Neurovascular Transduction During Exercise in Chronic Kidney Disease

NCT02947750 | Recruiting Phase 2 FDA Drug

• 2 other identifiers: IRB00091660R01HL135183
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 3

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.

Conditions

Renal Insufficiency, Chronic

Keywords

Hypertension; Kidney Disorder; Nephrology; Physiology

Outcome Measures

Primary Outcomes (3)

• Change in functional sympatholysis

  Muscle oxygenation during exercise and sympathoexcitation will be measured.

  Baseline, Week 12

• Change in vascular alpha 1 adrenergic responsiveness

  Changes in vascular diameter in response to phenylephrine will be measured.

  Baseline, Week 12

• Change in exaggerated pressor responses during exercise

  Blood pressure and sympathetic responses during exercise will be measured.

  Baseline, Week 12

Secondary Outcomes (3)

• Renal artery resistance during exercise

  Baseline, Week 12

• Change in endothelial function

  Baseline, Week 12

• Change in vascular stiffness

  Baseline, Week 12

Study Arms (6)

Exercise training + 6R-BH4

EXPERIMENTAL

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; Dietary Supplement: Folic acid; Other: Exercise training

Exercise training + 6R-BH4 placebo

ACTIVE COMPARATOR

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; Dietary Supplement: Folic acid; Other: Exercise training

Stretching + 6R-BH4

ACTIVE COMPARATOR

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; Dietary Supplement: Folic acid; Other: Stretching

Stretching + placebo

PLACEBO COMPARATOR

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; Dietary Supplement: Folic acid; Other: Stretching

Exercise training + histidine and beta-alanine

ACTIVE COMPARATOR

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; Dietary Supplement: Histidine and beta-alanine supplementation

Exercise training + histidine and beta-alanine placebo

ACTIVE COMPARATOR

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; Other: Histidine and beta-alanine placebo

Interventions

6R-BH4 DRUG

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.

Also known as: Tetrahydrobiopterin, Kuvan, Sapropterin dihydrochloride

Exercise training + 6R-BH4; Stretching + 6R-BH4

6R-BH4 placebo OTHER

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.

Exercise training + 6R-BH4 placebo; Stretching + placebo

Folic acid DIETARY_SUPPLEMENT

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

Exercise training + 6R-BH4; Exercise training + 6R-BH4 placebo; Stretching + 6R-BH4; Stretching + placebo

Exercise training OTHER

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.

Exercise training + 6R-BH4; Exercise training + 6R-BH4 placebo; Exercise training + histidine and beta-alanine; Exercise training + histidine and beta-alanine placebo

Stretching OTHER

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.

Also known as: Control for exercise training

Stretching + 6R-BH4; Stretching + placebo

Histidine and beta-alanine supplementation DIETARY_SUPPLEMENT

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.

Exercise training + histidine and beta-alanine

Histidine and beta-alanine placebo OTHER

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

Exercise training + histidine and beta-alanine placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Emory University: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (3)

Emory University Hospital Midtown

Atlanta, Georgia, 30308, United States

RECRUITING

Emory University Hospital

Atlanta, Georgia, 30322, United States

RECRUITING

Atlanta VA Health Care System

Decatur, Georgia, 30033, United States

RECRUITING

Related Publications (1)

• Jeong J, Sprick JD, DaCosta DR, Mammino K, Nocera JR, Park J. Exercise modulates sympathetic and vascular function in chronic kidney disease. JCI Insight. 2023 Feb 22;8(4):e164221. doi: 10.1172/jci.insight.164221.

  PMID: 36810250 DERIVED

MeSH Terms

Conditions

Renal Insufficiency, Chronic; Hypertension; Kidney Diseases

Interventions

sapropterin; Folic Acid; Exercise; Histidine

Condition Hierarchy (Ancestors)

Renal Insufficiency; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential

Study Officials

• Joe Nocera, PhD

  Emory University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jeanie Park, MD

CONTACT

404-727-2525; jeanie.park@emory.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: SUPPORTIVE CARE
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: October 17, 2016
• First Posted: October 28, 2016
• Study Start: October 1, 2016
• Primary Completion: January 1, 2026
• Study Completion: January 1, 2026
• Last Updated: March 5, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)