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

Overview

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.

1\. Background 1. Hyperuricemia is a condition that underlies the development of gout. Gout incidence has been reported as 1.1% with urate levels \<6 mg/dL and 3% with urate levels between 6-7 mg/dL in longitudinal studies. However, few studies have examined the incidence after suspending urate-lowering therapy following long-term maintenance of serum urate \<6 mg/dL. 2. A US study found that gout patients who maintained serum urate \<6.0 mg/dL for over 5 years and had resolved tophi did not experience flare-ups if levels remained \<7 mg/dL, while recurrence occurred in those with levels \>7 mg/dL. Based on these findings, the study proposed a two-stage gout treatment strategy, known as the "dirty dish" hypothesis. 3. The approved minimum dose of febuxostat is 40 mg/day. Previous studies observed that febuxostat 20 mg/day reduced serum urate levels to \<7.0 mg/dL, although it did not meet the current treatment goal during the initial phase. 4. Therefore, a low dose of febuxostat at 20 mg/day could be sufficient to meet the preventive treatment goal of \<7 mg/dL proposed by the "dirty dish" hypothesis 2\. Sample size determination 1. Average serum urate levels and standard deviations were extracted from 2 previous clinical trials for febuxostat (including 20 mg/day dose) and 3 observational studies on the effects of complete discontinuation of urate-lowering agents. The proportion of patients with serum uric acid levels \<7.0 mg/dL was calculated using the normal distribution curve. 2. Based on previous studies, we assumed that the smallest proportion of subjects with serum urate \<7.0 mg/dL is 5% for the discontinuing group and 56% for the reducing group. Fisher's exact test (1-β = 0.80, α = 0.05, 2:1 ratio) indicates that 12 subjects are needed for the discontinuing group and 24 for the reducing group. Adjusting for a 15% dropout rate, the final numbers are 15 and 29, respectively. 3. The urate-lowering therapy-maintaining group is expected to have a 100% rate of serum urate \<7.0 mg/dL as they are treated according to current guidelines. Therefore, in the case of the maintaining group, 15 subjects - half the number in the discontinuing group - will be assigned to this group without statistical calculation. 2\. General principles of statistical analysis 1\) Categorical variables will be presented as frequencies and percentages, with 95% CIs if needed. Chi-square tests and Fisher's exact tests will be used for categorical outcomes. For missing data or withdrawals, the analysis will use available data, replacing missing values with the previous measurement. 2\) Analysis population 1. SAS (Safety Analysis Set): Includes all participants who received at least one dose of the investigational drug. Safety data analysis will be conducted using SPSS or R. 2. FAS (Full Analysis Set or Intention-to-Treat Set): Includes participants who received at least one dose of the drug and have available primary outcome data (serum urate levels) before and after treatment. 3. PPS (Per-Protocol Set): Consists of FAS participants with no major protocol violations, such as significant inclusion/exclusion criteria breaches, prohibited medication use, or adherence issues. Efficacy analysis will be primarily conducted with the PPS, with additional analysis in the FAS. 3\) Efficacy analysis The primary analysis population is the PPS, with sensitivity analysis conducted in the FAS. 4\) Safety analysis The primary analysis population is the SAS. Descriptive statistics will be presented and analyzed for all adverse events occurring after the administration of the investigational drug, as well as for clinical laboratory results, vital signs, physical examinations, electrocardiograms, and liver function tests.