Evaluation of Allopurinol and Febuxostat in the Maintenance or Withdrawal of Urate-Lowering Therapy in Gout Patients: A Randomized Controlled Trial

The primary objective of this study is to demonstrate that the withdrawal of oral **urate lowering therapy** (ULT) in patients with **gout** in remission, monitored with ultrasound (US) scans, is not inferior to maintaining oral ULT in terms of the risk of flares over a period of two years. This is clinically relevant as it may inform treatment strategies for managing gout, potentially reducing medication burden and associated costs while maintaining patient outcomes.

Secondary objectives include evaluating:

• The proportion of patients experiencing one or more flares and mean flare rates.
• The incidence of US features of gout.
• The serum uric acid (SUA) levels.
• The Outcome Measures in Rheumatology (OMERACT) core outcome domains for long-term gout studies.
• The incidence of major cardiovascular events.
• The incidence of comorbidities and mortality.
• The kidney function, measured by estimated glomerular filtration rate (eGFR).
• The consumption of colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), and steroids over the study period.
• The tolerance and adverse events of medications.
• The adherence to ULT.
• The cost-effectiveness of ULT withdrawal with US monitoring.

The clinical trial involves **adult patients** diagnosed with **gout**, specifically those in remission. The study population includes both male and female participants aged 18 years and older. Participants are required to have been free of gout flares for at least two years and must not have any tophi. They should currently be receiving allopurinol or febuxostat for at least two years, with serum uric acid levels maintained at or below 60 mg/l. Additionally, participants must not have urate deposits on ultrasound at the inclusion visit at both the first metatarsophalangeal joints and knees. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants are expected to have the ability to provide informed consent and possess health insurance. The selection criteria ensure that the study focuses on a specific subset of the gout population, allowing for precise evaluation of the trial's objective.

The clinical trial is designed to evaluate the efficacy of **urate-lowering therapy** (ULT) withdrawal in patients with **gout** in remission, compared to the continuation of ULT, in terms of the risk of flares over a two-year period. This is a non-inferior, open-label, two-group, 1:1 randomized controlled, parallel-arm trial. The trial will involve adult patients diagnosed with gout, as defined by the 2015 ACR/EULAR classification criteria, who have been free of flares for at least two years and are currently receiving either **allopurinol** or **febuxostat**. The trial is set to commence recruitment on February 3, 2025, and is expected to conclude by February 3, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as the absence of tophi and urate deposits on ultrasound, and the ability to provide informed consent. Follow-up visits will occur at months 6, 12, 18, 24, 30, and 36, during which primary and secondary endpoints will be assessed. The primary endpoint is the proportion of patients experiencing one or more flares at two years, while secondary endpoints include flare rates at various intervals, ultrasound features of gout, urate levels, and changes in health-related quality of life, among others. The end-of-study visit will mark the completion of the trial for each participant.

The expected duration of participant involvement is up to 36 months, with conditions for early termination including the occurrence of adverse events or non-compliance with the study protocol. Participants will be monitored for adherence to ULT and the incidence of adverse events, with data collected on the consumption of medications such as colchicine, NSAIDs, and steroids. The trial will also evaluate the cost-effectiveness of ULT withdrawal versus maintenance, using incremental cost-effectiveness ratios. The study aims to provide valuable insights into the management of gout in patients in remission, with the potential to inform future treatment guidelines.

The clinical trial involves the administration of **Allopurinol**, a chemical compound used as an experimental medication. Allopurinol is provided in the form of tablets and is administered orally. The maximum daily dose is 900 mg, with a total maximum dose of 837 g over the treatment period. The treatment duration is set for a maximum of 30 days. Participants are required to adhere to the dosing schedule, and compliance will be monitored throughout the study. Allopurinol is not a pediatric formulation and is not classified as an orphan drug.

Another experimental medication used in the trial is **Febuxostat**, also a chemical compound. Febuxostat is available as a coated tablet and is administered orally. The maximum daily dose is 120 mg, with a total maximum dose of 111.6 g over the treatment period. Similar to Allopurinol, the treatment duration for Febuxostat is also limited to 30 days. Participant adherence to the dosing regimen will be closely monitored to ensure compliance. Febuxostat is not formulated for pediatric use and is not designated as an orphan drug.

Both Allopurinol and Febuxostat are utilized as test products in the study, with the primary objective being to evaluate the maintenance or withdrawal of urate-lowering therapy in patients with gout. The trial aims to determine if the withdrawal of oral urate-lowering therapy, monitored with ultrasound scans, is not inferior to maintaining the therapy in terms of the risk of flares over a two-year period. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are mentioned in the trial data provided.

Efficacy in the clinical trial titled "STING - Maintenance or withdrawal of urate lowering therapy according to ultrasound features in gout patients: a randomised controlled trial" will be assessed using both primary and secondary endpoints. The primary endpoint is the proportion of patients experiencing one or more flares at two years (M24) according to the Gaffo’s criteria. Secondary endpoints include the proportion of patients experiencing flares at various timepoints (M6, M12, M18, M30, M36) using both the Gaffo's criteria and the patient-reported Gout Attack Intensity Score (GAIS). Additionally, mean flare rates at these timepoints will be evaluated.

Other secondary endpoints involve assessing ultrasound (US) features of gout, such as the double contour sign, tophi, and aggregates at specific joints, and measuring urate levels at multiple timepoints. Changes from baseline in Outcome Measures in Rheumatology (OMERACT) core outcome domains, including patient’s global assessment of disease activity, health-related quality of life, and activity limitation, will also be evaluated. The incidence of major cardiovascular events, renal function, comorbidities, overall survival, and medication consumption will be monitored. Adverse events will be classified according to the CTCAE V5.0 classification, and adherence to urate-lowering therapy (ULT) will be assessed via a questionnaire. Incremental cost-effectiveness ratios will estimate cost per quality-adjusted life year (QALY) gained and cost per flare avoided.