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Study of Inflammation and Oxidative Stress in Persons Undergoing Dialysis

Primary Purpose

End Stage Renal Failure on Dialysis, Complication of Hemodialysis

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Placebo
Ramipril
Valsartan
Sponsored by
Vanderbilt University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for End Stage Renal Failure on Dialysis focused on measuring hemodialysis, oxidative stress, inflammation, kallikrein-kinin, angiotensin receptor blockade, angiotensin converting enzyme inhibition, RAAS, fibrinolysis, endothelial dysfunction

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Vanderbilt University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Arm Label

Placebo, then ramipril, then valsartan

Placebo, then valsartan, then ramipril

Ramipril, then placebo, then valsartan

Valsartan, then placebo, then ramipril

Ramipril, then valsartan, then placebo

Valsartan, then ramipril, then placebo

Arm Description

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.

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.

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

Interleukin 1 Beta
Mean difference in interleukin 1 beta concentration during treatment with ramipril versus treatment with placebo

Secondary Outcome Measures

F2-Isoprostanes
Mean difference in F2-isoprostanes during dialysis between treatment with ramipril or valsartan and placebo

Full Information

First Posted
August 6, 2008
Last Updated
June 22, 2013
Sponsor
Vanderbilt University
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT00732069
Brief Title
Study of Inflammation and Oxidative Stress in Persons Undergoing Dialysis
Official Title
Genes, Fibrinolysis and Endothelial Dysfunction- Dialysis Aim 2
Study Type
Interventional

2. Study Status

Record Verification Date
June 2013
Overall Recruitment Status
Completed
Study Start Date
August 2008 (undefined)
Primary Completion Date
December 2011 (Actual)
Study Completion Date
December 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt University
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
End Stage Renal Failure on Dialysis, Complication of Hemodialysis
Keywords
hemodialysis, oxidative stress, inflammation, kallikrein-kinin, angiotensin receptor blockade, angiotensin converting enzyme inhibition, RAAS, fibrinolysis, endothelial dysfunction

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
19 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo, then ramipril, then valsartan
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Placebo, then valsartan, then ramipril
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Ramipril, then placebo, then valsartan
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Valsartan, then placebo, then ramipril
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Ramipril, then valsartan, then placebo
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Valsartan, then ramipril, then placebo
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
matching placebo
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Ramipril
Other Intervention Name(s)
Ramipril 2.5mg/d for two days, then 5mg/d for 5 days.
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Valsartan
Other Intervention Name(s)
Valsartan 80mg/d for 2 days followed by 160mg/d for 5 days.
Intervention Description
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
Primary Outcome Measure Information:
Title
Interleukin 1 Beta
Description
Mean difference in interleukin 1 beta concentration during treatment with ramipril versus treatment with placebo
Time Frame
During dialysis after one week of study drug
Secondary Outcome Measure Information:
Title
F2-Isoprostanes
Description
Mean difference in F2-isoprostanes during dialysis between treatment with ramipril or valsartan and placebo
Time Frame
During dialysis after one week of study drug

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nancy J Brown, MD
Organizational Affiliation
Vanderbilt University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37323
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
22158433
Citation
Gamboa JL, Pretorius M, Todd-Tzanetos DR, Luther JM, Yu C, Ikizler TA, Brown NJ. Comparative effects of angiotensin-converting enzyme inhibition and angiotensin-receptor blockade on inflammation during hemodialysis. J Am Soc Nephrol. 2012 Feb;23(2):334-42. doi: 10.1681/ASN.2011030287. Epub 2011 Dec 8.
Results Reference
result
PubMed Identifier
26494370
Citation
Gamboa JL, Pretorius M, Sprinkel KC, Brown NJ, Ikizler TA. Angiotensin converting enzyme inhibition increases ADMA concentration in patients on maintenance hemodialysis--a randomized cross-over study. BMC Nephrol. 2015 Oct 22;16:167. doi: 10.1186/s12882-015-0162-x.
Results Reference
derived

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Study of Inflammation and Oxidative Stress in Persons Undergoing Dialysis

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