Clinical Trial of BR2251 Tablets for Patients With Primary Gout and Hyperuricemia

A Multicenter, Randomized, Double-blind, Non-benzylisoxazole Propionic Acid (BIPA) Controlled Phase II Clinical Study Evaluating the Efficacy and Safety of BR2251 Tablets in Patients With Primary Gout and Hyperuricemia

This study is a randomized, double-blind, non-befloxacin-controlled, multicenter, phase II clinical trial, evaluating the efficacy, safety, and pharmacokinetic characteristics of BR2251 tablets when administered multiple times in subjects with primary gout and hyperuricemia.

This study is a dose exploration study, including a screening period (up to 2 weeks), a double-blind treatment period (12 weeks), and a follow-up period (2 weeks). The screened subjects were stratified based on whether their serum uric acid (sUA) was less than 480 μmol/L or greater than or equal to 480 μmol/L. They were randomly assigned to 4 treatment groups in a 1:1:1:1 ratio: the test drug group 1 (low-dose group), the test drug group 2 (medium-dose group), the test drug group 3 (high-dose group), and the control group (non-befloxacin tablets 40 mg), with 40 subjects in each group. Each group will use titration dosing.

Inclusion Criteria:

• Only those subjects who meet all the following inclusion criteria are eligible to participate in this study:
• Voluntary participation in this trial and signing of the informed consent form, and those who can complete the trial according to the protocol;
• Age between 18 and 75 years old (inclusive of the boundary value, based on the date of signing the informed consent form), regardless of gender;
• Body Mass Index (BMI) ≥ 18 kg/m2 and ≤ 35 kg/m2;
• Meeting the 2015 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) gout classification criteria, and serum uric acid (sUA) ≥ 420 μmol/L during the screening period;
• Women of reproductive age with negative pregnancy test during the screening period and before the first administration of the investigational drug (D1 [allowing a time window of -7 days]), and both female and male subjects of reproductive age must agree to voluntarily take effective contraceptive measures from the date of signing the informed consent form until 3 months after the last administration of the drug

Exclusion Criteria:

• Those who are known or suspected to be allergic to the test drug or its components, or who have previously been intolerant to febuxostat or have contraindications.
• Subjects with secondary gout accompanied by hyperuricemia caused by other diseases or medications.
• Those who have had acute gout attacks within the previous 2 weeks.
• Those who have been diagnosed with uric acid nephropathy in the past or have imaging or clinical manifestations of urinary system stones (such as hematuria, back pain) within the previous 2 weeks.
• Those with other joint lesions that the investigator considers may confuse gouty arthritis, such as rheumatoid arthritis, pyogenic arthritis, traumatic arthritis, psoriatic arthritis, pseudogout, systemic lupus erythematosus, or joint lesions caused by chemotherapy, radiotherapy, chronic lead poisoning, acute obstructive nephropathy, etc.
• Those with any disease or surgical history that the investigator judges may affect the PK characteristics of the drug, such as peptic ulcer, irritable bowel syndrome, inflammatory bowel disease, digestive organ resection, kidney resection, etc.
• Those who have used any organic anion transporter 1 and 3 (OAT1&3) substrate drugs within the previous 2 weeks.
• Those who have used any other uric acid-lowering drugs within the previous 2 weeks and have other concomitant medications that affect uric acid levels (including but not limited to losartan, calcium channel blockers, fenofibrate, atorvastatin calcium, alpha-glucosidase inhibitor, insulin sensitizers, DPP4 inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, metformin) using a stable dose.
• Those who have used aspirin within the previous 2 weeks.
• Those who have used any diuretic within the previous 2 weeks.
• Those with diseases that require long-term use of drugs metabolized by xanthine oxidase, including but not limited to azathioprine, mercaptopurine, etc.
• Any abnormal laboratory test results at screening: a. Abnormal liver function, defined as AST or ALT values > 2× the upper limit of normal (ULN), or TBIL > 1.5× ULN; b. WBC < 3.0×109/L, PLT < 75×109/L, or HB < 90 g/L; c. Scr > 1.5× ULN, or estimated eGFR < 60 mL/min/1.73 m2 using the CKD-EPI formula; d. CK > 1.5× ULN.
• Viral test results at screening: a. Those with positive hepatitis B surface antigen (HBsAg) and HBV-DNA > 1000 IU/mL; b. Those with positive HCV antibody and positive HCV-RNA; d. Those with positive HIV serum reaction; e. Those with positive syphilis antibody and requiring treatment after consultation with the infectious disease department.
• Other serious diseases that may limit the participation of the subjects in this trial, such as: uncontrolled diabetes (glycated hemoglobin > 8.4% as assessed by the investigator); severe heart failure (NYHA class II or above); acute coronary syndrome, acute cerebrovascular accident within the past 6 months; coronary revascularization such as stent implantation, coronary artery bypass surgery, and other heart and large vessel-related surgeries within the past 6 months; severe arrhythmia within the past 6 months including frequent premature ventricular contractions, ventricular tachycardia, atrial fibrillation/atrial flutter, severe bradycardia; uncontrolled hypertension (greater than 160/100 mmHg); severe respiratory diseases (such as obstructive pulmonary disease and history of bronchospasm) etc.
• Electrocardiogram at screening showing prolonged QTcF interval (Fridericia formula) (males > 450 ms, females > 470 ms).
• Those who have had or currently have malignant tumors within the past 5 years (excluding skin squamous cell carcinoma, basal cell carcinoma, and cervical carcinoma in situ that have been successfully treated and without recurrence evidence).
• Had any active infection at the time of screening, or had a severe infection within 4 weeks before randomization (requiring intravenous antimicrobial treatment or hospitalization), or had any infection that required oral antibiotic treatment within 2 weeks before randomization.
• Have undergone organ/tissue transplantation or stem cell transplantation.
• Within 12 weeks before randomization or within the planned period of any major surgical operation.
• Judged by the investigator, had a history of prescription drug abuse or use of prohibited drugs within 6 months before randomization.
• Judged by the investigator, had a daily alcohol consumption of more than 14 units of alcohol (1 unit of alcohol = 360 mL of beer or 45 mL of alcohol with 40% content of spirits or 150 mL of wine) within 1 month before randomization.
• Pregnant or lactating women.
• Have participated in other drug clinical studies, and the time since the last medication is less than 30 days before screening or 5 half-lives of the original test drug (whichever is longer), or plan to participate in another drug clinical trial during the study period.
• Those considered by the investigator to have other symptoms or conditions that are not suitable for participating in this study.