Urate Lowering Therapies and Left Ventricular Diastolic Dysfunction

Study Overview
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Brief Summary
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Hyperuricemia is an additional risk factor for cardiovascular disease, associating with left ventricular diastolic dysfunction in individuals with metabolic syndrome. The effect of urate-lowering therapies on left ventricular diastolic dysfunction remains unclear. The study is conducted to investigate whether febuxostat or benzbromarone might improve left ventricular diastolic dysfunction in individuals with metabolic syndrome and hyperuricemia

Detailed Description
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Between 1, July 2018 and 31, Dec 2018, consecutive individuals with metabolic syndrome hyperuricemia are candidates of the present study. After the eligible candidates sign the informed consent, they will receive blood tests with a fasting time of 8 hours at least. The investigators will randomize the study participants by pre-specified random codes with a 1:1:1 ratio to the three groups. The study medication, febuxostat or benzbromarone, will be administered orally on the next day after transthoracic echocardiography is performed. The control group will only receive dietary control. All participant will receive transthoracic echocardiography and blood tests at baseline and at 3 months. The visit will be scheduled at baseline and at the 3rd month. The blood tests include high-sensitivity C-reactive protein, high-sensitivity interleukin-1 beta, high-sensitivity interleukin-6, tumor necrosis factor alpha, Dickkopf-related protein 3, galectin-3, ST2, fibroblast growth factor 23, xanthine oxidase activity, and thioredoxin.

Official Title
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The Cardiovascular Effects of Febuxostat and Benzbromarone on Left Ventricle Diastolic Dysfunction in Individuals With Metabolic Syndrome and Hyperuricemia - an Open-label Non-blinded Randomized-controlled Clinical Trial

Conditions
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Hyperuricemia, Metabolic Syndrome, Left Ventricular Diastolic Dysfunction

Intervention / Treatment
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* Drug: Febuxostat 40 mg
* Drug: Benzbromarone 50mg
* Other: Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (all of the four criteria) Aged between 40-75 years Metabolic syndrome Hyperuricemia, defined as a serum uric acid level of 7 mg/dl or more in men or 6 mg/dl or more in females, with a history of hyperuricemia within a year; or a serum uric acid level of 8 mg/dl or more in men or 7 mg/dl or more in females and it is hardly expected to be modified by dietary control; or persistent hyperuricemia after dietary control for 3 months Not take any of urate-lowering therapies (benzbromarone, allopurinol, or febuxostat) Exclusion Criteria: pregnancy hypersensitivity to febuxostat or benzbromarone acute gout a history of urinary tract stone chronic kidney disease stage IV or V valvular heart disease with moderate or severe regurgitation left ventricular ejection fraction of 40% or less hypertrophic cardiomyopathy or dilated cardiomyopathy or infiltrative cardiomyopathy or constrictive cardiomyopathy a history of congenital heart disease a history of pulmonary hypertension chronic atrial fibrillation or significant arrhythmia a history of intracardiac device implantation uncontrolled hypertension (systolic blood pressure > 160mm Hg or diastolic blood pressure > 100 mm Hg) alanine Aminotransferase > 3 times upper limit) acute infection suspected or diagnosed with malignancy a history of autoimmune disease limited to or dependent on daily activities life expectancy less than a year Acute coronary syndrome or received a percutaneous coronary intervention or received a coronary artery graft bypass surgery or stroke within 3 months Diabetes with insulin treatment or glucagon-like peptide 1 receptor agonist treatment Anemia (hemoglobin < 11 mg/dl in mem or <10mg/dl in women)

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Febuxostat 40mg<br>Febuxostat 40mg orally per day | Drug: Febuxostat 40 mg<br>* Febuxostat 40 mg orally per day plus dietary control only<br>* Other names: Feburic;|
| Active Comparator: Benzbromarone 50mg<br>Benzbromarone 50mg orally per day | Drug: Benzbromarone 50mg<br>* Benzbromarone 50mg orally per day plus dietary control only<br>* Other names: Nogout;|
| Other: Control<br>Dietary control only | Other: Control<br>* Dietary control only<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of average E/e' | the mean change of average E/e' in each group | At day1 and at week 12 | 
| Difference of average E/e' | the mean difference of average E/e' between among three groups | At day1 and at week 12 | 
| Automate office blood pressure (AOBP) | the mean difference of AOBP among three groups | At day1 and at week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of xanthine oxidase activity | the mean change of xanthine oxidase activity in each group | At day1 and at week 12 | 
| Difference of xanthine oxidase activity | the mean difference of xanthine oxidase activity among three groups | At day1 and at week 12 | 
| Change of left ventricular mass index | the mean change of left ventricular mass index in each group | At day1 and at week 12 | 
| Difference of left ventricular mass index | the mean difference of left ventricular mass index among three groups | At day1 and at week 12 | 
| Change of tumor necrosis factor alpha | the mean change of tumor necrosis factor alpha in each group | At day1 and at week 12 | 
| Difference of tumor necrosis factor alpha | the mean difference of tumor necrosis factor alpha among three groups | At day1 and at week 12 | 
| Change of high-sensitivity interleukin-6 | the mean change of high-sensitivity interleukin-6 in each group | At day1 and at week 12 | 
| Difference of high-sensitivity interleukin-6 | the mean difference of high-sensitivity interleukin-6 among three groups | At day1 and at week 12 | 
| Change of thioredoxin | the mean change of Thioredoxin in each group | At day1 and at week 12 | 
| Difference of Thioredoxin | the mean difference of Thioredoxin among three group | At day1 and at week 12 | 
| Change of fibroblast growth factor 23 | the mean Change of fibroblast growth factor 23 in each group | At day1 and at week 12 | 
| Difference of fibroblast growth factor 23 | the mean difference of fibroblast growth factor 23 among three groups | At day1 and at week 12 | 
| Change of Dickkopf-related protein 3 | the mean change of Dickkopf-related protein 3 in each group | At day1 and at week 12 | 
| Difference of Dickkopf-related protein 3 | the mean difference of Dickkopf-related protein 3 among three groups | At day1 and at week 12 | 
| Change of galectin-3 | the mean change of galectin-3 in each group | At day1 and at week 12 | 
| Difference of galectin-3 | the mean difference of galectin-3 among three groups | At day1 and at week 12 | 
| Change of ST2 | the mean change of ST2 in each group | At day1 and at week 12 | 
| Difference of ST2 | the mean difference of ST2 among three groups | At day1 and at week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Serum uric acid, Metabolic syndrome, Left ventricular diastolic dysfunction, Febuxostat, Benzbromarone