A Randomized, Multi-regional, Double-blind, Double-dummy Parallel-group, Placebo and Allopurinol-controlled Phase 3 Study to Assess the Efficacy and Safety of Tigulixostat in Gout Patients with Hyperuricemia

The primary objective of this study is to compare the **efficacy** of tigulixostat to appropriately titrated allopurinol (up to 800 mg/day) in achieving serum uric acid (sUA) levels of less than 6 mg/dL at Months 4, 5, and 6 in patients with gout and hyperuricemia. Achieving these sUA levels is clinically relevant as it is associated with a reduction in gout flares and the prevention of long-term complications associated with hyperuricemia.

Secondary objectives include:

• Comparing the efficacy of tigulixostat to allopurinol in achieving sUA levels of less than 5 mg/dL at Months 4, 5, and 6.
• Assessing the incidence of flare events from Month 6 to Month 12 in patients treated with tigulixostat and allopurinol.
• Comparing the efficacy of tigulixostat to allopurinol in tophi regression and resolution.
• Evaluating the safety of tigulixostat in patients with gout and hyperuricemia.

The clinical trial involves a total of **4362 participants** diagnosed with **gout with hyperuricemia**. The study population includes both male and female subjects, aged between 18 and 85 years. Participants were selected based on specific criteria, including a history or presence of gout as per ACR/EULAR 2015 criteria, and varying levels of serum uric acid (sUA) at screening. The trial includes individuals who are either currently on urate-lowering therapy (ULT) with an sUA level of ≥6.0 mg/dL or not on ULT with an sUA level of ≥7.0 mg/dL. Participants currently on ULT must undergo a washout period and have an sUA level of ≥7.0 mg/dL to be eligible for randomization. Additional health criteria include a body mass index (BMI) of ≤50 kg/m² and an estimated glomerular filtration rate (eGFR) of ≥30 mL/min/1.73m². The trial population is characterized by a diverse range of ages and includes vulnerable populations, ensuring a comprehensive assessment of the treatment's efficacy across different demographic groups.

The clinical trial is designed as a **randomized**, multi-regional, double-blind, double-dummy, parallel-group study. It is a placebo and allopurinol-controlled Phase 3 trial aimed at assessing the efficacy and safety of **tigulixostat** in patients with **gout** and **hyperuricemia**. The trial is expected to commence recruitment on January 2, 2024, and conclude by June 30, 2025. The primary objective is to compare the efficacy of tigulixostat to appropriately titrated allopurinol in achieving serum uric acid (sUA) levels of less than 6 mg/dL at months 4, 5, and 6. The trial will involve multiple study visits, including an initial screening visit, regular follow-up visits, and an end-of-study visit.

Participants will be involved in the study for a maximum treatment period of 12 months. The inclusion visit will involve screening to ensure participants meet the eligibility criteria, such as being between 18 and 85 years of age, having a history or presence of gout, and specific sUA levels. Follow-up visits will be scheduled to monitor the participants' sUA levels and assess the occurrence of any adverse events. The end-of-study visit will evaluate the primary and secondary endpoints, including the proportion of subjects with sustained sUA levels below 6.0 mg/dL and the occurrence of gout flares or resolution of tophi.

Participants may be withdrawn from the study if they experience serious adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The trial will utilize oral administration of the investigational product and comparators, with the maximum daily dose of tigulixostat being 300 mg. The study will also monitor secondary endpoints such as the proportion of subjects with sUA levels below 5.0 mg/dL, adverse events, and other safety parameters. The trial's design ensures rigorous assessment of the investigational product's efficacy and safety in the target population.

The clinical trial involves the administration of several treatments, including **Allopurinol OE Capsule**, which is an experimental medication. Allopurinol is provided in a **capsule** form and is administered orally. The maximum daily dose is 800 mg, with a total maximum dose of 252.8 g over a treatment period of up to 12 months. The active substance, allopurinol, is of chemical origin and is manufactured by LG CHEM, LTD. This medication is not a pediatric formulation and is used to manage hyperuricemia in patients with gout.

Another experimental treatment in the trial is **Tigulixostat**, which is also administered orally in a **tablet** form. The maximum daily dose for Tigulixostat is 300 mg, with a total maximum dose of 109.5 g over a 12-month period. Tigulixostat is a chemical substance produced by LG CHEM, LTD. This treatment is not intended for pediatric use and serves as a test medication in the study.

The trial also includes the use of **Colchicine**, which is provided in a pharmaceutical form identified as PHF1070MIG. Colchicine is administered orally, with a maximum daily dose of 1.8 mg and a total maximum dose of 547.2 mg over a 10-month period. The active substance is derived from the autumn crocus fresh flower fluid extract, with ethanol 96% (v/v) as the extraction solvent. This medication is not a pediatric formulation and is used as an auxiliary treatment in the study.

**Naproxen** is included as a non-experimental treatment, serving as an auxiliary medication. It is administered orally in a form identified as PHF00245MIG. The maximum daily dose is 1000 mg, with a total maximum dose of 304 g over a 10-month period. Naproxen is a chemical substance and a nonsteroidal anti-inflammatory drug (NSAID), used to manage pain and inflammation associated with gout.

The study also utilizes placebo treatments, including **Tigulixostat 200 mg Placebo Tablet** and **Tigulixostat 100 mg Placebo Tablet**, as well as **Allopurinol Placebo Capsules**. These placebos are used to maintain the double-blind nature of the trial and are administered in a manner consistent with their respective active counterparts. The placebo treatments do not contain active substances and are not intended for pediatric use.

The efficacy of the clinical trial will be assessed by evaluating the ability of **tigulixostat** to achieve and maintain serum uric acid (sUA) levels below 6 mg/dL at specific time points. The primary endpoint is the proportion of subjects with sUA levels less than 6.0 mg/dL sustained at Months 4, 5, and 6. Secondary endpoints include the proportion of subjects with sUA levels below 5.0 mg/dL sustained at the same time points, the occurrence of at least one gout flare from Month 6 to Month 12, and the complete resolution of at least one target tophus by Month 12. Additionally, safety will be monitored through adverse events (AEs), serious adverse events (SAEs), treatment-emergent adverse events (TEAEs), and adverse events of special interest (AESI), which include major adverse cardiovascular events (MACE), hepatic injury, renal events, and serious skin and hypersensitivity reactions. Physical examinations, vital signs, clinical safety laboratory parameters, and ECGs will also be part of the safety assessments.