the Effects of Febuxostat Dose Tapering in Gout Patients Optimally Controlled for 5 Years or More

Summary

The goal of this clinical trial is to compare the changes in serum urate levels and symptom recurrence after reducing or suspending urate-lowering agents in well-controlled gout patients (the 'after dishes are clean' state in the Dirty Dish hypothesis) Researchers will compare three randomized groups: the reducing group takes febuxostat 20 mg once daily for 12 months, the discontinuing group takes a placebo once daily for 6 months, followed by febuxostat 20 mg once daily for the next 6 months, and the maintaining group continues their pre-study urate-lowering agents for 12 months, serving as an observational reference group. During the 12-month study period, participants will visit every 3 months for laboratory evaluations including serum urate levels, and for checking symptomatic status using questionnaires and diaries. Additionally, musculoskeletal ultrasonography and serum sample collection will be performed at baseline to study predictors for maintaining serum urate levels \<7.0 mg/dL after reducing or suspending urate-lowering therapy.

Timeline

Start

2025-09-10

Primary completion

2027-02-19

Completion

2027-08-19

Publications

• Background Dalbeth N, Phipps-Green A, Frampton C, Neogi T, Taylor WJ, Merriman TR. Relationship between serum urate concentration and clinically evident incident gout: an individual participant data analysis. Ann Rheum Dis. 2018 Jul;77(7):1048-1052. doi: 10.1136/annrheumdis-2017-212288. Epub 2018 Feb 20.
• Background Robinson PC, Frampton C, Phipps-Green A, Neogi T, Stamp L, Taylor W, Merriman TR, Dalbeth N. Longitudinal development of incident gout from low-normal baseline serum urate concentrations: individual participant data analysis. BMC Rheumatol. 2021 Aug 28;5(1):33. doi: 10.1186/s41927-021-00204-4.
• Background FitzGerald JD, Dalbeth N, Mikuls T, Brignardello-Petersen R, Guyatt G, Abeles AM, Gelber AC, Harrold LR, Khanna D, King C, Levy G, Libbey C, Mount D, Pillinger MH, Rosenthal A, Singh JA, Sims JE, Smith BJ, Wenger NS, Bae SS, Danve A, Khanna PP, Kim SC, Lenert A, Poon S, Qasim A, Sehra ST, Sharma TSK, Toprover M, Turgunbaev M, Zeng L, Zhang MA, Turner AS, Neogi T. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res (Hoboken). 2020 Jun;72(6):744-760. doi: 10.1002/acr.24180. Epub 2020 May 11.
• Background Scheepers LEJM, van Onna M, Stehouwer CDA, Singh JA, Arts ICW, Boonen A. Medication adherence among patients with gout: A systematic review and meta-analysis. Semin Arthritis Rheum. 2018 Apr;47(5):689-702. doi: 10.1016/j.semarthrit.2017.09.007. Epub 2017 Oct 7.
• Background Kim A, Kim Y, Kim GT, Ahn E, So MW, Lee SG. Comparison of persistence rates between allopurinol and febuxostat as first-line urate-lowering therapy in patients with gout: an 8-year retrospective cohort study. Clin Rheumatol. 2020 Dec;39(12):3769-3776. doi: 10.1007/s10067-020-05161-w. Epub 2020 May 26.
• Background Perez-Ruiz F, Herrero-Beites AM, Carmona L. A two-stage approach to the treatment of hyperuricemia in gout: the "dirty dish" hypothesis. Arthritis Rheum. 2011 Dec;63(12):4002-6. doi: 10.1002/art.30649.
• Background Loebl WY, Scott JT. Withdrawal of allopurinol in patients with gout. Ann Rheum Dis. 1974 Jul;33(4):304-7. doi: 10.1136/ard.33.4.304. No abstract available.
• Background Perez-Ruiz F, Atxotegi J, Hernando I, Calabozo M, Nolla JM. Using serum urate levels to determine the period free of gouty symptoms after withdrawal of long-term urate-lowering therapy: a prospective study. Arthritis Rheum. 2006 Oct 15;55(5):786-90. doi: 10.1002/art.22232.
• Background Komoriya K, Hoshide S, Takeda K, Kobayashi H, Kubo J, Tsuchimoto M, Nakachi T, Yamanaka H, Kamatani N. Pharmacokinetics and pharmacodynamics of febuxostat (TMX-67), a non-purine selective inhibitor of xanthine oxidase/xanthine dehydrogenase (NPSIXO) in patients with gout and/or hyperuricemia. Nucleosides Nucleotides Nucleic Acids. 2004 Oct;23(8-9):1119-22. doi: 10.1081/NCN-200027381.
• Background Kamatani N, Fujimori S, Hada T, Hosoya T, Kohri K, Nakamura T, Ueda T, Yamamoto T, Yamanaka H, Matsuzawa Y. Placebo-controlled, double-blind study of the non-purine-selective xanthine oxidase inhibitor Febuxostat (TMX-67) in patients with hyperuricemia including those with gout in Japan: phase 3 clinical study. J Clin Rheumatol. 2011 Jun;17(4 Suppl 2):S19-26. doi: 10.1097/RHU.0b013e31821d36de.
• Background Liang N, Sun M, Sun R, Xu T, Cui L, Wang C, Ma L, Cheng X, Xue X, Sun W, Yuan X, Zhang H, Li H, He Y, Ji A, Wu X, Li C. Baseline urate level and renal function predict outcomes of urate-lowering therapy using low doses of febuxostat and benzbromarone: a prospective, randomized controlled study in a Chinese primary gout cohort. Arthritis Res Ther. 2019 Sep 2;21(1):200. doi: 10.1186/s13075-019-1976-x.
• Background Yan F, Xue X, Lu J, Dalbeth N, Qi H, Yu Q, Wang C, Sun M, Cui L, Liu Z, He Y, Yuan X, Chen Y, Cheng X, Ma L, Li H, Ji A, Hu S, Ran Z, Terkeltaub R, Li C. Superiority of Low-Dose Benzbromarone to Low-Dose Febuxostat in a Prospective, Randomized Comparative Effectiveness Trial in Gout Patients With Renal Uric Acid Underexcretion. Arthritis Rheumatol. 2022 Dec;74(12):2015-2023. doi: 10.1002/art.42266. Epub 2022 Nov 11.
• Background Morillon MB, Christensen R, Singh JA, Dalbeth N, Saag K, Taylor WJ, Neogi T, Kennedy MA, Pedersen BM, McCarthy GM, Shea B, Diaz-Torne C, Tedeschi SK, Grainger R, Abhishek A, Gaffo A, Nielsen SM, Noerup A, Simon LS, Lassere M, Tugwell P, Stamp LK, Gout Working Group FTO. Serum urate as a proposed surrogate outcome measure in gout trials: From the OMERACT working group. Semin Arthritis Rheum. 2021 Dec;51(6):1378-1385. doi: 10.1016/j.semarthrit.2021.11.004. Epub 2021 Nov 15.
• Background Khosravan R, Grabowski BA, Wu JT, Joseph-Ridge N, Vernillet L. Pharmacokinetics, pharmacodynamics and safety of febuxostat, a non-purine selective inhibitor of xanthine oxidase, in a dose escalation study in healthy subjects. Clin Pharmacokinet. 2006;45(8):821-41. doi: 10.2165/00003088-200645080-00005.
• Background Hirsch JD, Terkeltaub R, Khanna D, Singh J, Sarkin A, Shieh M, Kavanaugh A, Lee SJ. Gout disease-specific quality of life and the association with gout characteristics. Patient Relat Outcome Meas. 2010 Mar 1;2010:1-8. doi: 10.2147/PROM.S8310.
• Background Scire CA, Carrara G, Viroli C, Cimmino MA, Taylor WJ, Manara M, Govoni M, Salaffi F, Punzi L, Montecucco C, Matucci-Cerinic M, Minisola G; Study Group for the Kick-Off of the Italian Network for Gout Study. Development and First Validation of a Disease Activity Score for Gout. Arthritis Care Res (Hoboken). 2016 Oct;68(10):1530-7. doi: 10.1002/acr.22844. Epub 2016 Sep 6.
• Background La-Crette J, Jenkins W, Fernandes G, Valdes AM, Doherty M, Abhishek A. First validation of the gout activity score against gout impact scale in a primary care based gout cohort. Joint Bone Spine. 2018 May;85(3):323-325. doi: 10.1016/j.jbspin.2017.05.010. Epub 2017 May 17.
• Background Ichida K, Matsuo H, Takada T, Nakayama A, Murakami K, Shimizu T, Yamanashi Y, Kasuga H, Nakashima H, Nakamura T, Takada Y, Kawamura Y, Inoue H, Okada C, Utsumi Y, Ikebuchi Y, Ito K, Nakamura M, Shinohara Y, Hosoyamada M, Sakurai Y, Shinomiya N, Hosoya T, Suzuki H. Decreased extra-renal urate excretion is a common cause of hyperuricemia. Nat Commun. 2012 Apr 3;3:764. doi: 10.1038/ncomms1756.
• Background Gaffo AL, Dalbeth N, Saag KG, Singh JA, Rahn EJ, Mudano AS, Chen YH, Lin CT, Bourke S, Louthrenoo W, Vazquez-Mellado J, Hernandez-Llinas H, Neogi T, Vargas-Santos AB, da Rocha Castelar-Pinheiro G, Amorim RBC, Uhlig T, Hammer HB, Eliseev M, Perez-Ruiz F, Cavagna L, McCarthy GM, Stamp LK, Gerritsen M, Fana V, Sivera F, Taylor W. Brief Report: Validation of a Definition of Flare in Patients With Established Gout. Arthritis Rheumatol. 2018 Mar;70(3):462-467. doi: 10.1002/art.40381. Epub 2018 Feb 6.
• Background Cipolletta E, Di Battista J, Di Carlo M, Di Matteo A, Salaffi F, Grassi W, Filippucci E. Sonographic estimation of monosodium urate burden predicts the fulfillment of the 2016 remission criteria for gout: a 12-month study. Arthritis Res Ther. 2021 Jul 9;23(1):185. doi: 10.1186/s13075-021-02568-x.

Drugs

Indications