Clinical trial NCT00241839: Uric Acid and Hypertension in African Americans
Official title: Uric Acid and Hypertension in African Americans
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cardiovascular Diseases
Heart Diseases
Hypertension
Lead sponsor: University of Florida
Sponsor class: OTHER
First posted: 2005-10-19
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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 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

Primary outcomes:
measure: Change in Diastolic Blood Pressure by Cuff 8-10 Weeks Minus Baseline
timeFrame: Measured at 8-10 weeks on allopurinol / placebo
measure: Change in Systolic Blood Pressure by Cuff After 8-10 Weeks Minus Baseline
timeFrame: Measured at 8-10 weeks on allopurinol or placebo
Secondary outcomes:
measure: Change in Overall Mean BP From Those Obtained by 24 Hour Ambulatory Blood Pressure Measurements (ABPM) 8-10 Weeks Minus Baseline.
timeFrame: Baseline and end of treatment (8-10 weeks on allopurinol / placebo)
measure: Change in Uric Acid (UA) Levels: Baseline Less End of Treatment
timeFrame: Baseline UA levels compared to end of treatment levels (8-10 weeks on allopurinol / placebo)
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: University of Florida
state: Florida
Study officials:
affiliation: University of Florida
name: Mark S. Segal, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Johnson RJ, Segal MS, Sautin Y, Nakagawa T, Feig DI, Kang DH, Gersch MS, Benner S, Sanchez-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. doi: 10.1093/ajcn/86.4.899.
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. No abstract available.
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. doi: 10.1038/sj.ki.5000391.
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. doi: 10.1038/sj.ki.5002564. Epub 2007 Oct 10.
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. doi: 10.1681/ASN.2007040416. Epub 2007 Sep 12.
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.
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.
citation: Fravel MA, Ernst ME. Management of gout in the older adult. Am J Geriatr Pharmacother. 2011 Oct;9(5):271-85. doi: 10.1016/j.amjopharm.2011.07.004. Epub 2011 Aug 17.