Uric Acid and Hypertension in African Americans

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
University of Florida
ClinicalTrials.gov Identifier:
NCT00241839
First received: October 17, 2005
Last updated: July 18, 2013
Last verified: July 2013
  Purpose

This study will test the hypothesis that the administration of a xanthine oxidase inhibitor (allopurinol) will prevent thiazide-induced hyperuricemia, which will result in better blood pressure (BP) control in African Americans.


Condition Intervention Phase
Cardiovascular Diseases
Heart Diseases
Hypertension
Drug: Allopurinol
Drug: Placebo
Drug: Chlorthalidone
Drug: Potassium chloride
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Uric Acid and Hypertension in African Americans

Resource links provided by NLM:


Further study details as provided by University of Florida:

Primary Outcome Measures:
  • Change in Diastolic Blood Pressure by Cuff 8-10 Weeks Minus Baseline [ Time Frame: Measured at 8-10 weeks on allopurinol / placebo ] [ Designated as safety issue: No ]

    The Diastolic BP was taken at Baseline and after 8-10 weeks of treatment or placebo while on chlorthalidone and potassium chloride. The blood pressure was measured according to "Shared Care" protocol: 15 minutes of quiet, undisturbed rest with three BP measurements obtained subsequently at 5 minute intervals.

    The mean of the second and third reading was the value used for analysis for both the Baseline measurement and the measurement after 8 - 10 weeks of treatment. The dependent variable is baseline value minus ending value.

    Measures are in millimeters of mercury (mm hg)


  • Change in Systolic Blood Pressure by Cuff After 8-10 Weeks Minus Baseline [ Time Frame: Measured at 8-10 weeks on allopurinol or placebo ] [ Designated as safety issue: No ]

    The systolic BP was taken at Baseline and after 8-10 weeks of treatment on placebo, while on chlorthalidone and potassium chloride. The blood pressure was measured according to "Shared Care" protocol: 15 minutes of quiet, undisturbed rest with three BP measurements obtained subsequently at 5 minute intervals.

    The mean of the second and third reading was the value used for analysis for both the Baseline measurement and the measurement after 8 - 10 weeks of treatment. The dependent variable is baseline value minus ending value.

    Measures are in millimeters of mercury (mm hg)



Secondary Outcome Measures:
  • Change in Overall Mean BP From Those Obtained by 24 Hour Ambulatory Blood Pressure Measurements (ABPM) 8-10 Weeks Minus Baseline. [ Time Frame: Baseline and end of treatment (8-10 weeks on allopurinol / placebo) ] [ Designated as safety issue: No ]
    Subjects had 24 hr blood pressure monitoring (ABPM) at baseline and treatment end. The readings were averaged and the changes from baseline to treatment end were compared.

  • Change in Uric Acid (UA) Levels: Baseline Less End of Treatment [ Time Frame: Baseline UA levels compared to end of treatment levels (8-10 weeks on allopurinol / placebo) ] [ Designated as safety issue: No ]
    Subjects on allopurinol are expected to lower their uric acid levels relative to placebo.


Enrollment: 150
Study Start Date: August 2005
Study Completion Date: May 2011
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: A
Chlorthalidone 25 mg and Potassium Chloride 40-50meq were given daily for 5 weeks before baseline visit for testing. After baseline testing was completed, Allopurinol 300mg daily was added for 8-10 weeks at which time testing was repeated.
Drug: Allopurinol
Allopurinol (300 mg capsule) was given for 8-10 weeks compared to placebo group after initial baseline testing. After two weeks on the Allopurinol, a serum uric acid level was obtained. If the uric acid level was greater than 5.5, the Allopurinol dosage was increased to 600mg (two 300 mg capsules)for the duration of the trial, 6-8 weeks.
Other Name: Zyloprim
Drug: Chlorthalidone
Chlorthalidone 25 mg was given daily for 5 weeks before baseline visit for testing and continued through out the study.
Drug: Potassium chloride
Potassium Chloride 40-50meq was given daily for 5 weeks before baseline visit for testing and continued through out the study.
Placebo Comparator: B
Chlorthalidone 25 mg and Potassium Chloride 40-50meq were given daily for 5 weeks before baseline visit for testing. After baseline testing was completed, a Placebo,matched in appearance to Allopurinol, was added daily for 8-10 weeks, at which time testing was repeated.
Drug: Placebo
Placebo capsule (matched in appearance for Allopurinol and labeled 300mg) was given for 8-10 weeks compared to the Allopurinol group after initial baseline testing. After two weeks on the placebo, a serum uric acid level was obtained. If the uric acid level was greater than 5.5, the placebo dosage was increased to 600mg (two 300 mg capsules)for the duration of the study, 6-8 weeks.
Other Name: sugar pill
Drug: Chlorthalidone
Chlorthalidone 25 mg was given daily for 5 weeks before baseline visit for testing and continued through out the study.
Drug: Potassium chloride
Potassium Chloride 40-50meq was given daily for 5 weeks before baseline visit for testing and continued through out the study.

Detailed Description:

Thiazide diuretics when used in the treatment of hypertension are associated with many metabolic side effects, including hyperuricemia, gout, insulin resistance, and hyperlipidemia. Each of these conditions is already highly prevalent in African Americans. Our hypothesis is that thiazide-induced hyperuricemia decreases the efficacy of thiazides in controlling BP, leads to endothelial dysfunction, and increases the incidence of insulin resistance and impaired glucose tolerance. This hypothesis will be tested in a randomized, double-blind, placebo-controlled clinical trial of 8-10 weeks duration in which a total of 100 African American patients with hypertension will be enrolled, randomized, and treated as follows:

  1. Subjects with untreated stage I hypertension will receive chlorthalidone (25 mg/day) and potassium chloride (40 mEq/day) for 4 weeks. Serum potassium levels will be obtained after four weeks on chlorthalidone. If the level is below 3.5 mEg/L, a bolus of 40 mEq potassium 2 to 3 times daily will be given for 2 to 3 days, or as clinically indicated. A maintenance dose of 50 mEq will be initiated. After at least 7 days, they will then be randomized to add-on allopurinol (300 mg/day) or placebo. Treatment will continue for 8-10 weeks with the chlorthalidone, potassium chloride, and allopurinol/placebo regimen.
  2. Subjects with hypertension controlled (i.e. BP <140/90) or no higher than stage 1 hypertension (i.e., <160/100) on a single antihypertensive agent or two antihypertensive agents will be switched from their prior antihypertensive agent to chlorthalidone 25 mg/day, and potassium chloride (40mEq/day) for 4 weeks. Serum potassium levels will be obtained after four weeks on chlorthalidone. If the level is below 3.5 mEg/L, a bolus of 40 mEq potassium 2 to 3 times daily will be given for 2 to 3 days, or as clinically indicated. A maintenance dose of 50 mEq will be initiated. After at least 7 days, they will then be randomized to add-on allopurinol (300 mg/day) or placebo. Treatment will continue for 8-10 weeks with the chlorthalidone, potassium chloride, and allopurinol/placebo regimen.

The allopurinol (or placebo) dose will be adjusted to achieve serum uric acid levels between 4 and 5.5 mg/dL after 2 weeks on drug. All subjects will receive a low-sodium diet. The primary endpoint is reduction in systolic BP. Secondary endpoints measure endothelial function, ambulatory blood pressure, body composition, systemic inflammation, metabolic parameters, oxidant stress, and renal hemodynamics.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • African American (including black individuals born in the Caribbean, Africa, Canada, etc.)
  • Are either untreated with any antihypertensive agent, with an average sitting clinic BP of between 140/90 and 159/99 mm Hg OR subjects with hypertension controlled (i.e. BP less than 140/90) or no higher than stage 1 hypertension (i.e., less than 160/100) on a single antihypertensive agent or two antihypertensive agents (individuals on fixed dose ARB-diuretic or ACEI-diuretic combinations will also be considered as being on monotherapy for purposes of the study. Individuals on beta blockade or calcium channel blockade for coronary artery disease and/or arrhythmia will not be eligible for the study)
  • Random spot urine protein/creatinine ratio of less than 0.5 (approximates a 24-hour urinary protein excretion of 500 mg/day)
  • Calculated MDRD GFR of greater than or equal to 60 ml/min/1.73/m^2
  • No allopurinol or probenecid intake for at least one month prior to study entry
  • Willing and able to cooperate with study procedures
  • Willing to travel to the GCRC at Shands Hospital for overnight inpatient stays on two separate occasions

Exclusion Criteria:

  • History of malignant or accelerated hypertension
  • Confirmed total white cell count of less than 2,500/mm^3, anemia, or thrombocytopenia
  • Known history of liver disease
  • Known secondary cause of hypertension
  • Known presence of diabetes or fasting blood glucose greater than or equal to 126 mg/dL
  • History of heart failure, acute myocardial infarction, or stroke or on a β-blocker or calcium channel blocker for cardiovascular indications other than for lowering blood pressure
  • Abnormal EKG requiring medical intervention
  • History of clinical or renal biopsy or evidence of renal parenchymal disease
  • Acute gout attack within 2 weeks of study entry
  • History of drug abuse in the last 2 years, including narcotics, cocaine, or alcohol (greater than 21 drinks/week)
  • Arm circumference of greater than 52 cm, which precludes measurement with a 'thigh' BP cuff
  • History of a reaction to allopurinol or chlorthalidone
  • Pregnant or planning to become pregnant during the study, or breastfeeding
  • History of noncompliance, are unable to comply with the study requirements, or who are currently participating in another study
  • Not fasting prior to obtaining screening laboratory data. If a participant has clearly not fasted, we will exclude those individuals with casual blood glucose levels of greater than or equal to 200 mg/dL. In the event that a fasting blood sugar exceeds 126 mg/dL, it will be reconfirmed on a blood glucose measurement obtained on a subsequent day, per American Diabetes Association criteria
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00241839

Locations
United States, Florida
University of Florida
Gainesville, Florida, United States, 32610
Sponsors and Collaborators
University of Florida
Investigators
Principal Investigator: Mark S. Segal, MD, PhD University of Florida
  More Information

Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT00241839     History of Changes
Other Study ID Numbers: 332, R01 HL79352
Study First Received: October 17, 2005
Results First Received: March 28, 2013
Last Updated: July 18, 2013
Health Authority: United States: Federal Government
United States: Food and Drug Administration
United States: Institutional Review Board

Additional relevant MeSH terms:
Hypertension
Cardiovascular Diseases
Heart Diseases
Vascular Diseases
Allopurinol
Uric Acid
Chlorthalidone
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Enzyme Inhibitors
Gout Suppressants
Antirheumatic Agents
Therapeutic Uses
Free Radical Scavengers
Antioxidants
Protective Agents
Physiological Effects of Drugs
Antihypertensive Agents
Cardiovascular Agents
Diuretics
Natriuretic Agents
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators

ClinicalTrials.gov processed this record on September 30, 2014