Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Neurovascular Transduction During Exercise in Chronic Kidney Disease (NeurovEx)

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.
 
ClinicalTrials.gov Identifier: NCT02947750
Recruitment Status : Suspended (Study activities are temporarily suspended due to COVID-19.)
First Posted : October 28, 2016
Last Update Posted : May 21, 2020
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Jeanie Park, Emory University

Brief Summary:
The purpose of this study is to find out why patients with chronic kidney disease (CKD) have poor exercise capacity and to explore what causes an increase in blood pressure during exercise (i.e. increased adrenaline levels, or decreased ability of blood vessels to dilate). This study will also test whether or not regular exercise on a bicycle and/or treatment with 6R-BH4 (Kuvan) pills, or histidine and beta-alanine supplementation improves these measures during exercise. 6R-BH4 is currently FDA-approved for use in patients with certain forms of a disease called phenylketonuria, but it is not currently FDA approved for blood pressure or exercise capacity in people with CKD.

Condition or disease Intervention/treatment Phase
Renal Insufficiency, Chronic Drug: 6R-BH4 Other: 6R-BH4 placebo Dietary Supplement: Folic acid Other: Exercise training Other: Stretching Dietary Supplement: Histidine and beta-alanine supplementation Other: Histidine and beta-alanine placebo Phase 2

Detailed Description:

The major problem addressed in this study is to understand mechanisms underlying poor exercise capacity in patients with chronic kidney disease (CKD). Prior research has found that CKD patients have an exaggerated increase in blood pressure during certain forms of exercise that could contribute to exercise dysfunction as well as cardiovascular disease. This study will test the mechanisms underlying this exaggerated blood pressure response, as well as the potential benefits of simple measures such as exercise training on a stationary bicycle, and treatment with 6R-BH4, a drug that is currently FDA-approved for the treatment of phenylketonuria, but has been shown to have beneficial effects on vascular health in patients with kidney disease. This study will also examine the effects of exercise with histidine and beta-alanine supplementation. Histidine and beta-alanine are two over-the-counter supplements commonly used to enhance sports performance in athletes.

Prior to the intervention portion of this study, the researchers will measure how much the vein constricts in response to adrenaline in CKD patients versus controls. The study will also measure muscle pH, and muscle oxygenation during exercise in CKD patients and controls.

The intervention portion of the study will test whether aerobic exercise training with and without 6R-BH4, or with and without histidine and beta-alanine supplementation might help muscle pH and adrenaline levels, vascular reactivity, muscle oxygenation, and the exaggerated blood pressure response during exercise in CKD patients. Participants will be randomized using a 2x2 factorial design to exercise training (ET) with 6R-BH4, ET with placebo, stretching (control condition to exercise) with 6R-BH4, and stretching with placebo. Participants will undergo exercise training on a stationary bicycle, or stretching exercises, 3 times per week for 6-14 weeks (depending on availability of the participant).

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Single (Participant)
Primary Purpose: Supportive Care
Official Title: Neurovascular Regulation During Exercise in Humans With Chronic Kidney Disease
Actual Study Start Date : October 2016
Estimated Primary Completion Date : November 2021
Estimated Study Completion Date : November 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Exercise training + 6R-BH4
Participants randomized to this arm will exercise on a stationary bicycle for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take the study drug 6R-BH4.
Drug: 6R-BH4
Participants will receive 200 mg of 6R-BH4 twice daily for 12 weeks. Study pills are dissolved in water or apple juice, and taken with food.
Other Names:
  • Tetrahydrobiopterin
  • Kuvan
  • Sapropterin dihydrochloride

Dietary Supplement: Folic acid
Participants will take 1 mg of folic acid daily for 12 weeks. Folic acid is given because it enhances the binding affinity of BH4 to nitric oxide synthase (NOS), and also enhances the regeneration of BH4 from inactive BH2

Other: Exercise training
Participants will exercise 3 times a week on a stationary ergometer. Exercise intensity will begin at low levels (50% of maximal heart rate reserve) calculated utilizing the Karvonen method. Briefly, target exercise heart rate (HR) is calculated by subtracting the persons age from 220. Resting heart rate is then subtracted from this number. The answer is then multiplied by the target percent (50% for example) and the product is added back to resting heart rate to provide the target exercise session heart rate. Intensity will be increased by 5% every week (as tolerated by the participant) to a maximum of 80% of maximal heart rate. Exercise time will progress from an initial 20 minutes per session to a maximum of 45 minutes by increasing 5 minutes each week.

Active Comparator: Exercise training + 6R-BH4 placebo
Participants randomized to this arm will exercise on a stationary bicycle for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take a placebo to match the study drug 6R-BH4.
Other: 6R-BH4 placebo
Participants will receive a placebo that is identical to 200 mg of 6R-BH4. The placebo will be taken twice daily for 12 weeks. Study pills are dissolved in water or apple juice, and taken with food.

Dietary Supplement: Folic acid
Participants will take 1 mg of folic acid daily for 12 weeks. Folic acid is given because it enhances the binding affinity of BH4 to nitric oxide synthase (NOS), and also enhances the regeneration of BH4 from inactive BH2

Other: Exercise training
Participants will exercise 3 times a week on a stationary ergometer. Exercise intensity will begin at low levels (50% of maximal heart rate reserve) calculated utilizing the Karvonen method. Briefly, target exercise heart rate (HR) is calculated by subtracting the persons age from 220. Resting heart rate is then subtracted from this number. The answer is then multiplied by the target percent (50% for example) and the product is added back to resting heart rate to provide the target exercise session heart rate. Intensity will be increased by 5% every week (as tolerated by the participant) to a maximum of 80% of maximal heart rate. Exercise time will progress from an initial 20 minutes per session to a maximum of 45 minutes by increasing 5 minutes each week.

Active Comparator: Stretching + 6R-BH4
Participants randomized to this arm will do muscle stretching and toning for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take the study drug 6R-BH4.
Drug: 6R-BH4
Participants will receive 200 mg of 6R-BH4 twice daily for 12 weeks. Study pills are dissolved in water or apple juice, and taken with food.
Other Names:
  • Tetrahydrobiopterin
  • Kuvan
  • Sapropterin dihydrochloride

Dietary Supplement: Folic acid
Participants will take 1 mg of folic acid daily for 12 weeks. Folic acid is given because it enhances the binding affinity of BH4 to nitric oxide synthase (NOS), and also enhances the regeneration of BH4 from inactive BH2

Other: Stretching
Participants randomized to 'No Exercise Training' group will instead of aerobic exercise, undergo progressive whole body stretching and toning exercises designed for individuals 65 and older. This type of low intensity activity is designed not to increase heart rate and will serve as the Control group to the Exercise Training group. The Control group will come in for stretching sessions 3 times per week for 20-45 minutes.
Other Name: Control for exercise training

Placebo Comparator: Stretching + placebo
Participants randomized to this arm will do muscle stretching and toning for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take a placebo instead of the active study drug.
Other: 6R-BH4 placebo
Participants will receive a placebo that is identical to 200 mg of 6R-BH4. The placebo will be taken twice daily for 12 weeks. Study pills are dissolved in water or apple juice, and taken with food.

Dietary Supplement: Folic acid
Participants will take 1 mg of folic acid daily for 12 weeks. Folic acid is given because it enhances the binding affinity of BH4 to nitric oxide synthase (NOS), and also enhances the regeneration of BH4 from inactive BH2

Other: Stretching
Participants randomized to 'No Exercise Training' group will instead of aerobic exercise, undergo progressive whole body stretching and toning exercises designed for individuals 65 and older. This type of low intensity activity is designed not to increase heart rate and will serve as the Control group to the Exercise Training group. The Control group will come in for stretching sessions 3 times per week for 20-45 minutes.
Other Name: Control for exercise training

Active Comparator: Exercise training + histidine and beta-alanine
Participants randomized to this arm will exercise on a stationary bicycle for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take histidine and beta-alanine supplementation.
Other: Exercise training
Participants will exercise 3 times a week on a stationary ergometer. Exercise intensity will begin at low levels (50% of maximal heart rate reserve) calculated utilizing the Karvonen method. Briefly, target exercise heart rate (HR) is calculated by subtracting the persons age from 220. Resting heart rate is then subtracted from this number. The answer is then multiplied by the target percent (50% for example) and the product is added back to resting heart rate to provide the target exercise session heart rate. Intensity will be increased by 5% every week (as tolerated by the participant) to a maximum of 80% of maximal heart rate. Exercise time will progress from an initial 20 minutes per session to a maximum of 45 minutes by increasing 5 minutes each week.

Dietary Supplement: Histidine and beta-alanine supplementation
Histidine and beta-alanine are two over-the-counter supplements commonly used to enhance sports performance in athletes. Participants randomized to this study arm will receive combined histidine (4g/day) and beta-alanine (3.2g/day) supplementation.

Active Comparator: Exercise training + histidine and beta-alanine placebo
Participants randomized to this arm will exercise on a stationary bicycle for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take a placebo to match the histidine and beta-alanine supplementation.
Other: Exercise training
Participants will exercise 3 times a week on a stationary ergometer. Exercise intensity will begin at low levels (50% of maximal heart rate reserve) calculated utilizing the Karvonen method. Briefly, target exercise heart rate (HR) is calculated by subtracting the persons age from 220. Resting heart rate is then subtracted from this number. The answer is then multiplied by the target percent (50% for example) and the product is added back to resting heart rate to provide the target exercise session heart rate. Intensity will be increased by 5% every week (as tolerated by the participant) to a maximum of 80% of maximal heart rate. Exercise time will progress from an initial 20 minutes per session to a maximum of 45 minutes by increasing 5 minutes each week.

Other: Histidine and beta-alanine placebo
Participants randomized to this study arm will receive a placebo to match combined histidine (4g/day) and beta-alanine (3.2g/day) supplementation.




Primary Outcome Measures :
  1. Change in functional sympatholysis [ Time Frame: Baseline, Week 12 ]
    Muscle oxygenation during exercise and sympathoexcitation will be measured.

  2. Change in vascular alpha 1 adrenergic responsiveness [ Time Frame: Baseline, Week 12 ]
    Changes in vascular diameter in response to phenylephrine will be measured.

  3. Change in exaggerated pressor responses during exercise [ Time Frame: Baseline, Week 12 ]
    Blood pressure and sympathetic responses during exercise will be measured.


Secondary Outcome Measures :
  1. Renal artery resistance during exercise [ Time Frame: Baseline, Week 12 ]
    Renal artery blood flow will be measured.

  2. Change in endothelial function [ Time Frame: Baseline, Week 12 ]
    Endothelial function using peripheral arterial tonometry will be measured.

  3. Change in vascular stiffness [ Time Frame: Baseline, Week 12 ]
    Vascular stiffness using applanation tonometry.



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.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria for Chronic Kidney Disease Patients:

  • Stage III or IV Chronic Kidney Disease, defined as reduction in estimated glomerular filtration rate (eGFR) to 15-59 cc/minute as calculated by the modified Modification of Diet in Renal Disease (MDRD) Study equation or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
  • Stable renal function, with no greater than a 30% reduction in eGFR over the prior 3 months
  • Does not exercise regularly (defined as exercising less than 20 minutes twice per week)
  • Willing and able to cooperate with the study protocol

Inclusion Criteria for Control Study Participants:

  • Does not exercise regularly (defined as exercising less than 20 minutes twice per week)
  • Willing and able to cooperate with the study protocol

Exclusion Criteria:

  • severe CKD (eGFR<15 cc/minute)
  • ongoing drug or alcohol abuse
  • diabetic neuropathy
  • any serious systemic disease that might influence survival
  • severe anemia with hgb level <9 g/dL
  • clinical evidence of congestive heart failure or ejection fraction below 35%
  • symptomatic heart disease determined by prior electrocardiogram, stress test, and/or history
  • treatment with central alpha agonists (clonidine)
  • uncontrolled hypertension with BP greater than 170/100 mm Hg
  • low blood pressure with BP less than 100/50
  • pregnancy or plans to become pregnant
  • current treatment with monoamine oxidase (MAO) inhibitors
  • inability to exercise on a stationary bicycle

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): NCT02947750


Locations
Layout table for location information
United States, Georgia
Emory University Hospital Midtown
Atlanta, Georgia, United States, 30308
Emory University Hospital
Atlanta, Georgia, United States, 30322
Atlanta VA Health Care System
Decatur, Georgia, United States, 30033
Sponsors and Collaborators
Emory University
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Layout table for investigator information
Principal Investigator: Joe Nocera, PhD Emory University
Layout table for additonal information
Responsible Party: Jeanie Park, Assistant Professor, Emory University
ClinicalTrials.gov Identifier: NCT02947750    
Other Study ID Numbers: IRB00091660
R01HL135183 ( U.S. NIH Grant/Contract )
First Posted: October 28, 2016    Key Record Dates
Last Update Posted: May 21, 2020
Last Verified: May 2020

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Jeanie Park, Emory University:
Hypertension
Kidney Disorder
Nephrology
Physiology
Additional relevant MeSH terms:
Layout table for MeSH terms
Kidney Diseases
Renal Insufficiency, Chronic
Renal Insufficiency
Urologic Diseases
Folic Acid
Hematinics
Vitamin B Complex
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs