Study of Inflammation and Oxidative Stress in Persons Undergoing Dialysis

• Sponsor: Vanderbilt University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00732069
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 19
• Location: 1
• Arms: 6
• Duration (Months): 40
• Patients Per Site Per Month: 0.5

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
End Stage Renal Failure on Dialysis; Complication of Hemodialysis	Drug: Placebo; Drug: Ramipril; Drug: Valsartan	Phase 2

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• 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
• Study Start Date: Aug 1, 2008
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: Valsartan 80mg/d for 2 days followed by 160mg/d for 5 days.

Outcome Measures

Primary Outcome Measures

1. Interleukin 1 Beta [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

1. F2-Isoprostanes [During dialysis after one week of study drug]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Nancy J. Brown, Professor, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT00732069
• Other Study ID Numbers: Fibrinolysis in Dialysis; R01HL065193-08A2
• First Posted: Aug 11, 2008
• Last Update Posted: Jul 2, 2013
• Last Verified: Jun 1, 2013

• Keywords provided by Nancy J. Brown, Professor, Vanderbilt University: hemodialysis; oxidative stress; inflammation; kallikrein-kinin; angiotensin receptor blockade; angiotensin converting enzyme inhibition; RAAS; fibrinolysis; endothelial dysfunction
• Additional relevant MeSH terms: Kidney Failure, Chronic; Valsartan; Ramipril

Study Results

Participant Flow

Recruitment Details	Recruitment started in September 2008 and ended in January 2010 in Vanderbilt outpatients Dialysis Center.
Pre-assignment Detail	Three consented participants were excluded because of hyperkalemia, hypotension and uncontrollable hypertension.They were enrolled but did not start medication and were considered screen failures. The participants required a washout period from either an agiotensin receptor blocker or an angiotensin converting enzyme inhibitor.

Arm/Group Title	Placebo, Then Ramipril, Then Valsartan	Placebo, Valsartan, Then Ramipril	Ramipril, Then Placebo, Then Valsartan	Valsartan, Then Placebo, Then Ramipril	Ramipril, Valsartan, Then Placebo	Valsartan, Ramipril, Then Placebo
Arm/Group Description	Participants were randomized to treatment with ramipril, valsartan and placebo in one of six possible sequences.	Participants were randomized to treatment with ramipril, valsartan and placebo in one of six possible sequences.	Participants were randomized to treatment with ramipril, valsartan and placebo in one of six possible sequences.	Participants were randomized to treatment with ramipril, valsartan and placebo in one of six possible sequences.	Participants were randomized to treatment with ramipril, valsartan and placebo in one of six possible sequences.	Participants were randomized to treatment with ramipril, valsartan and placebo in one of six possible sequences.
Period Title: First Study Drug
STARTED	3	3	3	2	3	2
COMPLETED	3	3	3	2	3	2
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Study Drug
STARTED	3	3	3	2	3	2
COMPLETED	2	3	3	2	3	2
NOT COMPLETED	1	0	0	0	0	0
Period Title: First Study Drug
STARTED	2	3	3	2	3	2
COMPLETED	2	3	3	2	3	2
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Study Drug
STARTED	2	3	3	2	3	2
COMPLETED	2	3	3	2	3	2
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Study Drug
STARTED	2	3	3	2	3	2
COMPLETED	2	3	3	2	3	2
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	After a three week washout period, the subject will be undertake 3 study periods with one of three treatments, placebo, ramipril or valsartan
Overall Participants	16
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	13 81.3%
>=65 years	3 18.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.5 (3.1)
Sex: Female, Male (Count of Participants)
Female	8 50%
Male	8 50%
Region of Enrollment (participants) [Number]
United States	16 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants who completed the three arm treatment.

Arm/Group Title	Ramipril	Valsartan	Placebo
Arm/Group Description	After a three week washout period, the subject will be undertake 3 study periods with one of three treatments, placebo, ramipril or valsartan	After a three week washout period, the subject will be undertake 3 study periods with one of three treatments, placebo, ramipril or valsartan	After a three week washout period, the subject will be undertake 3 study periods with one of three treatments, placebo, ramipril or valsartan
Measure Participants	15	15	15
Mean (Standard Error) [pg/mL]	6.18 (3.56)	2.16 (2.16)	1.44 (1.49)

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ramipril	Valsartan	Placebo
Arm/Group Description	After a three week washout period, the subject will be undertake 3 study periods with one of three treatments, placebo, ramipril or valsartan	After a three week washout period, the subject will be undertake 3 study periods with one of three treatments, placebo, ramipril or valsartan	After a three week washout period, the subject will be undertake 3 study periods with one of three treatments, placebo, ramipril or valsartan
Measure Participants	15	15	15
Mean (Standard Error) [pg/mL]	59.55 (27.53)	59.03 (29.39)	50.23 (22.59)

Adverse Events

Time Frame	2 years
Arm/Group Title	Ramipril		Valsartan		Placebo
Arm/Group Description	All subjects receiving ramipril		All subjects receiving valsartan		All subjects receiving placebo
All Cause Mortality
	Ramipril		Valsartan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ramipril		Valsartan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)		1/16 (6.3%)
Nervous system disorders
Cerebrovascular ischemia	0/15 (0%)	0	0/15 (0%)	0	1/16 (6.3%)	1
Other (Not Including Serious) Adverse Events
	Ramipril		Valsartan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/15 (6.7%)		4/15 (26.7%)		7/15 (46.7%)
Cardiac disorders
Hypotension	1/15 (6.7%)	1	1/15 (6.7%)	1	1/15 (6.7%)	1
Pericarditis	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
Gastrointestinal disorders
Nausea	0/15 (0%)	0	2/15 (13.3%)	2	0/15 (0%)	0
Metabolism and nutrition disorders
Hyperkalemia	0/15 (0%)	0	1/15 (6.7%)	1	1/15 (6.7%)	1
Musculoskeletal and connective tissue disorders
Chest pain not cardiac	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
Respiratory, thoracic and mediastinal disorders
Dry cough	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders
Bruising after falling	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
Vascular disorders
Vascular acces complication	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.