EIRF: Exercise Intolerance in Renal Failure

• Sponsor: Emory University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01356966
• Collaborator: National Institutes of Health (NIH) (NIH), National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 74
• Locations: 2
• Arms: 2
• Duration (Months): 36
• Patients Per Site: 37
• Patients Per Site Per Month: 1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Kidney Failure, Chronic	Drug: Tetrahydrobiopterin; Drug: Placebo; Dietary Supplement: Folate	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 74 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Role of Neurovascular Dysfunction and Oxidative Stress in the Exercise Intolerance of Renal Failure
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tetrahydrobiopterin + Folate 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	Drug: Tetrahydrobiopterin; Tetrahydrobiopterin (BH4) 200 mg PO BID for 12 weeks; Other Names: Kuvan ; Dietary Supplement: Folate; Folate 1 mg daily for 12 weeks; Other Names: Folic Acid
Placebo Comparator: Placebo + Folate 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	Drug: Placebo; 2 placebo pills PO BID for12 weeks; Dietary Supplement: Folate; Folate 1 mg daily for 12 weeks; Other Names: Folic Acid

Outcome Measures

Primary Outcome Measures

1. Change in Resting Muscle Sympathetic Nerve Activity (MSNA) [Baseline, 12 weeks]

Secondary Outcome Measures

1. Change in Mean Central Augmentation Index (AIx) [Baseline, 12 weeks]

   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.

2. Change in Heart-rate-corrected Augmentation Index (AIx) [Baseline, 12 weeks]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University Hospital	Atlanta	Georgia	United States	30322
2	Atlanta VA Medical Center	Decatur	Georgia	United States	30033

Sponsors and Collaborators

• Emory University
• National Institutes of Health (NIH)
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Jeanie Park, MD, Emory University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jeanie Park, Assistant Professor of Medicine, Emory University
• ClinicalTrials.gov Identifier: NCT01356966
• Other Study ID Numbers: IRB00019181; K23HL098744
• First Posted: May 20, 2011
• Last Update Posted: Jun 1, 2015
• Last Verified: May 1, 2015

• Additional relevant MeSH terms: Renal Insufficiency; Kidney Failure, Chronic; Folic Acid

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from the Atlanta Veterans Affairs (VA) Medical Center from August 2010 to May 2014.
Pre-assignment Detail	42 subjects were withdrawn prior to group assignment. 16 were screen failures, 7 subjects withdrew, and 19 subjects were terminated early.

Arm/Group Title	Tetrahydrobiopterin + Folate	Placebo + Folate
Arm/Group Description	Male subjects with hypertension and chronic kidney disease stage 2 or 3 received Tetrahydrobiopterin (BH4) 200 mg twice daily and folic acid 1 mg daily	Male subjects with hypertension and chronic kidney disease stage 2 or 3 received 2 placebo pills twice daily and folic acid 1 mg daily
Period Title: Overall Study
STARTED	18	14
COMPLETED	16	12
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	Tetrahydrobiopterin + Folate	Placebo + Folate	Total
Arm/Group Description	Male subjects with hypertension and chronic kidney disease stage 2 or 3 received Tetrahydrobiopterin (BH4) 200 mg twice daily and folic acid 1 mg daily	Male subjects with hypertension and chronic kidney disease stage 2 or 3 received 2 placebo pills twice daily and folic acid 1 mg daily	Total of all reporting groups
Overall Participants	18	14	32
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.5 (1.3)	55.2 (2.2)	56.4 (1.8)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	18 100%	14 100%	32 100%

Outcome Measures

1. Primary Outcome

Title	Change in Resting Muscle Sympathetic Nerve Activity (MSNA)
Time Frame	Baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

Two subjects withdrawn from each arm due to adverse events. Additionally, two subjects from the treatment group and one subject from the placebo group were not included in this analysis because an adequate MSNA neurogram was unable to be obtained at the end of the study.

Arm/Group Title	Tetrahydrobiopterin + Folate	Placebo + Folate
Arm/Group Description	Male subjects with hypertension and chronic kidney disease stage 2 or 3 received Tetrahydrobiopterin (BH4) 200 mg twice daily and folic acid 1 mg daily	Male subjects with hypertension and chronic kidney disease stage 2 or 3 received 2 placebo pills twice daily and folic acid 1 mg daily
Measure Participants	14	11
Mean (Standard Error) [bursts/minute]	-7.5 (2.1)	3.2 (1.3)

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tetrahydrobiopterin + Folate	Placebo + Folate
Arm/Group Description	Male subjects with hypertension and chronic kidney disease stage 2 or 3 received Tetrahydrobiopterin (BH4) 200 mg twice daily and folic acid 1 mg daily	Male subjects with hypertension and chronic kidney disease stage 2 or 3 received 2 placebo pills twice daily and folic acid 1 mg daily
Measure Participants	18	14
Mean (Standard Error) [percent]	-5.8 (2.0)	1.8 (1.7)

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tetrahydrobiopterin + Folate	Placebo + Folate
Arm/Group Description	Male subjects with hypertension and chronic kidney disease stage 2 or 3 received Tetrahydrobiopterin (BH4) 200 mg twice daily and folic acid 1 mg daily	Male subjects with hypertension and chronic kidney disease stage 2 or 3 received 2 placebo pills twice daily and folic acid 1 mg daily
Measure Participants	18	14
Mean (Standard Error) [percent]	-3.2 (2.1)	1.1 (1.2)

Adverse Events

Arm/Group Title	Tetrahydrobiopterin + Folate		Placebo + Folate
Arm/Group Description	Male subjects with hypertension and chronic kidney disease stage 2 or 3 received Tetrahydrobiopterin (BH4) 200 mg twice daily and folic acid 1 mg daily		Male subjects with hypertension and chronic kidney disease stage 2 or 3 received 2 placebo pills twice daily and folic acid 1 mg daily
All Cause Mortality
	Tetrahydrobiopterin + Folate		Placebo + Folate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Tetrahydrobiopterin + Folate		Placebo + Folate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Tetrahydrobiopterin + Folate		Placebo + Folate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/18 (11.1%)		2/14 (14.3%)
Gastrointestinal disorders
Nausea	1/18 (5.6%)	1	0/14 (0%)	0
General disorders
Dysgeusia	0/18 (0%)	0	1/14 (7.1%)	1
Injury, poisoning and procedural complications
Eye injury	0/18 (0%)	0	1/14 (7.1%)	1
Renal and urinary disorders
Acute Kidney Injury	1/18 (5.6%)	1	0/14 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.