Clinical Study to Evaluate the Possible Efficacy and Safety of Febuxostat in Patients With Ulcerative Colitis Treated With Mesalamine

Overview

Evaluation the possible efficacy and safety of febuxostat in patients with ulcerative colitis treated with mesalamine.

Detailed description

Ulcerative colitis (UC) is a sub-category of inflammatory bowel diseases (IBD) that causes mucosal inflammation in the rectum and lower colon. Although the exact pathogenesis of ulcerative colitis remains unclear, potential risk factors include altered immune responses, overactive immune response toward commensal microflora, genetic susceptibility, and environmental factors that have been considered as potential risk factors for UC .

The pathogenesis of UC consists of immuno-inflammatory pathways related to the multiple components of the intestine, including the epithelial barrier, dysregulation of immunological responses, leukocyte recruitment, and genetic factors. The understanding of immuno-inflammatory pathways of UC might lead to the development of a specific therapy and/or a novel treatment that could be more efficient .

Mesalazine (also known as mesalamine or 5- amino salicylic acid, 5-ASA) has a well-established role in UC management. It is the first line therapy for mild to moderate UC and it is considered the cornerstone in the management of UC. The mechanism of action of mesalazine is diverse. It acts locally on colonic mucosa and reduces inflammation by several anti-inflammatory processes .

Febuxostat (FXT) is a medication used in management hyperuricemia espicially in gout, a condition characterized by joints pain as result of deposition of uric acid crystals due to elevated urate blood levels. It's a non-purine selective xanthine oxidase inhibitor. Xanthin oxidase is an enzyme that plays a main role in production of uric acid from xanthine and hypoxanthine.

Furthermore, there is no need for dose modification of FXT in case of renal impairment and so it's great choice for many patients as it may exhibit renal protective effect and delay progression of kidney injury and according to Zhou H et al. FXT appears to be well tolerated in healthy population who has normal serum uric acid levels with no serious adverse events were reported .

Lately, febuxostat's spectrum of use has expanded over hyperuricemia management as result of it's ability of amelioration oxidative stress and regulation inflammatory response due to pro -inflammatory cytokines modulation.

Keyvan Amirshahrokhi and El-Mahdy NA et al. inspected the potential of FXT in mitigating ulcerative colitis in mice. The findings from those studies suggest that febuxostat may exert anti- inflammatory effects in the context of ulcerative colitis. Febuxostat's anti- inflammatory effects in ulcerative colitis may be linked to its inhibition of the nuclear factor kappa B (NF-κB) signaling pathway, a key regulator of inflammation. This inhibition can reduce the production of proinflammatory cytokines, contributing to its anti-inflammatory properties .

Although, preclinical studies in animal models are promising, translating these results into clinical applications is necessary to evaluate the safety and efficacy of FXT in managing UC in human.

Interventions

• Drug Febuxostat
  40mg of Febuxostat once daily
• Drug Mesalamine
  1 g mesalamine three times daily for 3 months.

Primary outcome measures

• Assessment of disease activity using Partial Mayo Scoring Index (PMSI) assessment for Ulcerative Colitis Activity. [Time frame: 3 months]
• Health-related quality of life (HRQOL) using the short inflammatory bowel disease questionnaire . [Time frame: 3 months]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years old.
• Both male and female will be included.
• Mild and moderate UC patients diagnosed and confirmed by endoscope.
• Patient treated with 5-aminosalislic acid (mesalamine).

Exclusion criteria

• Patients with severe UC.
• Significant liver and kidney function abnormalities.
• Diabetic patients.
• Patients with Colorectal cancer patients.
• Patients taking rectal or systemic steroids.
• Patients on immunosuppressants or biological therapies.
• Addiction to alcohol and / or drugs.
• Known allergy to the studied medications.
• History of complete or partial colectomy.
• Patients with congestive heart failure, other heart disease (Arrhythmia, ischemic heart disease including angina and myocardial infarction).
• Patients with other inflammatory diseases and active infection.
• Patients with stressful condition (COPD, morbid obesity).
• Patients with liver disease.
• Patients with thrombocytopenia and neutropenia.
• Pregnant or lactating females.
• Patients were treated with mercaptopurine.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Abdel-Wahab BA, El-Shoura EAM, Shafiuddin Habeeb M, Zafaar D. Febuxostat alleviates Arsenic Trioxide-Induced renal injury in Rats: Insights on the crosstalk between NLRP3/TLR4, Sirt-1/NF-kappaB/TGF-beta signaling Pathways, and miR-23b-3p, miR-181a-5b expression. Biochem Pharmacol. 2023 Oct;216:115794. doi: 10.1016/j.bcp.2023.115794. Epub 2023 Sep 7. PMID 37689273
• Amirshahrokhi K. Febuxostat attenuates ulcerative colitis by the inhibition of NF-kappaB, proinflammatory cytokines, and oxidative stress in mice. Int Immunopharmacol. 2019 Nov;76:105884. doi: 10.1016/j.intimp.2019.105884. Epub 2019 Sep 6. PMID 31499267
• Cicero AFG, Fogacci F, Kuwabara M, Borghi C. Therapeutic Strategies for the Treatment of Chronic Hyperuricemia: An Evidence-Based Update. Medicina (Kaunas). 2021 Jan 10;57(1):58. doi: 10.3390/medicina57010058. PMID 33435164
• El-Mahdy NA, Saleh DA, Amer MS, Abu-Risha SE. Role of allopurinol and febuxostat in the amelioration of dextran-induced colitis in rats. Eur J Pharm Sci. 2020 Jan 1;141:105116. doi: 10.1016/j.ejps.2019.105116. Epub 2019 Oct 23. PMID 31654756
• Elsisi AEE, Sokar SS, Shalaby MF, Abu-Risha SE. Nephroprotective effects of febuxostat and/or mirtazapine against gentamicin-induced nephrotoxicity through modulation of ERK 1/2, NF-kappaB and MCP1. Expert Rev Clin Pharmacol. 2021 Aug;14(8):1039-1050. doi: 10.1080/17512433.2021.1933435. Epub 2021 Jun 9. PMID 34030558
• Fukui T, Maruyama M, Yamauchi K, Yoshitaka S, Yasuda T, Abe Y. Effects of Febuxostat on Oxidative Stress. Clin Ther. 2015 Jul 1;37(7):1396-401. doi: 10.1016/j.clinthera.2015.03.026. Epub 2015 Apr 23. PMID 25913922
• Hao G, Duan W, Sun J, Liu J, Peng B. Effects of febuxostat on serum cytokines IL-1, IL-4, IL-6, IL-8, TNF-alpha and COX-2. Exp Ther Med. 2019 Jan;17(1):812-816. doi: 10.3892/etm.2018.6972. Epub 2018 Nov 15. PMID 30651867
• Irvine EJ, Zhou Q, Thompson AK. The Short Inflammatory Bowel Disease Questionnaire: a quality of life instrument for community physicians managing inflammatory bowel disease. CCRPT Investigators. Canadian Crohn's Relapse Prevention Trial. Am J Gastroenterol. 1996 Aug;91(8):1571-8. PMID 8759664

Identifiers

NCT: NCT06525974 · MS.24.04.2758

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗