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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Brigham and Women's Hospital
Sponsor:
Collaborator:
Information provided by (Responsible Party):
John P. Forman, Brigham and Women's Hospital
ClinicalTrials.gov Identifier:
NCT01320722
First received: March 21, 2011
Last updated: June 27, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention
Renal Function
Endothelial Function
Blood Pressure
Overweight
Obesity
Drug: Vitamin D ergocalciferol
Drug: Probenecid
Drug: Allopurinol
Drug: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Modifiable Effectors of Renin System Activation: Treatment Evaluation (MODERATE)

Resource links provided by NLM:


Further study details as provided by Brigham and Women's Hospital:

Primary Outcome Measures:
  • kidney specific renin angiotensin system (RAS) activation [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    measured by the renal plasma flow response to captopril in high sodium balance

  • systemic renin angiotensin system (RAS) activation [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    measured by plasma renin activity and Angiotensin II concentration


Secondary Outcome Measures:
  • endothelial function [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    assessed by endothelium-dependent vasodilation using brachial artery ultrasonography

  • Ambulatory Blood Pressure [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    24-hour mean ambulatory blood pressure


Estimated Enrollment: 225
Study Start Date: March 2011
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Vitamin D Drug: Vitamin D ergocalciferol
50,000 unit soft gel capsule once per week for 8 weeks
Other Name: Vitamin D
Experimental: Probenecid 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)
Experimental: Allopurinol 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)
Placebo Comparator: Placebo- vitamin D Drug: Placebo
Placebo soft gel once per week for 8 weeks
Placebo Comparator: Placebo- uric acid Drug: Placebo
Placebo tablet once per day for 4 weeks then twice per day for 4 weeks (eight weeks total)

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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • 25(OH)D < 20 ng/mL OR Uric acid ≥ 5 mg/dL
  • Age ≥ 18, ≤ 75 years
  • BMI ≥ 25

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 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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01320722

Contacts
Contact: Ann L Wohlhueter, BA 617 264 3071 AWOHLHUETER@PARTNERS.ORG

Locations
United States, Massachusetts
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Ann L Wohlhueter, BA    617-264-3071    awohlhueter@partners.org   
Principal Investigator: John P Forman, MD, MSc         
Sponsors and Collaborators
Brigham and Women's Hospital
Investigators
Principal Investigator: John P Forman, MD, MSc Brigham and Women's Hospital
  More Information

No publications provided

Responsible Party: John P. Forman, INSTRUCTOR IN MEDICINE, BRIGHAM AND WOMEN'S HOSPITAL, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT01320722     History of Changes
Other Study ID Numbers: 2010-P-002049, 1R01HL105440
Study First Received: March 21, 2011
Last Updated: June 27, 2014
Health Authority: United States: Institutional Review Board
United States: Federal Government

Keywords provided by Brigham and Women's Hospital:
renin angiotensin system
vitamin D
uric acid
allopurinol
probenecid
endothelial function

Additional relevant MeSH terms:
Overweight
Body Weight
Signs and Symptoms
Vitamins
Vitamin D
Ergocalciferols
Allopurinol
Probenecid
Uric Acid
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Bone Density Conservation Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Gout Suppressants
Antirheumatic Agents
Therapeutic Uses
Free Radical Scavengers
Antioxidants
Protective Agents
Uricosuric Agents
Renal Agents

ClinicalTrials.gov processed this record on September 16, 2014