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

A Prospective, Multicenter, Randomized Investigator Initiative Clinical Trial Study on the Effects of Febuxostat Dose Tapering in Gout Patients Optimally Controlled for 5 Years or More

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.

• Inclusion Criteria:

  1. Adult gout patients aged ≥19 but <80 years.

  2. Gout patients treated with urate-lowering therapy (either allopurinol or febuxostat monotherapy, or a combination of two agents) for at least the past 5 years.

  3. Patients who have at least five serum urate level measurements over the past 5 years and meet one of the following criteria:

     All serum urate levels measured in the past 5 years have been maintained below 6.0 mg/dL; or the area under the curve (AUC) of serum urate levels over time for the past 5 years is less than 33.0 mg/dL x year

  4. Patients without palpable or visible tophi on physical examination (evaluated at pre-defined 18 joint sites and the ears).

  5. Patients without acute gouty attack or history of nephrolithiasis in the past 12 months

  6. Patients with an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73m² or higher, based on the Cockcroft-Gault formula.

  7. Patients who voluntarily provide written informed consent to participate.

• Exclusion Criteria:

  1. Subjects who continuously require prophylactic low-dose colchicine/NSAIDs.

  2. Subjects already having taken low-dose urate-lowering agents. The low-dose urate-lowering agents are defined as allopurinol ≤200 mg/day or febuxostat ≤20 mg/day. But patients on a combination of low-dose allopurinol and febuxostat are eligible.

  3. Subjects taking medications that could affect serum uric acid levels and uric acid fractional excretion rates, such as benzbromarone, fenofibrate, loop diuretics, thiazide or thiazide-like diuretics, and losartan.

  4. Subjects classified as having high-risk alcohol use according to the National Institute on Alcohol Abuse and Alcoholism (NIAAA):

     For men <65 years: more than 14 drinks per week or for men ≥65 years or women: more than 7 drinks per week

  5. Subjects with a history of hypersensitivity to febuxostat or allopurinol

  6. Subjects with unstable cardiovascular conditions, who require adjustment of urgent their therapy

  7. Subjects taking mercaptopurine or azathioprine

  8. Subjects with genetic issues such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption

  9. Subjects with moderate or severe liver dysfunction (AST or ALT levels greater than 3 times the upper normal limit)

  10. Subjects for whom investigators anticipate that a change in a urate-lowering agent dose could present significant risks or that any factor could severely impact drug adherence, complicating study registration.