Urate Lowering Therapies and Left Ventricular Diastolic Dysfunction

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

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

Study Overview

• Status: Unknown
• Conditions: Metabolic Syndrome; Hyperuricemia; Left Ventricular Diastolic Dysfunction
• Intervention / Treatment: Drug: Febuxostat 40 mg; Drug: Benzbromarone 50mg; Other: Control

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Cheng-Wei Liu, M.D.; Phone Number: 671401 886-2-27642151; Email: issac700319@gmail.com

Study Locations

• Taiwan
  • Songshan Dist.
    • Taipei, Songshan Dist., Taiwan, 105
      • Recruiting
      • Tri-service General Hospital, songshan branch
      • Contact: Liu, MD; Phone Number: +886-910682383; Email: issac700319@gmail.com
      • Principal Investigator: Cheng-Wei Liu, MD
      • Sub-Investigator: Wei-Cheng Chang, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria (all of the four criteria)

1. Aged between 40-75 years
2. Metabolic syndrome
3. 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
4. Not take any of urate-lowering therapies (benzbromarone, allopurinol, or febuxostat)

Exclusion Criteria:

1. pregnancy
2. hypersensitivity to febuxostat or benzbromarone
3. acute gout
4. a history of urinary tract stone
5. chronic kidney disease stage IV or V
6. valvular heart disease with moderate or severe regurgitation
7. left ventricular ejection fraction of 40% or less
8. hypertrophic cardiomyopathy or dilated cardiomyopathy or infiltrative cardiomyopathy or constrictive cardiomyopathy
9. a history of congenital heart disease
10. a history of pulmonary hypertension
11. chronic atrial fibrillation or significant arrhythmia
12. a history of intracardiac device implantation
13. uncontrolled hypertension (systolic blood pressure > 160mm Hg or diastolic blood pressure > 100 mm Hg)
14. alanine Aminotransferase > 3 times upper limit)
15. acute infection
16. suspected or diagnosed with malignancy
17. a history of autoimmune disease
18. limited to or dependent on daily activities
19. life expectancy less than a year
20. Acute coronary syndrome or received a percutaneous coronary intervention or received a coronary artery graft bypass surgery or stroke within 3 months
21. Diabetes with insulin treatment or glucagon-like peptide 1 receptor agonist treatment
22. Anemia (hemoglobin < 11 mg/dl in mem or <10mg/dl in women)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Febuxostat 40mg; Febuxostat 40mg orally per day	Drug: Febuxostat 40 mg; Febuxostat 40 mg orally per day plus dietary control only; Other Names: Feburic
Active Comparator: Benzbromarone 50mg; Benzbromarone 50mg orally per day	Drug: Benzbromarone 50mg; Benzbromarone 50mg orally per day plus dietary control only; Other Names: Nogout
Other: Control; Dietary control only	Other: Control; Dietary control only

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Defense Medical Center, Taiwan
• Investigators: Principal Investigator: Cheng-Wei Liu, M.D., 1.Tri-service General hospital, Songshan branch, Taipei, Taiwan

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2020
• Primary Completion (Anticipated): December 1, 2021
• Study Completion (Anticipated): December 1, 2021

Study Registration Dates

• First Submitted: May 11, 2018
• First Submitted That Met QC Criteria: May 11, 2018
• First Posted (Actual): May 23, 2018

Study Record Updates

• Last Update Posted (Actual): April 28, 2020
• Last Update Submitted That Met QC Criteria: April 26, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Metabolic syndrome; Febuxostat; Serum uric acid; Benzbromarone; Left ventricular diastolic dysfunction
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Disease; Insulin Resistance; Hyperinsulinism; Ventricular Dysfunction; Syndrome; Metabolic Syndrome; Hyperuricemia; Ventricular Dysfunction, Left; Antirheumatic Agents; Gout Suppressants; Renal Agents; Uricosuric Agents; Febuxostat; Benzbromarone
• Other Study ID Numbers: 1-107-05-112

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No