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| ID | Type | Description | Link |
|---|---|---|---|
| Grant# DK38226-21 |
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| Name | Class |
|---|---|
| National Institutes of Health (NIH) | NIH |
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The hypothesis is to test to see if the drug fenofibrate will increase important chemicals in the body and specifically in the kidney, help to rid the body of salt by the kidneys, decrease blood pressure and improve insulin sensitivity during high-salt intake in individuals with hypertension.
Hypertension affects 73 million people in the United States and a billion people worldwide and contributes to death due to stroke, myocardial infarction, end-stage kidney disease and congestive heart failure. Fifty to 60% of individuals with hypertension have "salt-sensitive" hypertension, characterized by an exaggerated blood pressure response to increased salt intake. Salt-sensitive hypertension is associated with increased mortality due to cardiovascular disease.
This study will test the hypothesis that administration of a PPARa agonist, an intervention increases renal tubular Cyp2c and 4a expression in rodents, will increase urinary excretion of 20-hydroxyeicosatetraenoic acid(HETE) and epoxyeicosatrienoic acids(EET)s, induce natriuresis, decrease blood pressure, and improve insulin sensitivity during high-salt intake in individuals with hypertension.
Metabolites of the P450 arachidonic acid monooxygenases play an important role in the regulation of blood pressure in rodent models.
Targeted disruption of murine Cyp4a genes provides insight into the roles of renal monooxygenases and epoxygenases in the regulation of salt excretion and blood pressure.
PPARa agonists induce the expression of renal tubular monoxygenases and epoxygenases and decrease blood pressure in both Ang II- dependent and salt-sensitive rodent models of hypertension.
PPARa agonists have been reported to reduce blood pressure in clinical trials in humans. The effect of PPARa agonist on renal vasodilation, sodium excretion and excretion of urinary epoxygenase or monooxygenase products in response to salt loading is not known.
The regulation of urinary 20-HETE excretion may be impaired in human hypertension.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo, then fenofibrate | Placebo Comparator | Randomized study of fenofibrate versus placebo during high salt diet |
|
| Fenofibrate, then placebo | Placebo Comparator | Randomized study of fenofibrate versus placebo during high salt intake. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| fenofibrate | Drug | Subjects will be randomized to receive either fenofibrate 160 mg/day or matching placebo for five days by mouth. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Blood Pressure During High Salt Intake and Fenofibrate Treatment Compared to High Salt Intake and Placebo Treatment | Difference in blood pressure (mean arterial pressure) measured on the last day of high salt intake and fenofibrate treatment minus blood pressure (mean arterial pressure) measured during high salt intake and placebo treatment in participants classified as being salt-sensitive versus salt-resistant. Participants were classified as salt-sensitive if the average study day mean arterial pressure (MAP) was at least 5 mmHg higher during the high salt placebo arm than during low salt intake. | pressure measured on day 6 of high salt fenofibrate minus pressure measured on day 6 of high salt placebo |
| Measure | Description | Time Frame |
|---|---|---|
| HDL-cholesterol Measured During High Salt Fenofibrate in Salt-resistant and Salt-sensitive Hypertension | HDL-cholesterol concentration measured on the last day of fenofibrate treatment in salt-resistant and salt-sensitive hypertensive patients | Measured on day 6 of high salt intake and fenofibrate treatment |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Nancy J Brown, MD | Vanderbilt University Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Vanderbilt University | Nashville | Tennessee | 37232 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23385647 | Result | Gilbert K, Nian H, Yu C, Luther JM, Brown NJ. Fenofibrate lowers blood pressure in salt-sensitive but not salt-resistant hypertension. J Hypertens. 2013 Apr;31(4):820-9. doi: 10.1097/HJH.0b013e32835e8227. | |
| 25173047 | Derived | Ramirez CE, Shuey MM, Milne GL, Gilbert K, Hui N, Yu C, Luther JM, Brown NJ. Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans. Prostaglandins Other Lipid Mediat. 2014 Oct;113-115:38-44. doi: 10.1016/j.prostaglandins.2014.08.001. Epub 2014 Aug 28. |
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All anti-hypertensive medications were discontinued for 3 weeks. Participants who met blood pressure safety criteria were discontinued. Remaining participants underwent a 6-day low salt diet period and study day prior to randomization. Thirty-three of 75 enrolled met inclusion criteria, and were not withdrawn for high blood pressure during washout.
After providing informed consent, subjects underwent a history and physical examination, screening electrocardiogram and laboratory assessment. Subjects were excluded if they did not meet inclusion and exclusion criteria.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo, Then Fenofibrate | Subjects underwent two consecutive high salt (200mmol/d) periods. During the first they received matching placebo. During the second they received fenofibrate 160mg/d. |
| FG001 | Fenofibrate, Then Placebo | Subjects underwent two consecutive high salt (200mmol/d) periods. During the first they received fenofibrate 160mg/d. During the second they received matching placebo. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Washout Period After Low Salt |
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| First Drug During High Salt Intake |
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| Second Washout Period |
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| Second Drug During High Salt Intake |
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Total number who completed the screening and low salt diet and were randomized.
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| ID | Title | Description |
|---|---|---|
| BG000 | Study Group |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | Change in Blood Pressure During High Salt Intake and Fenofibrate Treatment Compared to High Salt Intake and Placebo Treatment | Difference in blood pressure (mean arterial pressure) measured on the last day of high salt intake and fenofibrate treatment minus blood pressure (mean arterial pressure) measured during high salt intake and placebo treatment in participants classified as being salt-sensitive versus salt-resistant. Participants were classified as salt-sensitive if the average study day mean arterial pressure (MAP) was at least 5 mmHg higher during the high salt placebo arm than during low salt intake. | All subjects who completed entire protocol | Posted | Mean | Standard Deviation | mm Hg | pressure measured on day 6 of high salt fenofibrate minus pressure measured on day 6 of high salt placebo |
|
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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 | Placebo |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| IV infiltration or bruising | Injury, poisoning and procedural complications | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Nancy J. Brown, M.D. | Vanderbilt University | 615-343-8701 | nancy.j.brown@vanderbilt.edu |
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| ID | Term |
|---|---|
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D011345 | Fenofibrate |
| ID | Term |
|---|---|
| D058607 | Fibric Acids |
| D058610 | Isobutyrates |
| D002087 | Butyrates |
| D000144 | Acids, Acyclic |
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| Placebo | Drug | Subjects will be randomized to receive placebo or fenofibrate for five days by mouth |
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| NOT COMPLETED |
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| NOT COMPLETED |
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| NOT COMPLETED |
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| Participants |
|
| Age Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| OG001 | Salt-sensitive Hypertension | Subjects were classified as salt-sensitive if the average study day mean arterial pressure was at least 5 mmHg higher during high salt placebo compared to low salt intake |
|
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| Secondary | HDL-cholesterol Measured During High Salt Fenofibrate in Salt-resistant and Salt-sensitive Hypertension | HDL-cholesterol concentration measured on the last day of fenofibrate treatment in salt-resistant and salt-sensitive hypertensive patients | All subjects who completed the protocol | Posted | Mean | Standard Deviation | mg/dL | Measured on day 6 of high salt intake and fenofibrate treatment |
|
|
|
| 0 |
| 33 |
| 2 |
| 33 |
| EG001 | Fenofibrate | 0 | 33 | 2 | 33 |
| High blood pressure during washout phase | Vascular disorders | Systematic Assessment |
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| D002264 |
| Carboxylic Acids |
| D009930 | Organic Chemicals |
| D010647 | Phenyl Ethers |
| D004987 | Ethers |
| D001577 | Benzophenones |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D010636 | Phenols |
| D007659 | Ketones |