Oxidative StressPhase 3NCT00878969
Genes, Fibrinolysis and Endothelial Dysfunction- Dialysis Aim 3
A Phase 3 study testing valsartan (ARB) and ramipril (ACE inhibitor) in people with Oxidative Stress and Endothelial Dysfunction, run by Vanderbilt University at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Oxidative Stress, Endothelial Dysfunction
- What is being tested?
- valsartan (ARB) and ramipril (ACE inhibitor)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 78 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2010to Jun 2015
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Age 18 years or older
- On thrice weekly chronic hemodialysis for at least 6 months
- Clinically stable, adequately dialyzed [single-pool Kt/V > 1.2 or Urea Reduction Ratio (URR) > 65%] thrice weekly, with polysulphone membrane for at least 3 consecutive months prior to study
Who cannot join
- History of functional transplant less than 6 months prior to study
- Use of immunosuppressive drugs within 1 month prior to study
- History of active connective tissue disease
- History of acute infectious disease within one month prior to study
- AIDS (HIV seropositivity is not an exclusion criteria)
- History of myocardial infarction or cerebrovascular event within 3 months
Show all 17Show fewer
- Advanced liver disease
- Gastrointestinal dysfunction requiring parental nutrition
- Active malignancy excluding basal cell carcinoma of the skin
- History of ACE inhibitor-associated cough (intolerable) or angioedema
- Ejection fraction less than 30%
- Inability to discontinue ACE inhibitor or ARB
- Predialysis potassium repeatedly higher than 6.0 mmol/L (confirmed on a repeated blood draw)
- Anticipated live donor kidney transplant
- Pregnancy or breast-feeding
- History of poor adherence to hemodialysis or medical regimen
- Inability to provide consent
Trial locations and contacts
1 site in 1 country.
United States1 site
Vanderbilt University Medical Center
Nashville, Tennessee, 37232
About this study
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.
Read the detailed description
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.
- Conditions
- Oxidative Stress, Endothelial Dysfunction
- Being tested
- valsartan (ARB), ramipril (ACE inhibitor), Placebo
- Keywords
- Hemodialysis, fibrinolysis, oxidative stress, systemic inflammatory reaction, endothelial dysfunction, carotid intima media thickness (IMT, angiotensin receptor blockade, angiotensin converting enzyme inhibition
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
valsartan (ARB)Drug
Also called Diovan
ramipril (ACE inhibitor)Drug
Also called Altace
PlaceboDrug
Also called Inactive pill
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: Drug: valsartan (ARB) |
| 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 Receives: Drug: ramipril (ACE inhibitor) |
| 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 Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: baseline and 18 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Apr 2009 (estimated)
- Study startJan 2010
- Primary completionJun 2015
- Study completionJun 2015
Why it stopped: insufficient enrollment and retention
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Oxidative StressStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Health services research
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 78 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vanderbilt University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Alp Ikizler, Vanderbilt University
- Investigators
- Nancy J Brown, MD, Principal investigator, Vanderbilt University Medical CenterTalat A Ikilzer, MD, Principal investigator, Vanderbilt University Medical CenterJonathan Himmelfarb, MD, Principal investigator, University of Washington
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00878969
- Sponsor's protocol ID
- Fibrinolysis in Dialysis Aim 3
- Other IDs
- R01HL065193-08A2
- Status last verified
- Jan 2016
- First submitted
- 8 Apr 2009
- Last updated
- 15 Feb 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 15 Feb 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Genes, Fibrinolysis and Endothelial Dysfunction- Dialysis Aim 3
- ClinicalTrials.gov ID
- NCT00878969
- Acronym / sponsor ID
- Fibrinolysis in Dialysis Aim 3
- Conditions
- Oxidative Stress, Endothelial Dysfunction
- Keywords
- Hemodialysis, fibrinolysis, oxidative stress, systemic inflammatory reaction, endothelial dysfunction, carotid intima media thickness (IMT, angiotensin receptor blockade, angiotensin converting enzyme inhibition
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: insufficient enrollment and retention
- Enrolment
- 78 participants (actual)
- Lead sponsor
- Vanderbilt UniversityUniversity, hospital or other
- Collaborators
- University of Washington, National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- Jan 2010
- Primary completion
- Jun 2015 (actual)
- Study completion
- Jun 2015 (actual)
- First posted
- 9 Apr 2009 (estimated)
- Results
- Posted 15 Feb 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Health services research
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Valsartan | Active comparator | Drug: valsartan (ARB)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 | Drug: ramipril (ACE inhibitor)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 | Drug: Placebomatching placebo taken orally on a daily basis for 1 week followed by matching placebo taken orally on a daily basis for 18 months |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Age 18 years or older
- On thrice weekly chronic hemodialysis for at least 6 months
- Clinically stable, adequately dialyzed [single-pool Kt/V > 1.2 or Urea Reduction Ratio (URR) > 65%] thrice weekly, with polysulphone membrane for at least 3 consecutive months prior to study
Key exclusion criteria (17 listed)
- History of functional transplant less than 6 months prior to study
- Use of immunosuppressive drugs within 1 month prior to study
- History of active connective tissue disease
- History of acute infectious disease within one month prior to study
- AIDS (HIV seropositivity is not an exclusion criteria)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| valsartan (ARB)Also: Diovan | Drug | Valsartan |
| ramipril (ACE inhibitor)Also: Altace | Drug | Ramipril |
| PlaceboAlso: Inactive pill | Drug | Placebo |
Primary outcome
Interleukin-6 (IL-6)
Time frame: baseline and 18 months
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Feb 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nancy J Brown, MD principal investigator
Vanderbilt University Medical Center
Talat A Ikilzer, MD principal investigator
Vanderbilt University Medical Center
Jonathan Himmelfarb, MD principal investigator
University of Washington
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing valsartan (ARB) and ramipril (ACE inhibitor) in people with Oxidative Stress and Endothelial Dysfunction, run by Vanderbilt University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 15 Feb 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 15 Feb 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Interleukin-6 (IL-6) (time frame: baseline and 18 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Feb 2016.