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Exercise Intolerance in Renal Failure (EIRF)

Primary Purpose

Kidney Failure, Chronic

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Tetrahydrobiopterin
Placebo
Folate
Sponsored by
Emory University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Kidney Failure, Chronic

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • chronic kidney disease (CKD) stages I, II, and III and do not regularly exercise

    1. CKD Stages I, II, and III will be defined as reduction in estimated glomerular filtration rate (eGFR) to 30-59 cc/minute as calculated by the Modification of Diet in Renal Disease (MDRD) equation, or an eGFR>60 cc/minute with proteinuria greater than 500 mg/g of Creatinine or 500 mg per 24 hours.

  • willing and able to cooperate with the protocol
  • CKD patients must have stable renal function (no greater than a 20% reduction in eGFR over the prior 3 months)
  • controls will be matched for age, gender, race, and hypertensive status.

Exclusion Criteria:

  • severe CKD (eGFR<30 cc/minute)
  • drug or alcohol abuse
  • diabetes
  • any serious systemic disease that might influence survival
  • severe anemia with hgb level <10 g/dL
  • clinical evidence of congestive heart failure or ejection fraction below 35%
  • any history of past myocardial infarction or cerebrovascular accident
  • symptomatic heart disease determined by electrocardiogram, stress test, and/or history
  • treatment with central alpha agonists
  • uncontrolled hypertension with BP greater than 160/90 mm Hg
  • low blood pressure with BP less than 110/60
  • history of nephrolithiasis
  • pregnancy or plans to become pregnant
  • treatment with vitamin C within the past 3 months
  • hepatic enzyme concentrations greater than 2 times the upper limit of normal
  • HIV infection
  • surgery within the past 3 months
  • previous treatment with BH4
  • known hypersensitivity to BH4
  • any condition that places the participant at high risk of poor adherence or poor follow-up
  • patients must be willing to use an acceptable method of contraception if of childbearing age

Sites / Locations

  • Emory University Hospital
  • Atlanta VA Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Tetrahydrobiopterin + Folate

Placebo + Folate

Arm Description

Male subjects with hypertension and chronic kidney disease stage 2 or 3 will receive Tetrahydrobiopterin (6R-BH4) 200 mg twice daily and folic acid 1 mg daily

Male subjects with hypertension and chronic kidney disease stage 2 or 3 will receive 2 placebo pills twice daily and folic acid 1 mg daily

Outcomes

Primary Outcome Measures

Change in Resting Muscle Sympathetic Nerve Activity (MSNA)

Secondary Outcome Measures

Change in Mean Central Augmentation Index (AIx)
The augmentation index (AIx) is a measure of systemic arterial stiffness, and is defined as the ratio of augmentation (Δ P) to central pulse pressure and expressed as percent. AIx = (ΔP/PP) x 100, where P = pressure and PP = Pulse Pressure. The mean AIx for each group was estimated as an average and expressed as a change from baseline to 12 weeks.
Change in Heart-rate-corrected Augmentation Index (AIx)
The augmentation index (AIx) is a measure of systemic arterial stiffness, and is defined as the ratio of augmented aortic pressure (Δ P) to central pulse pressure expressed as a percent. AIx = (ΔP/PP) x 100, where P = pressure and PP = Pulse Pressure. Because heart rate (HR) affects AIx, AIx was corrected to a HR of 75 beats per minute (bpm) as follows: HR-corrected AIx = -0.39 x (75 - HR) + AIx. The mean AIx for each group was estimated as an average and expressed as a change from baseline to 12 weeks.

Full Information

First Posted
May 18, 2011
Last Updated
May 29, 2015
Sponsor
Emory University
Collaborators
National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT01356966
Brief Title
Exercise Intolerance in Renal Failure
Acronym
EIRF
Official Title
The Role of Neurovascular Dysfunction and Oxidative Stress in the Exercise Intolerance of Renal Failure
Study Type
Interventional

2. Study Status

Record Verification Date
May 2015
Overall Recruitment Status
Completed
Study Start Date
May 2011 (undefined)
Primary Completion Date
May 2014 (Actual)
Study Completion Date
May 2014 (Actual)

3. Sponsor/Collaborators

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

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Patients with chronic kidney disease have profound exercise intolerance which contributes to an increased risk of cardiovascular disease. The investigators have found that chronic kidney disease patients have an exaggerated increase in blood pressure during certain forms of exercise that could certainly contribute to exercise dysfunction as well as cardiovascular risk. The investigators will test the mechanisms underlying this exaggerated blood pressure response, as well as the potential benefits of short-term tetrahydrobiopterin (BH4) with folic acid on both exercise dysfunction and cardiovascular risk factors in chronic kidney disease. The investigators will test whether short-term treatment with tetrahydrobiopterin (BH4), a cofactor for nitric oxide, together with folic acid improves inflammation, vascular health, and adrenaline levels, both at rest and during exercise in chronic kidney disease.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Kidney Failure, Chronic

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Tetrahydrobiopterin + Folate
Arm Type
Experimental
Arm Description
Male subjects with hypertension and chronic kidney disease stage 2 or 3 will receive Tetrahydrobiopterin (6R-BH4) 200 mg twice daily and folic acid 1 mg daily
Arm Title
Placebo + Folate
Arm Type
Placebo Comparator
Arm Description
Male subjects with hypertension and chronic kidney disease stage 2 or 3 will receive 2 placebo pills twice daily and folic acid 1 mg daily
Intervention Type
Drug
Intervention Name(s)
Tetrahydrobiopterin
Other Intervention Name(s)
Kuvan
Intervention Description
Tetrahydrobiopterin (BH4) 200 mg PO BID for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
2 placebo pills PO BID for12 weeks
Intervention Type
Dietary Supplement
Intervention Name(s)
Folate
Other Intervention Name(s)
Folic Acid
Intervention Description
Folate 1 mg daily for 12 weeks
Primary Outcome Measure Information:
Title
Change in Resting Muscle Sympathetic Nerve Activity (MSNA)
Time Frame
Baseline, 12 weeks
Secondary Outcome Measure Information:
Title
Change in Mean Central Augmentation Index (AIx)
Description
The augmentation index (AIx) is a measure of systemic arterial stiffness, and is defined as the ratio of augmentation (Δ P) to central pulse pressure and expressed as percent. AIx = (ΔP/PP) x 100, where P = pressure and PP = Pulse Pressure. The mean AIx for each group was estimated as an average and expressed as a change from baseline to 12 weeks.
Time Frame
Baseline, 12 weeks
Title
Change in Heart-rate-corrected Augmentation Index (AIx)
Description
The augmentation index (AIx) is a measure of systemic arterial stiffness, and is defined as the ratio of augmented aortic pressure (Δ P) to central pulse pressure expressed as a percent. AIx = (ΔP/PP) x 100, where P = pressure and PP = Pulse Pressure. Because heart rate (HR) affects AIx, AIx was corrected to a HR of 75 beats per minute (bpm) as follows: HR-corrected AIx = -0.39 x (75 - HR) + AIx. The mean AIx for each group was estimated as an average and expressed as a change from baseline to 12 weeks.
Time Frame
Baseline, 12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: chronic kidney disease (CKD) stages I, II, and III and do not regularly exercise 1. CKD Stages I, II, and III will be defined as reduction in estimated glomerular filtration rate (eGFR) to 30-59 cc/minute as calculated by the Modification of Diet in Renal Disease (MDRD) equation, or an eGFR>60 cc/minute with proteinuria greater than 500 mg/g of Creatinine or 500 mg per 24 hours. willing and able to cooperate with the protocol CKD patients must have stable renal function (no greater than a 20% reduction in eGFR over the prior 3 months) controls will be matched for age, gender, race, and hypertensive status. Exclusion Criteria: severe CKD (eGFR<30 cc/minute) drug or alcohol abuse diabetes any serious systemic disease that might influence survival severe anemia with hgb level <10 g/dL clinical evidence of congestive heart failure or ejection fraction below 35% any history of past myocardial infarction or cerebrovascular accident symptomatic heart disease determined by electrocardiogram, stress test, and/or history treatment with central alpha agonists uncontrolled hypertension with BP greater than 160/90 mm Hg low blood pressure with BP less than 110/60 history of nephrolithiasis pregnancy or plans to become pregnant treatment with vitamin C within the past 3 months hepatic enzyme concentrations greater than 2 times the upper limit of normal HIV infection surgery within the past 3 months previous treatment with BH4 known hypersensitivity to BH4 any condition that places the participant at high risk of poor adherence or poor follow-up patients must be willing to use an acceptable method of contraception if of childbearing age
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeanie Park, MD
Organizational Affiliation
Emory University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Emory University Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Atlanta VA Medical Center
City
Decatur
State/Province
Georgia
ZIP/Postal Code
30033
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
26962106
Citation
Lin AM, Liao P, Millson EC, Quyyumi AA, Park J. Tetrahydrobiopterin ameliorates the exaggerated exercise pressor response in patients with chronic kidney disease: a randomized controlled trial. Am J Physiol Renal Physiol. 2016 May 1;310(10):F1016-25. doi: 10.1152/ajprenal.00527.2015. Epub 2016 Mar 9.
Results Reference
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Exercise Intolerance in Renal Failure

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