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| ID | Type | Description | Link |
|---|---|---|---|
| R01HL065193-08A2 | U.S. NIH Grant/Contract | View source |
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insufficient enrollment and retention
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| Name | Class |
|---|---|
| University of Washington | OTHER |
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
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The purpose of the study is to see how two classes of blood pressure medications,angiotensin-converting enzyme inhibitors (Ace inhibitors) and angiotensin receptor blockers (ARBs), differ in their long term effects on certain chemicals in the body and on the carotid arteries.
More than 400,000 individuals with chronic kidney disease undergo hemodialysis each year in the United States. Atherosclerotic cardiovascular disease is the leading cause of mortality in these patients. Conventional risk factors for coronary artery disease (CAD) do not adequately explain this increased mortality, whereas biomarker of oxidative stress and inflammation correlate with clinical outcomes. Even with the use of biocompatible membranes, hemodialysis induces a systemic inflammatory reaction characterized by complement activation, leukocyte activation and the generation of reactive oxygen species and cytokines. Oxidative stress and inflammation promote endothelial dysfunction, a predictor of atherosclerotic cardiovascular events.
The purpose of the study is to test the hypothesis that angiotensin-converting enzyme inhibition and angiotensin receptor blockade differ in their long term effects on biomarkers of fibrinolysis, oxidative stress,inflammation and on carotid intima-media thickness (IMT), a predictor of cardiovascular events, in patients with chronic kidney disease undergoing maintenance hemodialysis.
Endogenous Bradykinin (BK) contributes to the hypotensive and pro-fibrinolytic effects of ACE inhibitors. It has been determined that endogenous BK contributes to the vasodilator effects of acute and chronic ACE inhibition. Studies have found that BK stimulates vascular tissue plasminogen activator (t-PA) release through a BK B2 receptor-dependent, nitric oxide (NO) and cyclooxygenase-independent pathway. Hemodialysis patients demonstrates endothelial dysfunction. Data suggests that t-PA release may be attenuated during stimulation of the endogenous kallikrein-kinin system by hemodialysis.
Intra-arterial infusion of BK increases vascular release of F2- isoprostanes, markers of oxidative stress, BK infusions also increase net release of the inflammatory cytokine interleukin-6 (IL-6). Preliminary data raise the possibility that activation of the endogenous kallikrein-kinin system during dialysis could promote inflammation in individuals with chronic kidney disease who are treated with an ACE inhibitor.
Cardiopulmonary bypass activates the endogenous kallikrein-kinin system and causes a systemic inflammatory response. Like hemodialysis, cardiopulmonary bypass activates the endogenous kallikrein-kinin system, increasing BK concentrations. In smokers, who like hemodialysis patients exhibit endothelial dysfunction, the t-PA response to BK was attenuated during cardiopulmonary bypass.
ACE inhibition enhances fibrinolysis and decreases inflammation following cardiopulmonary bypass. The short-term effect of both ACE inhibition and angiotensin II type 1 (AT1) receptors on markers of fibrinolysis and inflammation during dialysis are currently being studied.
Circulating BK concentrations are increased during hemodialysis in individuals treated with an ACE inhibitors compared to those treated with an AT1 receptor blocker.
Bradykinin receptor blockade and the fibrinolytic and inflammatory response to hemodialysis. It is hypothesized that subjects with CAD, the t-PA response to hemodialysis will be blunted compared to that measured in subjects without evidence of CAD, whereas the inflammatory response wil be similar or enhanced.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Valsartan | Active Comparator | 80 mg of valsartan (ARB) taken orally on a daily basis for 1 week followed by 160 mg of valsartan taken orally on a daily basis for 18 months |
|
| Ramipril | Active Comparator | 2.5 mg of ramipril (ACE inhibitor) taken orally on a daily basis for 1 week followed by 5 mg of ramipril taken orally on a daily basis for 18 months |
|
| Placebo | Placebo Comparator | matching placebo taken orally on a daily basis for 1 week followed by matching placebo taken orally on a daily basis for 18 months |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| valsartan (ARB) | Drug |
|
| |
| ramipril (ACE inhibitor) |
| Measure | Description | Time Frame |
|---|---|---|
| Interleukin-6 (IL-6) | IL-6 is a sensitive laboratory assay for serum levels of interleukin-6, which is a pro-inflammatory cytokine used to evaluate the inflammatory response. | baseline and 18 months |
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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 |
| Talat A Ikilzer, MD | Vanderbilt University Medical Center | Principal Investigator |
| Jonathan Himmelfarb, MD | University of Washington | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Vanderbilt University Medical Center | Nashville | Tennessee | 37232 | United States |
There is a 3-week period between enrollment and assignment to treatment group. This "washout" period is to ensure that no blood pressure medicines (ARBs or ACE inhibitors) are left in the body. Although 123 subjects were enrolled, only 78 were assigned to a treatment group (45 subjects were screen failures).
This study was conducted at the Vanderbilt University Medical Center and at the University of Washington between January 2010 and June 2015.
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| ID | Title | Description |
|---|---|---|
| FG000 | Valsartan | 80 mg of valsartan (ARB) taken orally on a daily basis for 1 week followed by 160 mg of valsartan taken orally on a daily basis for 18 months |
| FG001 | Ramipril | 2.5 mg of ramipril (ACE inhibitor) taken orally on a daily basis for 1 week followed by 5 mg of ramipril taken orally on a daily basis for 18 months |
| FG002 | Placebo | matching placebo taken orally on a daily basis for 1 week followed by matching placebo taken orally on a daily basis for 18 months |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Valsartan | 80 mg of valsartan (ARB) taken orally on a daily basis for 1 week followed by 160 mg of valsartan taken orally on a daily basis for 18 months |
| BG001 | Ramipril | 2.5 mg of ramipril (ACE inhibitor) taken orally on a daily basis for 1 week followed by 6 mg of ramipril taken orally on a daily basis for 18 months |
| 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 | Interleukin-6 (IL-6) | IL-6 is a sensitive laboratory assay for serum levels of interleukin-6, which is a pro-inflammatory cytokine used to evaluate the inflammatory response. | Based on our power calculations, we needed 210 subjects to complete the study to be able to detect an effect. Given that only 37 subjects completed the study (18% of goal), no formal analyses were performed. Specifically, data were not collected for this assessment for any of the participants enrolled in the study. | Posted | baseline and 18 months |
|
18 months
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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 | Valsartan | 80 mg of valsartan (ARB) taken orally on a daily basis for 1 week followed by 160 mg of valsartan taken orally on a daily basis for 18 months |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| infection | Infections and infestations | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| access related | Vascular disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| T. Alp Ikizler, MD | Vanderbilt University | 615-343-6104 | alp.ikizler@vanderbilt.edu |
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| ID | Term |
|---|---|
| D000068756 | Valsartan |
| D017257 | Ramipril |
| D000806 | Angiotensin-Converting Enzyme Inhibitors |
| ID | Term |
|---|---|
| D013777 | Tetrazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| Drug |
|
|
| Placebo | Drug |
|
|
| kidney transplant |
|
| Adverse Event |
|
| Lost to Follow-up |
|
| Protocol Violation |
|
| Death |
|
| Pregnancy |
|
| BG002 | Placebo | matching placebo taken orally on a daily basis for 1 week followed by matching placebo taken orally on a daily basis for 18 months |
| 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 |
|
2.5 mg of ramipril (ACE inhibitor) taken orally on a daily basis for 1 week followed by 5 mg of ramipril taken orally on a daily basis for 18 months |
| OG002 | Placebo | matching placebo taken orally on a daily basis for 1 week followed by matching placebo taken orally on a daily basis for 18 months |
|
| 8 |
| 25 |
| 19 |
| 25 |
| EG001 | Ramipril | 2.5 mg of ramipril (ACE inhibitor) taken orally on a daily basis for 1 week followed by 5 mg of ramipril taken orally on a daily basis for 18 months | 9 | 27 | 15 | 27 |
| EG002 | Placebo | matching placebo taken orally on a daily basis for 1 week followed by matching placebo taken orally on a daily basis for 18 months | 9 | 26 | 15 | 26 |
| pulmonary | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| cardiac | Cardiac disorders | Non-systematic Assessment |
|
| electroyte disorder | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| hypertension/hypotension | Vascular disorders | Non-systematic Assessment |
|
| musculoskeletal | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| GI upset | Gastrointestinal disorders | Non-systematic Assessment |
|
| generalized symptoms | General disorders | Non-systematic Assessment |
|
| Death | General disorders | Non-systematic Assessment |
|
| access related | Vascular disorders | Non-systematic Assessment |
|
| cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Non-systematic Assessment |
|
| trauma | General disorders | Non-systematic Assessment |
|
| pain | General disorders | Non-systematic Assessment |
|
| blood clot | Vascular disorders | Non-systematic Assessment |
|
| suicide ideation | Psychiatric disorders | Non-systematic Assessment |
|
| excessive bleeding | Vascular disorders | Non-systematic Assessment |
|
| excessive fluid in abdomen | Gastrointestinal disorders | Non-systematic Assessment |
|
| GI upset | Gastrointestinal disorders | Non-systematic Assessment |
|
| cardiac | Cardiac disorders | Non-systematic Assessment |
|
| neurological | Nervous system disorders | Non-systematic Assessment |
|
| hypertension/hypotension | Vascular disorders | Non-systematic Assessment |
|
| electrolyte disorder | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| pain | General disorders | Non-systematic Assessment |
|
| pulmonary | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| musculoskeletal | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| infection | Infections and infestations | Non-systematic Assessment |
|
| generalized symptoms | General disorders | Non-systematic Assessment |
|
| trauma | General disorders | Non-systematic Assessment |
|
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| D014633 |
| Valine |
| D000597 | Amino Acids, Branched-Chain |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D000601 | Amino Acids, Essential |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D011480 | Protease Inhibitors |
| D004791 | Enzyme Inhibitors |
| D045504 | Molecular Mechanisms of Pharmacological Action |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |