in adult humans with elevated blood pressure to a greater extent than either metoprolol or placebo. The investigators further hypothesize that the improvement in the capacity of the vascular endothelium to release t-PA with nebivolol is mediated, in part, by the compound's antioxidant properties.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Nebivolol | Active Comparator |
| |
| Metoprolol | Active Comparator |
| |
| Placebo | Placebo Comparator |
| |
| Bradykinin | Other |
| |
| Saline | Other |
| |
| Vitamin C | Other |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Nebivolol | Drug | 5 mg tablet to be taken by mouth once per day for 12 weeks |
|
| Measure | Description | Time Frame |
|---|---|---|
| Heart Rate | Resting heart rate in the seated position | Heart rate was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention. |
| Systolic Blood Pressure | Systolic blood pressure was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention. | |
| Diastolic Blood Pressure | Diastolic blood pressure was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention. | |
| Endothelial t-PA Release in Response to Bradykinin (BDK) Before and After the 12 Week Intervention | Net endothelial release of t-PA antigen in response to bradykinin (BDK) was calculated using the following equation: Net Release of t-PA Antigen=(Cv-Ca) x (FBF x [101-hematocrit/100]) where Cv and Ca represent the concentration of t-PA in the vein and artery respectively. A positive difference indicates a net release and a negative difference net uptake. Arterial and venous blood samples are collected simultaneously at baseline and each dose of the drug (BDK). t-PA concentration were determined by enzyme immunoassay. Hematocrit was measured in triplicate using the standard microhematocrit technique and corrected for trapped plasma volume within the trapped red blood cells. | t-PA release was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention. |
| Endothelial t-PA Release in Response to Bradykinin (BDK) and Bradykinin+Vitamin C (BDK+C) Before and After 12 Weeks of Nebivolol Therapy. | Net endothelial release of t-PA antigen in response to bradykinin (BDK) and bradykinin+vitamin C (BDK+C) was calculated using the following equation: Net Release of t-PA Antigen=(Cv-Ca) x (FBF x [101-hematocrit/100]) where Cv and Ca represent the concentration of t-PA in the vein and artery respectively. A positive difference indicates a net release and a negative difference net uptake. Arterial and venous blood samples are collected simultaneously at baseline and each dose of the drug (BDK) and BDK+Vit C. t-PA concentration were determined by enzyme immunoassay. Hematocrit was measured in triplicate using the standard microhematocrit technique and corrected for trapped plasma volume within the trapped red blood cells. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Christopher DeSouza, Ph.D. | University of Colorado at Boulder | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UC-Boulder Clinical and Translational Research Center | Boulder | Colorado | 80309 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29122812 | Derived | Stauffer BL, Dow CA, Diehl KJ, Bammert TD, Greiner JJ, DeSouza CA. Nebivolol, But Not Metoprolol, Treatment Improves Endothelial Fibrinolytic Capacity in Adults With Elevated Blood Pressure. J Am Heart Assoc. 2017 Nov 9;6(11):e007437. doi: 10.1161/JAHA.117.007437. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Nebivolol | Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks |
| FG001 | Metoprolol | Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks |
| FG002 | Placebo | Placebo: Gelatin capsule to be taken by mouth once per day for 12 weeks |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Nebivolol | Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks |
| BG001 | Metoprolol | Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Heart Rate | Resting heart rate in the seated position | Posted | Mean | Standard Error | bpm | Heart rate was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention. |
|
Adverse event data for each participant was assessed every 2 weeks during their check-in visits at the CU-Boulder CTRC over the 12 weeks.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Nebivolol | Nebivolol: 5 mg tablet to be taken by mouth once per day for 12 weeks |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Christopher DeSouza | University of Colorado | 303-492-2988 | desouzac@colorado.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 25, 2015 | May 1, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D058246 | Prehypertension |
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D000068577 | Nebivolol |
| D008790 | Metoprolol |
| D001920 | Bradykinin |
| D012965 | Sodium Chloride |
| D001205 | Ascorbic Acid |
| ID | Term |
|---|---|
| D004983 | Ethanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
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| Metoprolol | Drug | 100 mg tablet to be taken by mouth once per day for 12 weeks |
|
|
| Placebo | Drug | Gelatin capsule to be taken by mouth once per day for 12 weeks |
|
| Bradykinin | Other | Bradykinin is infused into the brachial artery at doses of 12.5, 25.0 and 50.0 ng/100 mL of forearm tissue /min. BDK stimulates the endothelial cells to release tissue type plasminogen activator (t-PA). Blood flow in mL/100 mL tissue/min is also measured to BDK. |
|
|
| Saline | Other | Baseline or resting forearm blood flow is measured in response to saline for 5 minutes before each drug infusion. t-PA release in response to the saline is also measured. |
|
| Vitamin C | Other | The acute effects of into-arterial vitamin C on the ability of the endothelium to release t-PA was determined before and after the nebivolol and metoprolol intervention. After allowing sufficient time (~20 minutes) for FBF and plasma t-PA concentrations to return to baseline following the initial infusion of BDK, vitamin C (24 mg/min) was infused at a constant rate while the BDK dose-response curves were repeated. t-PA and FBF were measured. |
|
| t-PA release was measured before the 12 week drug intervention and after the 12 week drug intervention. |
| Endothelial t-PA Release in Response to BDK and BDK+C Before and After 12 Weeks of Metoprolol Therapy. | Net endothelial release of t-PA antigen in response to BDK and BDK+C was calculated using the following equation: Net Release of t-PA Antigen=(Cv-Ca) x (FBF x [101-hematocrit/100]) where Cv and Ca represent the concentration of t-PA in the vein and artery respectively. A positive difference indicates a net release and a negative difference net uptake. Arterial and venous blood samples are collected simultaneously at baseline and each dose of the drug (BDK) and BDK+Vit C. t-PA concentration were determined by enzyme immunoassay. Hematocrit was measured in triplicate using the standard microhematocrit technique and corrected for trapped plasma volume within the trapped red blood cells. | t-PA release was measured before the 12 week drug intervention and after the 12 week drug intervention. |
| BG002 | Placebo | Placebo: Gelatin capsule to be taken by mouth once per day for 12 weeks |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
|
| Primary | Systolic Blood Pressure | Posted | Mean | Standard Error | mmHg | Systolic blood pressure was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention. |
|
|
|
| Primary | Diastolic Blood Pressure | Posted | Mean | Standard Error | mmHg | Diastolic blood pressure was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention. |
|
|
|
| Primary | Endothelial t-PA Release in Response to Bradykinin (BDK) Before and After the 12 Week Intervention | Net endothelial release of t-PA antigen in response to bradykinin (BDK) was calculated using the following equation: Net Release of t-PA Antigen=(Cv-Ca) x (FBF x [101-hematocrit/100]) where Cv and Ca represent the concentration of t-PA in the vein and artery respectively. A positive difference indicates a net release and a negative difference net uptake. Arterial and venous blood samples are collected simultaneously at baseline and each dose of the drug (BDK). t-PA concentration were determined by enzyme immunoassay. Hematocrit was measured in triplicate using the standard microhematocrit technique and corrected for trapped plasma volume within the trapped red blood cells. | Posted | Mean | Standard Error | ng/100 mL tissue/min | t-PA release was measured before the 12 week drug or placebo intervention and after the 12 week drug or placebo intervention. |
|
|
|
| Primary | Endothelial t-PA Release in Response to Bradykinin (BDK) and Bradykinin+Vitamin C (BDK+C) Before and After 12 Weeks of Nebivolol Therapy. | Net endothelial release of t-PA antigen in response to bradykinin (BDK) and bradykinin+vitamin C (BDK+C) was calculated using the following equation: Net Release of t-PA Antigen=(Cv-Ca) x (FBF x [101-hematocrit/100]) where Cv and Ca represent the concentration of t-PA in the vein and artery respectively. A positive difference indicates a net release and a negative difference net uptake. Arterial and venous blood samples are collected simultaneously at baseline and each dose of the drug (BDK) and BDK+Vit C. t-PA concentration were determined by enzyme immunoassay. Hematocrit was measured in triplicate using the standard microhematocrit technique and corrected for trapped plasma volume within the trapped red blood cells. | Posted | Mean | Standard Error | ng/100 mL tissue/min | t-PA release was measured before the 12 week drug intervention and after the 12 week drug intervention. |
|
|
|
| Primary | Endothelial t-PA Release in Response to BDK and BDK+C Before and After 12 Weeks of Metoprolol Therapy. | Net endothelial release of t-PA antigen in response to BDK and BDK+C was calculated using the following equation: Net Release of t-PA Antigen=(Cv-Ca) x (FBF x [101-hematocrit/100]) where Cv and Ca represent the concentration of t-PA in the vein and artery respectively. A positive difference indicates a net release and a negative difference net uptake. Arterial and venous blood samples are collected simultaneously at baseline and each dose of the drug (BDK) and BDK+Vit C. t-PA concentration were determined by enzyme immunoassay. Hematocrit was measured in triplicate using the standard microhematocrit technique and corrected for trapped plasma volume within the trapped red blood cells. | Posted | Mean | Standard Error | ng/100 mL tissue/min | t-PA release was measured before the 12 week drug intervention and after the 12 week drug intervention. |
|
|
|
| 0 |
| 16 |
| 0 |
| 16 |
| 0 |
| 16 |
| EG001 | Metoprolol | Metoprolol: 100 mg tablet to be taken by mouth once per day for 12 weeks | 0 | 16 | 0 | 16 | 0 | 16 |
| EG002 | Placebo | Placebo: Gelatin capsule to be taken by mouth once per day for 12 weeks | 0 | 12 | 0 | 12 | 0 | 12 |
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| D000588 |
| Amines |
| D001578 | Benzopyrans |
| D011714 | Pyrans |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D050198 | Phenoxypropanolamines |
| D011412 | Propanolamines |
| D020005 | Propanols |
| D007705 | Kinins |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D009479 | Neuropeptides |
| D009842 | Oligopeptides |
| D011506 | Proteins |
| D009419 | Nerve Tissue Proteins |
| D012898 | Autacoids |
| D018836 | Inflammation Mediators |
| D001685 | Biological Factors |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |
| D013400 | Sugar Acids |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D006880 | Hydroxy Acids |
| D002241 | Carbohydrates |
|
|
| Amount of t-PA release to BDK 12.5 |
|
| Amount of t-PA release to BDK 25.0 |
|
| Amount of t-PA release to BDK 50.0 |
|
| Amount of t-PA release to BDK 12.5 |
|
| Amount of t-PA release to BDK 25.0 |
|
| Amount of t-PA release to BDK 50.0 |
|
| Amount of t-PA release to BDK 12.5 |
|
| Amount of t-PA release to BDK 25.0 |
|
| Amount of t-PA release to BDK 50.0 |
|