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Study of Inflammation and Oxidative Stress in Persons Undergoing Dialysis

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00732069
First Posted: August 11, 2008
Last Update Posted: July 2, 2013
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Nancy J. Brown, Vanderbilt University
  Purpose
Little is known about how some drugs affect inflammation or clotting factors in people receiving hemodialysis. It is not yet known if these drugs help prevent heart damage as they do in people not undergoing hemodialysis or whether they could increase the risk of heart problems. The purpose of the study is to measure certain chemicals in the blood and see how those chemicals may change during hemodialysis when certain drugs are given.

Condition Intervention Phase
End Stage Renal Failure on Dialysis Complication of Hemodialysis Drug: Placebo Drug: Ramipril Drug: Valsartan Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Genes, Fibrinolysis and Endothelial Dysfunction- Dialysis Aim 2

Resource links provided by NLM:


Further study details as provided by Nancy J. Brown, Vanderbilt University:

Primary Outcome Measures:
  • Interleukin 1 Beta [ Time Frame: During dialysis after one week of study drug ]
    Mean difference in interleukin 1 beta concentration during treatment with ramipril versus treatment with placebo


Secondary Outcome Measures:
  • F2-Isoprostanes [ Time Frame: During dialysis after one week of study drug ]
    Mean difference in F2-isoprostanes during dialysis between treatment with ramipril or valsartan and placebo


Enrollment: 19
Study Start Date: August 2008
Study Completion Date: December 2011
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Placebo, then ramipril, then valsartan
placebo, ramipril, valsartan: Subjects were treated sequentially with placebo, ramipril (5mg/day by mouth), then valsartan (160mg/day by mouth). Each drug was given for 7 days after a 3-week washout.
Drug: Placebo
Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis
Other Name: matching placebo
Drug: Ramipril
Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis
Other Name: Ramipril 2.5mg/d for two days, then 5mg/d for 5 days.
Drug: Valsartan
Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis
Other Name: Valsartan 80mg/d for 2 days followed by 160mg/d for 5 days.
Active Comparator: Placebo, then valsartan, then ramipril
placebo, ramipril, valsartan: Subjects were treated sequentially with placebo, valsartan (160mg/day by mouth), then ramipril (5mg/day by mouth). Each drug was given for 7 days after a 3-week washout.
Drug: Placebo
Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis
Other Name: matching placebo
Drug: Ramipril
Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis
Other Name: Ramipril 2.5mg/d for two days, then 5mg/d for 5 days.
Drug: Valsartan
Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis
Other Name: Valsartan 80mg/d for 2 days followed by 160mg/d for 5 days.
Active Comparator: Ramipril, then placebo, then valsartan
placebo, ramipril, valsartan: Subjects were treated sequentially with ramipril (5mg/day by mouth), then placebo (once a day by mouth), then valsartan (160mg/day by mouth). Each drug was given for 7 days after a 3-week washout.
Drug: Placebo
Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis
Other Name: matching placebo
Drug: Ramipril
Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis
Other Name: Ramipril 2.5mg/d for two days, then 5mg/d for 5 days.
Drug: Valsartan
Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis
Other Name: Valsartan 80mg/d for 2 days followed by 160mg/d for 5 days.
Active Comparator: Valsartan, then placebo, then ramipril
placebo, ramipril, valsartan: Subjects were treated sequentially with valsartan (160mg/day by mouth), then placebo (once a day by mouth), then ramipril (5mg/day by mouth). Each drug was given for 7 days after a 3-week washout.
Drug: Placebo
Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis
Other Name: matching placebo
Drug: Ramipril
Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis
Other Name: Ramipril 2.5mg/d for two days, then 5mg/d for 5 days.
Drug: Valsartan
Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis
Other Name: Valsartan 80mg/d for 2 days followed by 160mg/d for 5 days.
Active Comparator: Ramipril, then valsartan, then placebo
placebo, ramipril, valsartan: Subjects were treated sequentially with ramipril (5mg/day by mouth), then valsartan (160mg/day by mouth), then placebo (once a day by mouth). Each drug was given for 7 days after a 3-week washout.
Drug: Placebo
Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis
Other Name: matching placebo
Drug: Ramipril
Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis
Other Name: Ramipril 2.5mg/d for two days, then 5mg/d for 5 days.
Drug: Valsartan
Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis
Other Name: Valsartan 80mg/d for 2 days followed by 160mg/d for 5 days.
Active Comparator: Valsartan, then ramipril, then placebo
placebo, ramipril, valsartan: Subjects were treated sequentially with then valsartan (160mg/day by mouth), then ramipril (5mg/day by mouth), then placebo (once a day by mouth). Each drug was given for 7 days after a 3-week washout.
Drug: Placebo
Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis
Other Name: matching placebo
Drug: Ramipril
Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis
Other Name: Ramipril 2.5mg/d for two days, then 5mg/d for 5 days.
Drug: Valsartan
Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis
Other Name: Valsartan 80mg/d for 2 days followed by 160mg/d for 5 days.

Detailed Description:
  • Cardiovascular disease in the leading cause of death in patients with chronic kidney disease undergoing hemodialysis.
  • Traditional risk factors do not adequately predict cardiovascular morbidity and mortality in patients with chronic kidney disease.
  • Increased oxidative stress, inflammation and impaired fibrinolysis contribute to cardiovascular risk in chronic kidney disease patients undergoing hemodialysis.
  • Activation of the renin-angiotensin-aldosterone system(RAAS) may contribute to oxidative stress and inflammation in individuals with chronic kidney disease
  • Activation of the kallikrein-kinin system during hemodialysis may increase fibrinolysis but may also contribute to inflammation in chronic kidney disease
  • Despite data from clinical trials demonstrating that ARBs and ACE inhibitors decrease cardiovascular mortality, delay progression to cardiovascular disease and decrease the incidence of diabetes in the general population little is known about the impact of these agents on cardiovascular morbidity and mortality in patients with end- stage renal disease (ESRD) undergoing hemodialysis
  • Angiotensin-converting enzyme(ACE) inhibitors and angiotensin receptor blockers (ARB)S differ in their mechanisms of action and their effects on inflammatory biomarkers
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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) thrice weekly, with polysulphone membrane for at least 3 consecutive months prior to study

Exclusion Criteria:

  • Body mass index > 35 mg/kg
  • History of functional transplant less than 6 months prior to study
  • Use of anti-inflammatory medications other than aspirin < 325 mg/d
  • 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
  • Advanced liver disease
  • Gastrointestinal dysfunction requiring parental nutrition
  • Active malignancy excluding basal cell carcinoma of the skin
  • History of ACE inhibitor-associated cough or angioedema
  • Ejection fraction less than 40%
  • Inability to discontinue ACE inhibitor or ARB
  • Predialysis potassium repeatedly higher than 5.5 mmol/L (confirmed on a repeated blood draw)
  • Anticipated live donor kidney transplant
  • Use of vitamin E >60 IU/d or vitamin C >500 mg/d
  • Pregnancy, breast-feeding or child-bearing potential
  • History of poor adherence to hemodialysis or medical regimen
  • Inability to provide consent
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00732069


Locations
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37323
Sponsors and Collaborators
Vanderbilt University
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Nancy J Brown, MD Vanderbilt University Medical Center
  More Information

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Nancy J. Brown, Professor, Vanderbilt University
ClinicalTrials.gov Identifier: NCT00732069     History of Changes
Other Study ID Numbers: Fibrinolysis in Dialysis
R01HL065193-08A2 ( U.S. NIH Grant/Contract )
First Submitted: August 6, 2008
First Posted: August 11, 2008
Results First Submitted: July 18, 2012
Results First Posted: June 20, 2013
Last Update Posted: July 2, 2013
Last Verified: June 2013

Keywords provided by Nancy J. Brown, Vanderbilt University:
hemodialysis
oxidative stress
inflammation
kallikrein-kinin
angiotensin receptor blockade
angiotensin converting enzyme inhibition
RAAS
fibrinolysis
endothelial dysfunction

Additional relevant MeSH terms:
Renal Insufficiency
Kidney Failure, Chronic
Kidney Diseases
Urologic Diseases
Renal Insufficiency, Chronic
Valsartan
Ramipril
Angiotensin Receptor Antagonists
Angiotensin-Converting Enzyme Inhibitors
Enzyme Inhibitors
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Molecular Mechanisms of Pharmacological Action
Protease Inhibitors