Effects of Febuxostat for Lowering Uric Acid in NAFLD Patients With Gout

Study Overview
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Brief Summary
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Nonalcoholic fatty liver disease (NAFLD) is the most common and harmful chronic liver disease. NAFLD accounts for 49.3% of the total number of chronic liver disease patients in China. It is important to effectively prevent and control NAFLD and its related diseases. Previous studies show the level of serum uric acid is significantly elevated in patients with NAFLD. Xanthine oxidase is a key enzyme in uric acid metabolism. It is a new therapeutic target for NAFLD. This study is aimed to further confirm that hyperuricemia is a new risk factor for NAFLD through a large sample prospective study. Furthermore, this study explore whether Xanthine oxidase (XO), a key enzyme in uric acid metabolism, plays an important role in regulating NAFLD.

Detailed Description
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Nonalcoholic fatty liver disease (NAFLD) is the most common and harmful chronic liver disease. NAFLD accounts for 49.3% of the total number of chronic liver disease patients in China. It is important to effectively prevent and control NAFLD and its related diseases. Previous studies show the level of serum uric acid is significantly elevated in patients with NAFLD. In a large cross-sectional study, the researcher were the first to confirm that serum uric acid level was significantly increased in patients with NAFLD. The results were published in J Hepatol. Xanthine oxidase is a key enzyme in uric acid metabolism. It is a new therapeutic target for NAFLD. This study is aimed to further confirm that hyperuricemia is a new risk factor for NAFLD through a large sample prospective study. Furthermore, this study explore whether Xanthine oxidase (XO), a key enzyme in uric acid metabolism, plays an important role in regulating NAFLD.

Official Title
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Effects of Febuxostat for Interventions of Lowering Uric Acid in Patients With Gout With Nonalcoholic Fatty Liver Disease: a Multicenter, Open-label, Randomized, Controlled Study

Conditions
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Nonalcoholic Fatty Liver Disease

Intervention / Treatment
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* Drug: febuxostat treatment
* Behavioral: lifestyle intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: with informed consent; Ages 18-65; Overweight/obesity: BMI ≥24kg/m2; A history of gout with serum uric acid levels of > 420μmol/L in men and postmenopausal women, and >360 μmol/L in premenopausal women; Moderate or above fatty liver was found in the initial screening by ultrasound, and the liver fat content was more than 15% as determined by MRI-PDFF. Exclusion Criteria: with a history of allergy to febuxostat and allopurinol; in the acute active phase of gout; Drinking equivalent to alcohol intake ≥30g/d(male), ≥20g/d(female); Patients with obvious abnormal liver function: serum transaminase (ALT, AST, GGT one of them) or serum bilirubin (direct bilirubin, indirect bilirubin one of them) exceed 2 times the upper limit of normal reference value; Serum albumin <35g/L; Have a history of viral hepatitis, or serological examination suggests hepatitis virus infection, or have a history of other liver diseases; Complicated with renal insufficiency (SCr >133μmol/L) or urinary protein +; Complicated coronary heart disease; Cardiac dysfunction (cardiac function grade 2 or above); Complementation with diabetes, or fasting blood glucose >7.8mmol/L, or HbA1c >7.5%; Severe hypertension, blood pressure ≥ 160/100 mmHg; Patients with asthma and other respiratory diseases; Intestinal diseases such as inflammatory bowel disease; Any history of systemic malignancy in the past 5 years; Morbid obesity (BMI>37.5kg/m2); Triglyceride ≥5.0 mmol/L was found to be significantly abnormal in baseline examination; had received systemic hormone or immunosuppressive therapy within 3 months prior to screening, or expected to receive hormone or immunosuppressive therapy in the future; Use of uric-lowering drugs in the 4 weeks before screening: febuxostat, benzobromarone, allopurinol; Use of other drugs affecting uric acid metabolism were adjusted within 4 weeks before screening: losartan, fenofibrate, irbesartan, thiazide diuretics, loop medullaral diuretics, compound antihypertensive agents containing diuretics; Other drugs that may affect liver fat content were taken within 4 weeks before screening; Weight change ≥5% within 3 months before screening; Women who are lactating or pregnant or who plan to become pregnant within one year; were enrolled in other studies within 6 months before screening; unsuitable for participants to participate in this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Interventional Model Description: A total of 200 subjects are enrolled in this study. After the initial screening, the subjects were randomly divided into the control group and the drug treatment group. The control group was given lifestyle intervention at 0-24 weeks, and the experimental group was given febuxostat oral therapy on the basis of lifestyle intervention. If the results showed that the reduction of liver fat content of subjects in the lifestyle intervention combined with febuxostat treatment group was significantly better than that in the lifestyle intervention group alone, the original intervention was continued in the drug treatment group, and the control group was given febuxostat orally on the basis of the lifestyle intervention at 24-48 weeks.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group: Lifestyle intervention + febuxostat (40mg, once a day, orally)<br>participants accept febuxostat treatment in addition to lifestyle intervention for 0-48 week. | Drug: febuxostat treatment<br>* According to NAFLD guidelines, participants accept febuxostat treatment (40mg, once a day, orally)<br>Behavioral: lifestyle intervention<br>* According to NAFLD guidelines, participants receive lifestyle intervention (diet and exercise).<br>|
| Active Comparator: Control group: Lifestyle intervention<br>participants receive lifestyle intervention for 0-24 week. If the results of the 0-24 week study showed that the liver fat content of subjects in the experimental group was significantly lower than that in the control group, control group will accept febuxostat treatment in addition to lifestyle intervention in the next 25-48 week. | Behavioral: lifestyle intervention<br>* According to NAFLD guidelines, participants receive lifestyle intervention (diet and exercise).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver fat content of subjects in different groups | Liver fat was assessed based on Magnetic Resonance Imaging (MRI). | at the first week. | 
| Liver fat content of subjects in different groups | Liver fat was assessed based on Magnetic Resonance Imaging (MRI). | at the 24th week . | 
| Liver fat content of subjects in different groups | Liver fat was assessed based on Magnetic Resonance Imaging (MRI). | at the 48th week. | 
| Serum uric acid levels of subjects in different groups | blood samples was assessed after 12 hours overnight fasting for the determination of hematological and biochemical variables, which were measured using an automated hematology analyzer by standard methods. | at the first week | 
| Serum uric acid levels of subjects in different groups | blood samples was assessed after 12 hours overnight fasting for the determination of hematological and biochemical variables, which were measured using an automated hematology analyzer by standard methods. | at the forth week. | 
| Serum uric acid levels of subjects in different groups | blood samples was assessed after 12 hours overnight fasting for the determination of hematological and biochemical variables, which were measured using an automated hematology analyzer by standard methods. | at the twelfth week. | 
| Serum uric acid levels of subjects in different groups | blood samples was assessed after 12 hours overnight fasting for the determination of hematological and biochemical variables, which were measured using an automated hematology analyzer by standard methods. | at the 24th week. | 
| Serum uric acid levels of subjects in different groups | blood samples was assessed after 12 hours overnight fasting for the determination of hematological and biochemical variables, which were measured using an automated hematology analyzer by standard methods. | at the 36th week. | 
| Serum uric acid levels of subjects in different groups | blood samples was assessed after 12 hours overnight fasting for the determination of hematological and biochemical variables, which were measured using an automated hematology analyzer by standard methods. | at the 48th week. |