Study of Vitamin D and Uric Acid Lowering on Kidney and Blood Vessel Function

NCT ID: NCT01320722

Last Updated: 2017-06-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 242 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-03-31
• Study Completion Date: 2015-06-30

Brief Summary

The investigators hypothesize that, among non-hypertensive overweight and obese individuals, treatment of vitamin D deficiency and lowering uric acid concentrations (by either xanthine oxidase inhibition or increased renal excretion) will attenuate renin angiotensin system (RAS) activation, improve endothelial function, and lower blood pressure.

Detailed Description

We have demonstrated that lower levels of 25-hydroxyvitamin D (25[OH]D) and higher concentrations of uric acid are both potentially modifiable factors that are independently associated with an increased risk of developing hypertension (high blood pressure) in humans. Other investigators have shown that vitamin D supplementation, or lowering uric acid with allopurinol, may reduce blood pressure. Animal experiments suggest that activation of both the systemic and local kidney-specific renin angiotensin systems (RAS) may be the principal mechanism linking 25(OH)D and uric acid with hypertension. In human parallels to these animal studies, we have shown in cross-sectional analyses that non-hypertensive individuals with lower 25(OH)D and higher uric acid levels have increased activation of their systemic and kidney-specific RAS, independent of other factors. However, whether vitamin D supplementation or uric acid lowering attenuates RAS activation has never been demonstrated in humans. Both lower 25(OH)D and higher uric acid concentrations are also associated with endothelial dysfunction in humans, and endothelial function may modulate the RAS and provide an alternate mechanism for the development of hypertension. It remains unclear, however, whether an intervention to increase 25(OH)D or decrease uric acid levels among non-hypertensive adults improves endothelial function; furthermore, it is unknown whether treatment of these individuals would lower blood pressure. Determining whether treatment of 25(OH)D and uric acid concentrations, per se, can attenuate RAS activation, improve endothelial function, and lower blood pressure among nonhypertensive individuals is critically important, with implications stretching beyond hypertension prevention, since RAS activation, endothelial dysfunction, and blood pressure are also implicated in the pathology of cardiovascular and chronic kidney disease. Individuals who are overweight and obese (two-thirds of US adults) represent an important population who are known to have lower 25(OH)D levels, higher uric acid concentrations, activation of the RAS, endothelial dysfunction, and an increased risk of hypertension, cardiovascular disease, and chronic kidney disease. Interestingly, our preliminary data demonstrate that among overweight and obese individuals with normal 25(OH)D or low uric acid levels, adiposity is no longer associated with activation of the RAS, suggesting that low 25(OH)D and high uric acid concentrations might be mediators of the adverse consequences of overweight and obesity.

Conditions

Renal Function; Endothelial Function; Blood Pressure; Overweight; Obesity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Vitamin D

Vitamin D ergocalciferol 50,000 unit soft gel capsule once per week for 8 weeks.

Group Type: EXPERIMENTAL

Vitamin D ergocalciferol

Intervention Type: DRUG

50,000 unit soft gel capsule once per week for 8 weeks

Probenecid

Probenecid 500 mg tablet once per day for 4 weeks, then either 500 mg tablet once per day for 4 weeks or 1000 mg once per day for 4 weeks (8 weeks total).

Group Type: EXPERIMENTAL

Probenecid

Intervention Type: DRUG

500 mg tablet once per day for 4 weeks, then either 500 mg tablet once per day for 4 weeks or 1000 mg once per day for 4 weeks (8 weeks total)

Allopurinol

Allopurinol 300 mg tablet once per day for 4 weeks then either 300 mg once per day or 600 mg once per day for 4 weeks (8 weeks total).

Group Type: EXPERIMENTAL

Allopurinol

Intervention Type: DRUG

300 mg tablet once per day for 4 weeks then either 300 mg once per day or 600 mg once per day for 4 weeks (8 weeks total)

Placebo- Vitamin D

Placebo soft gel once per week for 8 weeks.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo soft gel once per week for 8 weeks

Placebo- Uric Acid

Placebo tablet once per day for 4 weeks then twice per day for 4 weeks (eight weeks total).

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo tablet once per day for 4 weeks then twice per day for 4 weeks (eight weeks total)

Interventions

Vitamin D ergocalciferol

50,000 unit soft gel capsule once per week for 8 weeks

Intervention Type: DRUG

Probenecid

500 mg tablet once per day for 4 weeks, then either 500 mg tablet once per day for 4 weeks or 1000 mg once per day for 4 weeks (8 weeks total)

Intervention Type: DRUG

Allopurinol

300 mg tablet once per day for 4 weeks then either 300 mg once per day or 600 mg once per day for 4 weeks (8 weeks total)

Intervention Type: DRUG

Placebo

Placebo soft gel once per week for 8 weeks

Intervention Type: DRUG

Placebo

Placebo tablet once per day for 4 weeks then twice per day for 4 weeks (eight weeks total)

Intervention Type: DRUG

Other Intervention Names

Vitamin D

Eligibility Criteria

Inclusion Criteria

• 25(OH)D < 20 ng/mL OR Uric acid ≥ 5 mg/dL
• Age ≥ 18, ≤ 75 years
• Body Mass Index (BMI) ≥ 25 kg/m^2

Exclusion Criteria

• Hypertension, or on BP-lowering medicine
• Diabetes
• Coronary Heart Disease
• estimated glomerular filtration rate (EGFR) <60 mL/min
• Kidney stones
• Active cancer (except non-melanoma skin cancer)
• Pregnant
• Taking vitamin D supplements and unwilling to stop
• Osteoporosis
• Hypo- or hypercalcemia
• Hypo- or hyperphosphatemia
• Known allergy to angiotensin-converting enzyme (ACE)-inhibitors
• Taking medication for hyperuricemia
• Gout, anemia, cirrhosis, active/chronic hepatitis, abnormal aspartate aminotransferase (AST), alanine aminotransferase (ALT) or total bilirubin levels, or anemia
• Known allergy to either allopurinol or probenecid
• Current use of didanosine, azothioprine, methotrexate, ketoprofen, ketorolac, mycophenolate, or ACE-inhibitors

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Brigham and Women's Hospital

OTHER

Sponsor Role: lead

Responsible Party

John P. Forman

INSTRUCTOR IN MEDICINE, BRIGHAM AND WOMEN'S HOSPITAL

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

John P Forman, MD, MSc

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital

Locations

Brigham and Women's Hospital

Boston, Massachusetts, United States

Countries

United States

Other Identifiers

1R01HL105440

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2010-P-002049

Identifier Type: -

Identifier Source: org_study_id