Comparative Study Between Febuxostat Versus Vitamin E in Non-alcoholic Steatohepatitis Patients With Hyperuricemia

NCT ID: NCT05574036

Last Updated: 2025-01-23

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 70 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-08-25
• Study Completion Date: 2026-12-25

Brief Summary

This study aims at evaluating and comparing the protective outcomes of using Febuxostat versus Vitamin E in Hyperuricemia non-alcoholic steatohepatitis patients without cirrhosis. The intervention is 6-months duration and the study will assess the efficacy of either drug as fibrosis improvement (≥ 1 stage) with no worsening of NASH or NASH resolution with no worsening of fibrosis with the study considered successful if either 1ry end point is met. Also, assessment of biochemical markers related to steatosis, inflammation, oxidative stress, insulin resistance and liver fibrosis will be done.

Detailed Description

Nonalcoholic fatty liver disease (NAFLD) is defined as the accumulation of excessive fat in the liver in the setting of no significant alcohol consumption and the absence of any secondary cause. NAFLD has reached epidemic proportions and currently affects 20-40% of the general population. In recent years, along with the increasing trend of obesity and type 2 diabetes, NAFLD has become one of the most common chronic liver diseases worldwide. The spectrum of the disease ranges from simple steatosis to hepatocellular injury with inflammatory infiltration characterized as nonalcoholic steatohepatitis (NASH) that may eventually progress to liver fibrosis, cirrhosis and hepatocellular carcinoma. Despite significant disease burden and mortality associated mainly with advanced disease, i.e., NASH and fibrosis, there is currently no approved medication for NASH, therefore, lifestyle modifications remain the mainstay of treatment. What is the pathogenesis of NAFLD? Although the proposal of "two hits" involving insulin resistance (IR) and oxidative stress has been well accepted, the mechanism of NAFLD was thought very complex and still remained unclearly.

Besides metabolic syndrome-related conditions, hyperuricemia has also been linked to NASH. Several epidemiological studies have demonstrated that patients with NASH have significantly higher serum uric acid (UA) levels relative to controls, and elevated serum UA levels are an independent risk factor for NAFLD. Notably, UA itself has been reported to promote de novo lipogenesis and induce IR, both in vivo and in vitro, through increased NADPH oxidase (NOX)-mediated reactive oxygen species (ROS) generation and activation of the Nucleotide-binding and oligomerization domain (NOD-like) receptor family pyrin domain containing 3 (NLRP3) inflammasome. It is thought that hyperuricemia in NAFLD is primarily due to increased expression and/or activity of hepatic xanthine oxidase (XO). These observations indicate that hyperuricemia plays a causative role in the development of NASH.

The xanthine oxidase (XO) inhibitor, febuxostat, decreases free fatty acids-induced fat accumulation in the liver of high-fat diet containing trans-fatty acids (HFDT) fed mice. It was further found that the underlying mechanism is related to the reduction in expression of NLRP3 and improved insulin resistance. This finding highlights the possible molecular pathways involving NLRP3 activation for management of ROS and IR. In conclusion, febuxostat may be a promising potential treatment for patients with NASH.

It is acknowledged that vitamin E is the major lipid-soluble chain-breaking antioxidant found in the human body. In addition to its anti-oxidative properties, molecules of vitamin E family exert anti-atherogenic and anti-inflammatory activities. According to American Association for the Study of Liver Diseases (AASLD) and National Institute for Health and Care Excellence (NICE) guidelines, vitamin E is approved at a dose of 800 IU/day in adults with biopsy-proven NASH.

Therefore, This study aims at evaluating and comparing the protective outcomes of using Febuxostat versus Vitamin E in hyperuricemic NASH patients without cirrhosis.

The primary endpoint of this 6-months study would be fibrosis improvement (≥

1 stage) with no worsening of NASH or NASH resolution with no worsening of fibrosis with the study considered successful if either 1ry end point is met.

The secondary endpoint of this study is improvement of biochemical markers related to steatosis, inflammation, oxidative stress, insulin resistance and liver fibrosis.

Study Population:

• This study is conducted on 60 patients diagnosed with Hyperuricemic NASH according to the study protocol.
• Patients has been recruited from Tropical Medicine and Infectious Diseases Department, Tanta University Hospital, Tanta, Egypt.
• The study was approved by the Research Ethics Committee of Tanta University.
• All patients have provided signed written informed consent and agreed to comply with the study protocol.
• All data of the patients will be private and confidential.
• Any unexpected risks appeared during the course of the research was cleared to the patients and the ethical committee on time.

This study is randomized controlled, parallel and prospective 6-months duration study. Accepted patients was randomized into 2 groups as the following:

• Group 1 (Febuxostat group): 30 patients will receive 80 mg/day febuxostat for 6 months.
• Group 2 (Control group): 30 patients will receive Vitamin E 400 mg twice daily for 6 months.

Any side effects will be reported and graded according to common terminology criteria for adverse events version 5.00 (CTCAE). Any potential drug interactions between administered drugs is monitored for each patient and corrective actions is taken.

Statistical Analysis

• All data will be represented as mean ± slandered deviation (SD).
• Unpaired Student's t-test will be used to compare data between the two groups.
• Paired Student's t-test will be used to compare data within the same group before and after treatment with the studied medications.
• Chi-square test will be used for statistical analysis of nominal data.
• The statistical analysis will be carried out using Statistical Package for the Social Sciences (SPSS) statistical package version 27.0 (December 2020), IBM (International Business Machines) corporation software group, USA.
• The level of significance will be set at P< 0.05.

Conditions

Non Alcoholic Steatohepatitis; Hyperuricemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Group 1 Febuxostat group

35 non alcoholic steatohepatitis hyperuricemic patients receiving Febuxostat 80 mg once daily for 6 months duration

Group Type: ACTIVE_COMPARATOR

Febuxostat 80 MG Oral Tablet

Intervention Type: DRUG

Febuxostat used as 80 mg oral tablet once daily for 6 months

Group 2 vitamin E group

35 non alcoholic steatohepatitis Hyperuricemic patients receiving vitamin E 400 mg twice daily for 6 months duration

Group Type: ACTIVE_COMPARATOR

vit E

Intervention Type: DRUG

Vitamin E used as 400 mg soft gelatin capsules twice daily for 6 months

Interventions

Febuxostat 80 MG Oral Tablet

Febuxostat used as 80 mg oral tablet once daily for 6 months

Intervention Type: DRUG

vit E

Vitamin E used as 400 mg soft gelatin capsules twice daily for 6 months

Intervention Type: DRUG

Other Intervention Names

Andouristat 80 mg, Staturic 80 mg; Vitamin E 400 mg

Eligibility Criteria

Inclusion Criteria

• Males or females aged ≥18 years.
• All patients are diagnosed to have fatty liver grading 1, 2 or 3 on abdominal ultrasound with Hepatic steatosis index > 36 to be considered as a NAFLD patient.
• Serum uric acid level ≥ 6 mg/dl.
• Confirmed diagnosis of NASH using at least three of the following non-invasive tests:
• HAIR score
• Fibroscan detecting steatosis with F0-3 fibrosis stage
• Cytokeratin-18 >240 U/L
• Mild to moderate elevation of serum aminotransferases (>2 but <5 times upper normal limit)

Exclusion Criteria

• Current or history of significant alcohol consumption.
• Use of drugs historically associated with nonalcoholic fatty liver disease (NAFLD) (amiodarone, methotrexate, systemic glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used for hormone replacement, anabolic steroids, valproic acid, and other known hepatotoxins).
• Prior or planned bariatric surgery.
• Patients with Hemoglobin A1c 9.5% or higher.
• Evidence of other forms of chronic liver disease as Hepatitis B, Hepatitis C, Wilson's disease, Alpha-1-antitrypsin(A1AT) deficiency, Hemochromatosis, drug-induced liver disease.
• Serum creatinine of 2.0 mg/dL or greater.
• Pregnancy, planned pregnancy, potential for pregnancy and unwillingness to use effective birth control during the trial and breast feeding.
• Use of other drugs known to have possible positive effects on steatosis.
• Patients on oral anticoagulants as warfarin.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Tanta University

OTHER

Sponsor Role: lead

Responsible Party

Hadier Mohammed El-Sheikh

Assistant lecturer of clinical pharmacy- Clinical pharmacy department- Faculty of pharmacy

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Hadier m. El-sheikh

Role: PRINCIPAL_INVESTIGATOR

Department of Clinical pharmacy, Faculty of Pharmacy, Tanta university

Locations

Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine,Tanta University

Tanta, , Egypt

Countries

Egypt

References

El Hadi H, Vettor R, Rossato M. Vitamin E as a Treatment for Nonalcoholic Fatty Liver Disease: Reality or Myth? Antioxidants (Basel). 2018 Jan 16;7(1):12. doi: 10.3390/antiox7010012.

Reference Type: BACKGROUND

PMID: 29337849 (View on PubMed)

Afzali A, Weiss NS, Boyko EJ, Ioannou GN. Association between serum uric acid level and chronic liver disease in the United States. Hepatology. 2010 Aug;52(2):578-89. doi: 10.1002/hep.23717.

Reference Type: BACKGROUND

PMID: 20683957 (View on PubMed)

Zhu Y, Hu Y, Huang T, Zhang Y, Li Z, Luo C, Luo Y, Yuan H, Hisatome I, Yamamoto T, Cheng J. High uric acid directly inhibits insulin signalling and induces insulin resistance. Biochem Biophys Res Commun. 2014 May 16;447(4):707-14. doi: 10.1016/j.bbrc.2014.04.080. Epub 2014 Apr 21.

Reference Type: BACKGROUND

PMID: 24769205 (View on PubMed)

Tang W, Mu J, Chen QI, Li X, Liu H. The involvement and mechanism of febuxostat in non-alcoholic fatty liver disease cells. J Biol Regul Homeost Agents. 2018 May-Jun;32(3):545-551.

Reference Type: BACKGROUND

PMID: 29921379 (View on PubMed)

Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018 Jan;67(1):328-357. doi: 10.1002/hep.29367. Epub 2017 Sep 29. No abstract available.

Reference Type: BACKGROUND

PMID: 28714183 (View on PubMed)

El-Sheikh H, El-Haggar S, Badawi R, Habba E. Comparative efficacy of febuxostat and vitamin E in the management of MASLD: Insights from a randomized parallel clinical study. Eur J Pharmacol. 2025 Aug 5;1000:177735. doi: 10.1016/j.ejphar.2025.177735. Epub 2025 May 16.

Reference Type: DERIVED

PMID: 40383220 (View on PubMed)

Related Links

https://www.clinicaltrials.gov/ct2/show/NCT04772352

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

https://www.mayoclinic.org/drugs-supplements-vitamin-e/art-20364144

Vitamin E and NAFLD

Other Identifiers

34512/2/22

Identifier Type: -

Identifier Source: org_study_id