Uric Acid and Hypertension in African Americans

• Sponsor: University of Florida (Other)
• Overall Status: Completed
• CT.gov ID: NCT00241839
• Collaborator: (none)
• Enrollment: 150
• Location: 1
• Arms: 2
• Duration (Months): 69
• Patients Per Site Per Month: 2.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cardiovascular Diseases; Heart Diseases; Hypertension	Drug: Allopurinol; Drug: Placebo; Drug: Chlorthalidone; Drug: Potassium chloride	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Uric Acid and Hypertension in African Americans
• Study Start Date: Aug 1, 2005
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: May 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
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 Names: 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 Names: 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.

Outcome Measures

Primary Outcome Measures

1. Change in Diastolic Blood Pressure by Cuff 8-10 Weeks Minus Baseline [Measured at 8-10 weeks on allopurinol / placebo]

   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)

2. Change in Systolic Blood Pressure by Cuff After 8-10 Weeks Minus Baseline [Measured at 8-10 weeks on allopurinol or placebo]

   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

1. Change in Overall Mean BP From Those Obtained by 24 Hour Ambulatory Blood Pressure Measurements (ABPM) 8-10 Weeks Minus Baseline. [Baseline and end of treatment (8-10 weeks on allopurinol / placebo)]

   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.

2. Change in Uric Acid (UA) Levels: Baseline Less End of Treatment [Baseline UA levels compared to end of treatment levels (8-10 weeks on allopurinol / placebo)]

   Subjects on allopurinol are expected to lower their uric acid levels relative to placebo.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT00241839
• Other Study ID Numbers: 332; R01HL079352
• First Posted: Oct 19, 2005
• Last Update Posted: Jul 26, 2013
• Last Verified: Jul 1, 2013

• Additional relevant MeSH terms: Hypertension; Cardiovascular Diseases; Heart Diseases; Allopurinol; Chlorthalidone

Study Results

Participant Flow

Recruitment Details	Recruitment was through flyers and voluntary blood pressure checks and hypertension lectures throughout the county in churches, health fairs, community art festivals, new business openings and celebrations, and in hospital lobbies, business employee lounges, store front spaces at grocery stores and super stores. Individuals also self-refered.
Pre-assignment Detail	150 subjects signed consents;8 were withdrawn prior to randomization. All participants were placed on chlorthalidone 25mg daily for blood pressure stabilization along with potassium chloride (KCL) 40meq daily. Potassium chloride was increased to 50meq daily for those subjects whose serum potassium was less than 3.5 before baseline visit.

Arm/Group Title	A (Allopurinol)	B(Placebo)
Arm/Group Description	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. Serum uric acid (UA) levels were checked at study visit 2 weeks post baseline. If UA levels were above 5.0 an additional 300mg allopurinol was added with total dose of 600mg daily. The dosage of allopurinol then remained constant throughout the remainder of the study. Testing was repeated at 8-10 weeks after baseline.	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, having the same appearance and dosage label(300mg)as allopurinol, was added for 8-10 weeks. Serum uric acid (UA) levels were checked at study visit 2 weeks post baseline. If UA levels were above 5.0 an additional placebo (300mg)was added with total dose of 600mg daily. The dosage of placebo then remained constant throughout the remainder of the study. Testing was repeated at 8-10 weeks after baseline.
Period Title: Overall Study
STARTED	71	71
COMPLETED	52	53
NOT COMPLETED	19	18

Baseline Characteristics

Arm/Group Title	A (Allopurinol)	B (Placebo)	Total
Arm/Group Description	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. Serum uric acid (UA) levels were checked at study visit 2 weeks post baseline. If UA levels were above 5.0 an additional 300mg allopurinol was added with total dose of 600mg daily. The dosage of allopurinol then remained constant throughout the remainder of the study. Testing was repeated at 8-10 weeks after baseline.	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, having the same appearance and dosage label(300mg)as allopurinol, was added for 8-10 weeks. Serum uric acid (UA) levels were checked at study visit 2 weeks post baseline. If UA levels were above 5.0 an additional placebo (300mg)was added with total dose of 600mg daily. The dosage of placebo then remained constant throughout the remainder of the study. Testing was repeated at 8-10 weeks after baseline.	Total of all reporting groups
Overall Participants	71	71	142
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	70 98.6%	71 100%	141 99.3%
>=65 years	1 1.4%	0 0%	1 0.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.7 (10.1)	48.0 (7.7)	47.9 (8.8)
Sex: Female, Male (Count of Participants)
Female	51 71.8%	51 71.8%	102 71.8%
Male	20 28.2%	20 28.2%	40 28.2%
Region of Enrollment (participants) [Number]
United States	71 100%	71 100%	142 100%

Outcome Measures

1. Primary Outcome

Title	Change in Diastolic Blood Pressure by Cuff 8-10 Weeks Minus Baseline
Description	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)
Time Frame	Measured at 8-10 weeks on allopurinol / placebo

Outcome Measure Data

Analysis Population Description

Participants were individuals with essential hypertension (BP 140/90-160/100) on none or up 2 antihypertensive drugs without any other chronic condition or illness. For their data to be included in analysis they had to complete the study (includes baseline to last visit).

Arm/Group Title	A (Allopurinol)	B (Placebo)
Arm/Group Description	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. Serum uric acid (UA) levels were checked at study visit 2 weeks post baseline. If UA levels were above 5.0 an additional 300mg allopurinol was added with total dose of 600mg daily. The dosage of allopurinol then remained constant throughout the remainder of the study. Testing was repeated at 8-10 weeks after baseline.	Chlorthalidone 25 mg and Potassium Chloride 40-50meq were given daily for 5 weeks before baseline visit for testing. After baseline testing was completed, Placebo 300mg daily (identical in size, color, and dosage as allopurinol) was added for 8-10 weeks. Serum uric acid (UA) levels were checked at study visit 2 weeks post baseline. If UA levels were above 5.0 an additional 300mg placebo was added with total dose of 600mg daily. The dosage of placebo then remained constant throughout the remainder of the study. Testing was repeated at 8-10 weeks after baseline.
Measure Participants	52	53
Mean (Standard Deviation) [mm Hg]	3.44 (12.25)	-0.83 (10.63)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A (Allopurinol), B (Placebo)
	Comments	We compared the drop in baseline of diastolic BP for the two treatment groups Allopurinol vs. Placebo by a Satterthwaite corrected t-test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.059
	Comments
	Method	t-test, 2 sided
	Comments	Satterthwaite correction for possibly unequal variance was made
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	4.27
	Confidence Interval	(2-Sided) 95%; -0.17 to 8.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.24
	Estimation Comments	A positive value of the estimated value would favor the allopurinol arm. The analysis is limited to those with both baseline and 8-10 week data on this variable.

2. Primary Outcome

Title	Change in Systolic Blood Pressure by Cuff After 8-10 Weeks Minus Baseline
Description	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)
Time Frame	Measured at 8-10 weeks on allopurinol or placebo

Outcome Measure Data

Analysis Population Description

Participants were individuals with essential hypertension (BP 140/90-160/100) on none or up 2 antihypertensive drugs without any other chronic condition or illness. For their data to be included in analysis they had to complete the study (includes baseline to last visit).

Arm/Group Title	A (Allopurinol)	B (Placebo)
Arm/Group Description	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. Serum uric acid (UA) levels were checked at study visit 2 weeks post baseline. If UA levels were above 5.0 an additional 300mg allopurinol was added with total dose of 600mg daily. The dosage of allopurinol then remained constant throughout the remainder of the study. Testing was repeated at 8-10 weeks after baseline.	Chlorthalidone 25 mg and Potassium Chloride 40-50meq were given daily for 5 weeks before baseline visit for testing. After baseline testing was completed, Placebo 300mg daily (identical in size, color, and dosage as allopurinol) was added for 8-10 weeks. Serum uric acid (UA) levels were checked at study visit 2 weeks post baseline. If UA levels were above 5.0 an additional 300mg placebo was added with total dose of 600mg daily. The dosage of placebo then remained constant throughout the remainder of the study. Testing was repeated at 8-10 weeks after baseline.
Measure Participants	52	53
Mean (Standard Deviation) [mm Hg]	0.21 (7.37)	-0.95 (8.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A (Allopurinol), B (Placebo)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.47
	Comments	Positive numbers indicate a drop. We compared baseline minus value at treatment end for the two treatments.
	Method	t-test, 2 sided
	Comments	Satterthwaite correction was used for potentially unequal variances.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95%; -2.0 to 4.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.59
	Estimation Comments	The analysis is limited to those with both baseline and 8-10 week data on this variable.

3. Secondary Outcome

Title	Change in Overall Mean BP From Those Obtained by 24 Hour Ambulatory Blood Pressure Measurements (ABPM) 8-10 Weeks Minus Baseline.
Description	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.
Time Frame	Baseline and end of treatment (8-10 weeks on allopurinol / placebo)

Outcome Measure Data

Analysis Population Description

We obtained over 90% of those with cuff measures on the 24 hour BP measures (ABPM).

Arm/Group Title	A (Allopurinol)	B (Placebo)
Arm/Group Description	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. Serum uric acid (UA) levels were checked at study visit 2 weeks post baseline. If UA levels were above 5.0 an additional 300mg allopurinol was added with total dose of 600mg daily. The dosage of allopurinol then remained constant throughout the remainder of the study. Testing was repeated at 8-10 weeks after baseline.	Chlorthalidone 25 mg and Potassium Chloride 40-50meq were given daily for 5 weeks before baseline visit for testing. After baseline testing was completed, Placebo 300mg daily (identical in size, color, and dosage as allopurinol) was added for 8-10 weeks. Serum uric acid (UA) levels were checked at study visit 2 weeks post baseline. If UA levels were above 5.0 an additional 300mg placebo was added with total dose of 600mg daily. The dosage of placebo then remained constant throughout the remainder of the study. Testing was repeated at 8-10 weeks after baseline.
Measure Participants	49	50
Mean (Standard Deviation) [mm Hg]	-5.9 (11.9)	0.90 (8.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A (Allopurinol), B (Placebo)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0020
	Comments
	Method	t-test, 2 sided
	Comments	Sattherthwaite correction was used
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-6.76
	Confidence Interval	(2-Sided) 95%; -11.0 to -2.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.11
	Estimation Comments	The analysis is limited to those with both baseline and 8-10 week data on this variable. The 24 hour was in the opposite direction of the cuff.

4. Secondary Outcome

Title	Change in Uric Acid (UA) Levels: Baseline Less End of Treatment
Description	Subjects on allopurinol are expected to lower their uric acid levels relative to placebo.
Time Frame	Baseline UA levels compared to end of treatment levels (8-10 weeks on allopurinol / placebo)

Outcome Measure Data

Analysis Population Description

Change in uric acid from baseline to end of treatment.

Arm/Group Title	A (Allopurinol)	B (Placebo)
Arm/Group Description	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. Serum uric acid (UA) levels were checked at study visit 2 weeks post baseline. If UA levels were above 5.0 an additional 300mg allopurinol was added with total dose of 600mg daily. The dosage of allopurinol then remained constant throughout the remainder of the study. Testing was repeated at 8-10 weeks after baseline.	Chlorthalidone 25 mg and Potassium Chloride 40-50meq were given daily for 5 weeks before baseline visit for testing. After baseline testing was completed, Placebo 300mg daily (identical in size, color, and dosage as allopurinol) was added for 8-10 weeks. Serum uric acid (UA) levels were checked at study visit 2 weeks post baseline. If UA levels were above 5.0 an additional 300mg placebo was added with total dose of 600mg daily. The dosage of placebo then remained constant throughout the remainder of the study. Testing was repeated at 8-10 weeks after baseline.
Measure Participants	50	53
Mean (Standard Deviation) [mg/dl]	2.29 (1.29)	0.14 (0.88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A (Allopurinol), B (Placebo)
	Comments	We expected allopurinol to be associated with a decrease in uric acid.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments	Satterthwaite correction was used.
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	2.15
	Confidence Interval	(2-Sided) 95%; 1.72 to 2.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.22
	Estimation Comments	Allopurinol was associated with a significant decrease in uric acid over the treatment period as compared to placebo. The analysis is limited to those with both baseline and 8-10 week data on this variable.

Adverse Events

Time Frame	Adverse event data were collected for 5 years, 1 month which represents the time the first consent was signed until the last subject completed participation in the study.
Arm/Group Title	A (Allopurinol)		B (Placebo)
Arm/Group Description	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. Serum uric acid (UA) levels were checked at study visit 2 weeks post baseline. If UA levels were above 5.0 an additional 300mg allopurinol was added with total dose of 600mg daily. The dosage of allopurinol then remained constant throughout the remainder of the study. Testing was repeated at 8-10 weeks after baseline.		Chlorthalidone 25 mg and Potassium Chloride 40-50meq were given daily for 5 weeks before baseline visit for testing. After baseline testing was completed, Placebo 300mg daily (identical in size, color, and dosage as allopurinol) was added for 8-10 weeks. Serum uric acid (UA) levels were checked at study visit 2 weeks post baseline. If UA levels were above 5.0 an additional 300mg placebo was added with total dose of 600mg daily. The dosage of placebo then remained constant throughout the remainder of the study. Testing was repeated at 8-10 weeks after baseline.
All Cause Mortality
	A (Allopurinol)		B (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	A (Allopurinol)		B (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/71 (5.6%)		3/71 (4.2%)
Cardiac disorders
Chest Pain	1/71 (1.4%)	1	0/71 (0%)	0
Gastrointestinal disorders
Nausea/Vomiting	0/71 (0%)	0	1/71 (1.4%)	1
Nervous system disorders
Fatigue	0/71 (0%)	0	1/71 (1.4%)	1
Panic Attack	1/71 (1.4%)	1	0/71 (0%)	0
Syncope	0/71 (0%)	0	1/71 (1.4%)	1
Skin and subcutaneous tissue disorders
Rash	1/71 (1.4%)	1	0/71 (0%)	0
Social circumstances
Car Accident	1/71 (1.4%)	1	0/71 (0%)	0
Other (Not Including Serious) Adverse Events
	A (Allopurinol)		B (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/71 (36.6%)		11/71 (15.5%)
General disorders
Headache	7/71 (9.9%)	7	6/71 (8.5%)	6
Musculoskeletal and connective tissue disorders
Musculoskeletal pain/ache	9/71 (12.7%)	9	2/71 (2.8%)	3
Respiratory, thoracic and mediastinal disorders
Cold	10/71 (14.1%)	10	3/71 (4.2%)	3

Limitations/Caveats

For all 4 outcomes analyzed, patients required to have data at both baseline and 8-10 weeks on that field to be included. Thus, the numbers of subjects varies slightly from analysis to analysis.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.