Uric Acid and Hypertension in African Americans

Hypertension Clinical Trial

Official title:

Uric Acid and Hypertension in African Americans

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00241839
• Other study ID #: 332
• Secondary ID: R01HL079352
• Status: Completed
• Phase: Phase 3
• First received: October 17, 2005
• Last updated: July 18, 2013
• Start date: August 2005
• Est. completion date: May 2011

Study information

• Verified date: July 2013
• Source: University of Florida
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 150
• Est. completion date: May 2011
• Est. primary completion date: May 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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 ß-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

Related Conditions & MeSH terms

• Cardiovascular Diseases
• Heart Diseases
• Hypertension

Intervention

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.
• 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.
• Chlorthalidone
Chlorthalidone 25 mg was given daily for 5 weeks before baseline visit for testing and continued through out the study.
• Potassium chloride
Potassium Chloride 40-50meq was given daily for 5 weeks before baseline visit for testing and continued through out the study.

Locations

Country	Name	City	State
United States	University of Florida	Gainesville	Florida

Sponsors (1)

Lead Sponsor	Collaborator
University of Florida

Country where clinical trial is conducted

United States, 

References & Publications (7)

Johnson RJ, Segal MS, Sautin Y, Nakagawa T, Feig DI, Kang DH, Gersch MS, Benner S, Sánchez-Lozada LG. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr. 2007 Oct;86(4):899-906. Review. — View Citation

Kim KM, Henderson GN, Frye RF, Galloway CD, Brown NJ, Segal MS, Imaram W, Angerhofer A, Johnson RJ. Simultaneous determination of uric acid metabolites allantoin, 6-aminouracil, and triuret in human urine using liquid chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Jan 1;877(1-2):65-70. doi: 10.1016/j.jchromb.2008.11.029. Epub 2008 Nov 25. — View Citation

Kim KM, Henderson GN, Ouyang X, Frye RF, Sautin YY, Feig DI, Johnson RJ. A sensitive and specific liquid chromatography-tandem mass spectrometry method for the determination of intracellular and extracellular uric acid. J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Jul 15;877(22):2032-8. doi: 10.1016/j.jchromb.2009.05.037. Epub 2009 May 27. — View Citation

Nakagawa T, Johnson RJ. Hypertension: Is there a dark side to thiazide therapy for hypertension? Nat Rev Nephrol. 2010 Oct;6(10):564-6. doi: 10.1038/nrneph.2010.114. — View Citation

Nakagawa T, Kang DH, Feig D, Sanchez-Lozada LG, Srinivas TR, Sautin Y, Ejaz AA, Segal M, Johnson RJ. Unearthing uric acid: an ancient factor with recently found significance in renal and cardiovascular disease. Kidney Int. 2006 May;69(10):1722-5. Review. — View Citation

Reungjui S, Hu H, Mu W, Roncal CA, Croker BP, Patel JM, Nakagawa T, Srinivas T, Byer K, Simoni J, Wesson D, Sitprija V, Johnson RJ. Thiazide-induced subtle renal injury not observed in states of equivalent hypokalemia. Kidney Int. 2007 Dec;72(12):1483-92. Epub 2007 Oct 10. — View Citation

Reungjui S, Roncal CA, Mu W, Srinivas TR, Sirivongs D, Johnson RJ, Nakagawa T. Thiazide diuretics exacerbate fructose-induced metabolic syndrome. J Am Soc Nephrol. 2007 Oct;18(10):2724-31. Epub 2007 Sep 12. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Diastolic Blood Pressure by Cuff 8-10 Weeks Minus Baseline	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)	Measured at 8-10 weeks on allopurinol / placebo
Primary	Change in Systolic Blood Pressure by Cuff After 8-10 Weeks Minus Baseline	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)	Measured at 8-10 weeks on allopurinol or placebo
Secondary	Change in Overall Mean BP From Those Obtained by 24 Hour Ambulatory Blood Pressure Measurements (ABPM) 8-10 Weeks Minus Baseline.	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.	Baseline and end of treatment (8-10 weeks on allopurinol / placebo)
Secondary	Change in Uric Acid (UA) Levels: Baseline Less End of Treatment	Subjects on allopurinol are expected to lower their uric acid levels relative to placebo.	Baseline UA levels compared to end of treatment levels (8-10 weeks on allopurinol / placebo)