Pharmaceutical composition, method for reducing serum uric acid level of gout patient and application of topiromilast in preparation of medicine for treating hyperuricemia / gout with hyperuricemia

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition, a method for reducing the serum uric acid level of a gout patient and application of topiromilast to preparation of a medicine for treating hyperuricemia / gout with hyperuricemia. The medicine is continuously administered according to the following dosage scheme: the initial dosage is 40-80mg / day, and the duration period is 2-4 weeks; the first adjusting dosage is 120-160mg / day, and the duration period is 2-4 weeks; the maximum dose is 160-320 mg / day, and the dose lasts for at least 8 weeks. According to the pharmaceutical composition, high-efficiency treatment of Chinese patients with hyperuricemia / gout is realized through a staged dosage increasing scheme, and renal function impairment is improved. The invention further provides a method for reducing the serum uric acid level of gout patients, continuous administration is carried out according to the dosage scheme, and the topiromilast is applied to preparation of the medicine for treating hyperuricemia / gout with hyperuricemia and is suitable for people with renal insufficiency.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a pharmaceutical composition, a method for reducing serum uric acid levels in gout patients, and the use of topiramate in preparing a medicament for treating hyperuricemia / gout with hyperuricemia. Background Art

[0002] Hyperuricemia and gout are systemic diseases caused by disorders of purine metabolism, affecting multiple systems. Xanthine oxidoreductase (XOR) is involved in purine metabolism in the human body and is the rate-limiting enzyme in this metabolic process. Its end products are reactive oxygen species and uric acid. Topiramate competitively inhibits XOR (Ki value: 5.1 nmol / L), inhibiting uric acid production, sharing the same mechanism of action as febuxostat. Topiramate shares its binding mode with febuxostat in that it binds to the same hydrophobic cavity in XOR. However, it also forms a Mo-OC covalent bond with the molybdopterin center of the enzyme, inhibiting enzyme-substrate binding and thus exerting its anti-gout effect. The long decomposition half-life of the topiramate-XOR complex contributes to its long-lasting uric acid-lowering effect, which is its advantage over febuxostat. Therefore, topiramate has great potential for clinical application.

[0003] Topiramate has been used in numerous clinical trials for the treatment of gout and hyperuricemia. In clinical trials, the original study used an initial dose of 40 mg, a maintenance dose of 120 mg, and a maximum dose of 160 mg. To ensure the necessity and scientificity of exploratory studies of topiramate in the Chinese population, a method suitable for Chinese patients is urgently needed.

[0004] The reasons are as follows: First, according to clinical studies of topiramate and febuxostat in Chinese patients, the rate of serum uric acid reduction after starting with 40 mg / day for two weeks and then titrating to 80 mg / day for four weeks was similar to the rate of serum uric acid reduction after starting with 20 mg / day for two weeks of febuxostat. Therefore, based on the recommended starting dose of febuxostat at 20 mg / day, the rate of uric acid reduction after titrating from 40 mg / day for topiramate is lower, indicating that the initial dose of 40 mg in the original clinical trial was flawed, and the initial dose needs to be adjusted for Chinese patients. Second, baseline serum uric acid levels in Chinese patients (570-590 μmol / L) are higher than those in Japanese patients (520 μmol / L). Japanese clinical studies have shown that a 160 mg dose achieves target serum uric acid levels at a baseline level of 9.6 mg / dL (576 μmol / L). Therefore, the expected efficacy of the maximum dose of 160 mg in the original Japanese clinical trial in the Chinese population is significantly insufficient.

[0005] In short, due to the differences in disease characteristics among Chinese patients with hyperuricemia and gout, the starting dose, titration cycle, dosing regimen, and commonly used dose selection of positive control drugs proposed by the Japanese original manufacturer during the clinical study of this product are not suitable for the treatment of Chinese patients, and the necessity and scientific nature of the exploratory research cannot be guaranteed. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the above-mentioned defects of the prior art and provide a pharmaceutical composition comprising a therapeutically effective amount of topiramate, which achieves efficient treatment of Chinese hyperuricemia / gout patients and improves renal function damage through a staged dose escalation regimen (initial dose 40-80 mg / day → first adjustment dose 120-160 mg / day → maximum dose 160-320 mg / day).

[0007] The present invention also provides a method for reducing serum uric acid levels in patients with gout, wherein continuous administration of the above-mentioned dosage regimen reduces the patient's serum uric acid level to ≤360 μmol / L at 12 weeks of treatment, a significant decrease from baseline. The present invention also provides the following: the change in serum uric acid level from baseline at 2, 4, 6, 8, and 12 weeks of treatment; the percentage change in serum uric acid level from baseline at 2, 4, 6, 8, and 12 weeks of treatment; the average number of acute gout attacks within 12 weeks of treatment; the renal injury index at 12 weeks of treatment; and safety analysis results, such as a summary of adverse events.

[0008] The present invention also provides a use of topiramate in the preparation of a medicament for treating hyperuricemia / gout with hyperuricemia, which is particularly suitable for people with renal insufficiency and balances efficacy and renal safety through step-by-step dosage adjustment.

[0009] The use of the topiramate of the present invention in the preparation of a medicament for treating hyperuricemia or gout with hyperuricemia: the medicament is continuously administered according to the following dosage regimen:

[0010] (a) Initial dose: 40-80 mg / day for 2-4 weeks;

[0011] (b) First adjusted dose: 120-160 mg / day for 2-4 weeks;

[0012] (c) Maximum dose: 160-320 mg / day for at least 8 weeks.

[0013] Preferably, the drug is administered continuously according to the following dosage regimen:

[0014] (a) Initial dose: 60-80 mg / day for 2-4 weeks;

[0015] (b) First adjusted dose: 140-160 mg / day for 2-4 weeks;

[0016] (c) Maximum dose: 160-240 mg / day for at least 8 weeks.

[0017] Further preferably, the drug is administered continuously according to the following dosage regimen:

[0018] (a) Starting dose: 80 mg / day for 2 weeks;

[0019] (b) First adjusted dose: 160 mg / day for 2 weeks;

[0020] (c) Maximum dose: 160 mg / day for 8 weeks.

[0021] Further preferably, the drug is administered continuously according to the following dosage regimen:

[0022] (a) Starting dose: 80 mg / day for 2 weeks;

[0023] (b) First adjusted dose: 160 mg / day for 2 weeks;

[0024] (c) Maximum dose: 200 mg / day for 8 weeks.

[0025] Further preferably, the drug is administered continuously according to the following dosage regimen:

[0026] (a) Starting dose: 80 mg / day for 2 weeks;

[0027] (b) First adjusted dose: 160 mg / day for 2 weeks;

[0028] (c) Maximum dose: 240 mg / day for 8 weeks.

[0029] The use of topiramate in preparing a drug for treating hyperuricemia and gout with hyperuricemia is particularly suitable for people with renal insufficiency.

[0030] The use of the topiramate in the preparation of a medicament for treating hyperuricemia and gout with hyperuricemia: after the medicament is administered according to the dosage regimen, renal injury indicators at 12 weeks of treatment are evaluated by improvement in at least one of serum cystatin C, urine microalbumin / urine creatinine ratio, urine transferrin, urine α-1 microglobulin, urine β-2 microglobulin, and urine retinol-binding protein.

[0031] A pharmaceutical composition comprises the drug of item 1, wherein a therapeutically effective amount of topirastat is administered according to the dosage regimen. The drug is a topirastat tablet, each tablet containing 40 mg or 20 mg of topirastat.

[0032] A method for reducing serum uric acid levels in gout patients, comprising administering the drug according to the dosage regimen, wherein the serum uric acid level is reduced to ≤360 μmol / L after 12 weeks of treatment, which is significantly decreased compared to the baseline.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] (1) The pharmaceutical composition of the present invention has an initial dose increased to 80 mg / day (compared to 40 mg / day of the original Japanese drug), which significantly improves the initial treatment response rate of Chinese patients; flexible dosage design: through the 20 mg / 40 mg tablet specification, it accurately matches the phased incremental demand (such as 80 mg→160 mg→240 mg), covering the individualized treatment window.

[0035] (2) The method of the present invention for lowering serum uric acid levels in patients with gout solves the problem of achieving target levels in Chinese patients. The maximum dose is increased to 160-240 mg / day (the upper limit of the original study is 160 mg), which significantly improves the SUA target rate (≤360 μmol / L) in patients with high baseline (570-590 μmol / L) after 12 weeks of treatment; the titration path is optimized, with an initial dose of 80 mg / day combined with a 2-week short-cycle adjustment (compared to the original study of 4 weeks), shortening the time to target by more than 40%.

[0036] (3) The use of the present invention's topiramate in the preparation of drugs for the treatment of hyperuricemia / gout with hyperuricemia is the first to create an exclusive program for people with renal insufficiency. It avoids the deterioration of renal damage through a step-by-step increase (80 mg→160 mg→240 mg), and dynamically monitors safety in combination with multi-dimensional renal function markers (seven items such as serum Cys-C and UACR); it transforms the mechanism advantage and utilizes the long-term XOR inhibition property of topiramate (Mo-OC covalent bond stable binding), so that it still maintains excellent renal tolerance after the dose is increased, breaking through the high-dose nephrotoxicity limit of febuxostat. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 The present invention is a flow chart of the research use of topiramate in the preparation of a drug for treating hyperuricemia / gout with hyperuricemia. DETAILED DESCRIPTION

[0038] The present invention will be further described below with reference to specific embodiments.

[0039] Unless otherwise specified, the raw materials and additives used in the following examples and comparative examples are all commercially available products.

[0040] 1. Drug Source

[0041] (1) Experimental drugs

[0042] Drug name: Topiramate tablets;

[0043] Active ingredient: Topiramate;

[0044] Specifications: 20mg, 40mg;

[0045] Storage: Keep in a dark place and sealed, below 30℃;

[0046] Provided by: Shandong Xinhua Pharmaceutical Co., Ltd.

[0047] (2) Positive control drug

[0048] Drug name: Allopurinol tablets;

[0049] Trade name: Allopurinol tablets;

[0050] Active ingredient: Allopurinol;

[0051] Specifications: 100mg / tablet;

[0052] Storage: Keep in a dark place and sealed, below 30℃;

[0053] Provided by: Shandong Xinhua Pharmaceutical Co., Ltd.

[0054] (3) Test drug simulant (same as topiramate tablets except for the inactive ingredients)

[0055] Drug name: Topiramate analog tablets;

[0056] Active ingredient: None (includes 20 mg and 40 mg topiralast dummy tablets);

[0057] Specifications: 20mg, 40mg;

[0058] Storage: Keep in a dark place and sealed, below 30℃;

[0059] Provided by: Shandong Xinhua Pharmaceutical Co., Ltd.

[0060] (4) Positive control drug simulant (same as allopurinol tablets except for the inactive ingredients)

[0061] Drug name: Allopurinol analog tablets;

[0062] Active ingredient: None.

[0063] 2. Patient Criteria

[0064] (1) Aged 18 to 70 years (inclusive), regardless of gender;

[0065] (2) Patients were clinically diagnosed with gout according to the "Guidelines for the Diagnosis and Treatment of Hyperuricemia and Gout in China (2019)" and the 2015 ACR / EULAR Gout Guidelines, and their serum uric acid (sUA) level at the end of the washout period was ≥480 μmol / L (8.0 mg / dL); for patients who did not need washout, their serum uric acid (sUA) level during the screening period was ≥480 μmol / L (8.0 mg / dL);

[0066] (3)18kg / m 2 Body mass index (BMI) ≤ 35 kg / m 2 .

[0067] 3. Experimental Design

[0068] A multicenter, randomized, double-blind, double-dummy, positive drug (allopurinol tablets) parallel controlled trial was planned to enroll 160 patients (40 patients in each group).

[0069] IV. Dose-finding Design

[0070] The starting dose of the test drug (topiramate tablets) in the experimental group was 80 mg / day, and the maximum doses were 160 mg / day, 200 mg / day, and 240 mg / day, respectively; the starting dose of the positive control drug (allopurinol tablets) in the control group was 100 mg / day, and the maximum dose was 300 mg / day.

[0071] The titration cycle is 4 weeks, and the maintenance treatment cycle is 8 weeks.

[0072] Titration process:

[0073] Topiramate group: 80 mg / day for 2 weeks → 160 mg / day for 2 weeks → 160 mg / day for 8 weeks;

[0074] Topiramate group: 80 mg / day for 2 weeks → 160 mg / day for 2 weeks → 200 mg / day for 8 weeks;

[0075] Topiramate group: 80 mg / day for 2 weeks → 160 mg / day for 2 weeks → 240 mg / day for 8 weeks;

[0076] Allopurinol group: 100 mg / day for 2 weeks → 200 mg / day for 2 weeks → 300 mg / day for 8 weeks.

[0077] 5. Study endpoint setting

[0078] Main evaluation indicators:

[0079] The achievement rate of serum uric acid ≤360 μmol / L (6.0 mg / dL) at 12 weeks of treatment.

[0080] Secondary evaluation indicators:

[0081] 1. Changes in serum uric acid levels compared to baseline at 2, 4, 6, 8, and 12 weeks of treatment;

[0082] 2. Percentage change in serum uric acid level compared with baseline at 2, 4, 6, 8, and 12 weeks of treatment;

[0083] 3. The average number of acute gout attacks within 12 weeks of treatment;

[0084] 4. Changes in renal injury indicators (including serum cystatin C, urine microalbumin / urine creatinine ratio, urine transferrin, urine α-1 microglobulin, urine β-2 microglobulin, and urine retinol-binding protein) compared with baseline at 12 weeks of treatment.

[0085] Safety indicators: type, incidence, and severity of TEAEs / SAEs, as well as laboratory tests, 12-lead ECG, vital signs, physical examination, and other safety indicators.

[0086] 6. Multidimensional dataset construction and analysis methods:

[0087] A multidimensional data set of subjects was constructed, including the full analysis set FAS, the safety analysis set SS, and the per-protocol set PPS.

[0088] Efficacy analysis was performed: 1) For the primary efficacy evaluation index: the treatment efficacy of the experimental group and the control group was calculated, and the CMH test was used for statistical analysis; 2) For the secondary evaluation indexes: the change value / percentage change of serum uric acid level compared with the baseline at 2, 4, 6, 8, and 12 weeks of treatment, the average number of acute gout attacks within 12 weeks of treatment, and the change value of renal injury index compared with the baseline at 12 weeks of treatment were tested using the Wilcoxon rank sum test or t-test.

[0089] Safety analyses will also be conducted: 1) All adverse events will be summarized and described using the latest version of the Medical Dictionary for Regulatory Activities. The severity of adverse events will be graded from 1 to 5 according to the Common Criteria for Adverse Events (CTCAE, version 5.0). TEAEs, SAEs, TEAEs related to the investigational drug, and TEAEs leading to subject withdrawal will be summarized by system organ class, preferred term, and treatment group, with the number, frequency, and percentage of cases. Furthermore, TEAEs of varying severity will be summarized by SOC, PT, and drug group. All adverse events will be presented in a table. 2) Laboratory tests, vital signs, physical examinations, and 12-lead electrocardiograms will be analyzed using descriptive statistics. For vital signs, descriptive statistics will be presented for observed values ​​and changes from baseline. For laboratory tests, physical examinations, and 12-lead electrocardiograms, cross-tabulations will be used to summarize changes in each parameter before and after treatment. For all examination items, a list of subjects with abnormalities after treatment will be provided.

[0090] Example 1

[0091] 1. Specific method of administration:

[0092] (1) Experimental drug group (administering orally 40 subjects in each group) with one of the following three doses of topiramate tablets and allopurinol dummy tablets:

[0093] a. Topiramate tablets 160 mg / day dose group (maximum dose)

[0094] Titration period (weeks 1 and 2): Take 40 mg of topiralast tablets (40 mg × 1 tablet) orally every morning, and take 1 allopurinol analog tablet orally at the same time, and 40 mg of topiralast tablets (40 mg × 1 tablet) orally in the evening;

[0095] Maintenance period (weeks 3 and 4): Take 80 mg of topiralast tablets (40 mg x 2 tablets) and 1 allopurinol simulant tablet orally once in the morning and evening each day;

[0096] Maintenance medication period (weeks 5 to 12): Take 80 mg of topiralast tablets (40 mg × 2 tablets), 40 mg of topiralast simulant tablets (40 mg × 1 tablet), 20 mg of topiralast simulant tablets (20 mg × 1 tablet) and 1 tablet of allopurinol simulant orally once in the morning and evening each day, and take 1 tablet of allopurinol simulant orally at noon.

[0097] b. Topiramate tablets 200 mg / day dose group (maximum dose)

[0098] First titration period (weeks 1 and 2): Take 40 mg of topiralast tablets (40 mg × 1 tablet) orally every morning and 1 allopurinol analog tablet orally at the same time, and 40 mg of topiralast tablets (40 mg × 1 tablet) orally in the evening;

[0099] Second titration period (weeks 3 and 4): Take 80 mg of topiramate tablets (40 mg × 2 tablets) and 1 allopurinol simulant tablet orally once in the morning and evening each day;

[0100] Maintenance medication period (weeks 5 to 12): Take 80 mg of topiralast tablets (40 mg × 2 tablets), 20 mg of topiralast tablets (20 mg × 1 tablet), 40 mg of topiralast simulant tablets (40 mg × 1 tablet) and 1 tablet of allopurinol simulant tablet orally once in the morning and evening each day, and take 1 tablet of allopurinol simulant tablet orally at noon.

[0101] c. Topiramate tablets 240 mg / day dose group (maximum dose)

[0102] First titration period (weeks 1 and 2): Take 40 mg of topiralast tablets (40 mg × 1 tablet) orally every morning and 1 allopurinol analog tablet orally at the same time, and 40 mg of topiralast tablets (40 mg × 1 tablet) orally in the evening;

[0103] Second titration period (weeks 3 and 4): Take 80 mg of topiramate tablets (40 mg × 2 tablets) and 1 allopurinol simulant tablet orally once in the morning and evening each day;

[0104] Maintenance medication period (weeks 5 to 12): Take 120 mg of topiralast tablets (40 mg × 3 tablets), 20 mg of topiralast analog tablets (20 mg × 1 tablet) and 1 tablet of allopurinol analog tablet orally once in the morning and evening each day, and take 1 tablet of allopurinol analog tablet orally at noon.

[0105] (2) Positive control group, 40 subjects:

[0106] First titration period (weeks 1 and 2): Take 40 mg of topiramate analog tablets (40 mg × 1 tablet) orally every morning and 100 mg of allopurinol tablets orally at the same time, and take 40 mg of topiramate analog tablets (40 mg × 1 tablet) orally in the evening;

[0107] Second titration period (weeks 3 and 4): Take 80 mg of 40 mg of topiramate analog tablets (2 tablets) and 100 mg of allopurinol tablets orally once in the morning and evening respectively;

[0108] Maintenance medication period (weeks 5 to 12): Take 120 mg of topiralast analog tablets (40 mg × 3 tablets), 20 mg of topiralast analog tablets (20 mg × 1 tablet) and 100 mg of allopurinol tablets orally once in the morning and evening each day, and take 100 mg of allopurinol tablets orally at noon.

[0109] 2. Data Collection Process

[0110] This Phase II, multicenter, randomized, double-blind, double-dummy, active-controlled study is expected to enroll 160 subjects. The 14-week study is divided into three phases: screening (Days -21 to -1), baseline (Day 1), treatment (Days 14 to 84), efficacy follow-up (Days 84±5), and safety follow-up (Days 98±5), totaling eight planned visits.

[0111] (1) Screening period (days -21 to -1): At visit V0, subjects were screened according to the inclusion and exclusion criteria of the trial. At the same time, information such as gender, age, ethnicity, height, weight, past medical history, medication use, history of drug or alcohol abuse, and previous participation in clinical trials were collected. Vital signs and 12-lead electrocardiogram were measured. Laboratory tests (blood biochemistry, blood routine, coagulation function, urine routine, glycosylated hemoglobin) and imaging examinations (joint ultrasound and hand / foot X-ray) were performed. Blood pregnancy test for women of childbearing potential, HLA-B*5801 gene testing and physical examination were performed. The subjects signed the written informed consent provided before any project assessment specified in the protocol to participate in the study. After completing visit V0, subjects who are eligible to continue to participate in the study will avoid taking prohibited drugs throughout the study period. Concomitant medication / treatment was recorded.

[0112] (2) Baseline period (Day -1 to Day 1): At visit point V1, baseline data of the subjects were collected within 1 day or on the day before drug administration, including vital signs, 12-lead electrocardiogram, laboratory tests (blood biochemistry, blood routine, coagulation function, urine routine, urine microalbumin / urine creatinine ratio, cystatin C, urine transferrin, α-1 microglobulin, β-2 microglobulin, retinol binding protein), urine pregnancy test and physical examination for women of childbearing potential. If there are examination items that need to be performed 2 or more times during this stage, the baseline collection will be based on the last one. If the same examination has been performed in this hospital 7 days before the baseline period, the previous data (except pregnancy test) can be used. The researcher will review the inclusion criteria again, and eligible subjects will enter the next trial stage. The study drug, gout acute attack medication and subject diary card will be distributed to record adverse events, concomitant medications and gout acute attack treatment.

[0113] (3) Treatment visit (Day 14 ± 3): At visit point V2, vital signs, 12-lead electrocardiogram, laboratory tests, and physical examinations as specified in the protocol were performed; study drugs and diary cards were distributed / collected; adverse events, concomitant medications, and treatment of acute gout attacks were recorded;

[0114] (4) Treatment visit (Day 28 ± 3): Visit point V3, perform protocol-specified vital signs, 12-lead electrocardiogram, laboratory tests, and physical examinations, distribute / collect study drugs and diary cards, and record adverse events, concomitant medications, and treatment of acute gout attacks;

[0115] (5) Treatment visit (Day 42 ± 3): Visit point V4, perform protocol-specified vital signs, 12-lead electrocardiogram, laboratory tests, urine pregnancy test for women of childbearing potential, and physical examination, distribute / collect study drugs and diary cards, and record adverse events, concomitant medications, and treatment of acute gout attacks;

[0116] (6) Treatment visit (Day 56 ± 3): Visit point V5, perform protocol-specified vital signs, 12-lead electrocardiogram, laboratory tests, and physical examinations, distribute / collect study drugs and diary cards, and record adverse events, concomitant medications, and treatment of acute gout attacks;

[0117] (7) Effectiveness follow-up period (Day 84 ± 5): Visit point V6, perform protocol-specified vital signs, 12-lead electrocardiogram, laboratory tests (blood biochemistry, blood routine, coagulation function, urine routine, urine microalbumin / urine creatinine ratio, cystatin C, urine transferrin, α-1 microglobulin, β-2 microglobulin, retinol-binding protein) and physical examination, collect study drugs and diary cards, record adverse events, concomitant medications and treatment of acute gout attacks, and distribute safety follow-up diary cards;

[0118] (8) Safety follow-up period (Day 98 ± 5): Visit point V7, perform protocol-specified vital signs, 12-lead electrocardiogram, laboratory tests, urine pregnancy test for women of childbearing potential, and physical examination, collect safety follow-up diary cards, and record adverse events and concomitant medications.

[0119] Subjects who have taken the trial drug and withdraw from the trial early must be followed up as specified, and undergo vital signs, 12-lead electrocardiogram, laboratory tests, urine pregnancy test for women of childbearing potential, and physical examination as specified in the protocol. The study drug and diary card must be collected, and adverse events, concomitant medications, and treatment of acute gout attacks must be recorded.

[0120] like Figure 1 As shown in the figure, W0, W1, ..., represent the first week, the second week and so on.

[0121] 3. Statistical Analysis Methods

[0122] 1. Effectiveness Analysis

[0123] The effectiveness analysis will be conducted based on FAS and PPS.

[0124] (1) Primary endpoint

[0125] The achievement rate of serum uric acid ≤360 μmol / L (6.0 mg / dL) at 12 weeks of treatment:

[0126] The serum uric acid target achievement rate at week 12 of treatment was calculated using the following formula: Serum uric acid target achievement rate (%) at week 12 of treatment in each group = Number of subjects in each group with serum uric acid ≤ 360 μmol / L (6.0 mg / dL) at week 12 of treatment / Total number of subjects in each group × 100. The serum uric acid target achievement rate at week 12 of treatment was summarized by group.

[0127] Primary Analysis Methods: To evaluate the difference in efficacy between the experimental and control groups, a stratified chi-square test (CMH test) will be used, with baseline uric acid level as the stratification factor (categorized as ≤540 and >540). The effective rate of each treatment group, the rate difference between the experimental group and the control group, and between the experimental groups, the two-sided 95% confidence interval (CI) of the rate difference, and the P value will be reported.

[0128] Sensitivity analysis: Chi-square test or Fisher's exact probability method will be used (the influence of stratification factors will not be considered in this analysis).

[0129] (2) Secondary endpoints

[0130] a. Changes in serum uric acid levels compared with baseline at weeks 2, 4, 6, 8, and 12 of treatment: Changes in serum uric acid levels compared with baseline at weeks 2, 4, 6, 8, and 12 of treatment were summarized by treatment group, including the number of cases, mean, standard deviation, median, Q1, Q3, minimum, and maximum values. Comparisons were made using the Wilcoxon signed-rank test.

[0131] b. Percent change in serum uric acid levels compared to baseline at weeks 2, 4, 6, 8, and 12 of treatment: Percent change in serum uric acid levels compared to baseline for each treatment week in each group (%) = (serum uric acid result for each treatment week in each group - baseline serum uric acid result) / baseline serum uric acid result × 100%. The percentage change in serum uric acid levels compared to baseline at weeks 2, 4, 6, 8, and 12 of treatment was summarized by treatment group using the same analysis method as above.

[0132] c. Average number of acute gout attacks within 12 weeks of treatment: The average number of acute gout attacks within 12 weeks of treatment was summarized by treatment group, and the analysis method was the same as above.

[0133] d. Changes from baseline in renal injury markers at 12 weeks of treatment (including serum cystatin C, urine microalbumin / urine creatinine ratio, urine transferrin, urine α-1 microglobulin, urine β-2 microglobulin, and urine retinol-binding protein): Changes from baseline in renal injury markers at 12 weeks of treatment were summarized by treatment group, using the same analysis method as above.

[0134] Unless otherwise specified, all confidence intervals are two-sided with a 95% confidence level. All statistical comparisons will be two-sided at the α = 0.05 level.

[0135] (3) Other analyses

[0136] Frequency of acute gout attacks at 2, 4, 6, 8, and 12 weeks of treatment: The frequency of acute gout attacks at 2, 4, 6, 8, and 12 weeks of treatment were summarized by treatment group and compared using the chi-square test or Fisher's exact probability method.

[0137] 2. Safety Analysis

[0138] The safety analysis will be based on SS for analysis.

[0139] (1) Adverse Events

[0140] The adverse events will be coded using the International Medical Dictionary for Regulatory Activities (MedDRA) version 28.0 or above.

[0141] The definition of treatment-emergent adverse events (TEAE) is an adverse event that starts or worsens on or after the date / time of the first study drug administration. An existing AE that started before the date / time of the first study drug administration but did not worsen in severity after the date of the first study drug administration will not be considered a TEAE. TEAE related to the investigational drug is defined as a TEAE that is definitely related, probably related, possibly related, or of uncertain relevance to the study drug.

[0142] If the date is missing or partially missing, the adverse event will be considered a treatment-emergent adverse event, unless there is clear evidence (by comparison of partial dates) that the adverse event started before the first administration of the investigational drug.

[0143] (2) Laboratory Test Data

[0144] The summary by visit will summarize the last non-missing assessment recorded at each visit. If a visit window is used, the non-missing assessment closest to the midpoint of the visit window (including repeated and unscheduled assessments) will be summarized. For visit cross-tabulations (e.g., maximum after baseline), planned assessments, unscheduled assessments, and repeated assessments will be considered.

[0145] All values outside the clinical reference range will be marked in the list. Abnormal values below the lower limit of the clinical reference range will be denoted by "L", and values above the upper limit of the clinical reference range will be denoted by "H". The investigator will evaluate the clinical abnormality of values outside the clinical reference range, and these values will be reported as not clinically significant (NCS) or clinically significant (CS) abnormalities.

[0146] For results reported as "<X" or ">X", X will be used for the summary analysis, but the list will be presented in the recorded form, showing "<X" or ">X".

[0147] Although the present invention is described in detail with reference to the accompanying drawings and in combination with the preferred embodiments, the present invention is not limited thereto and includes all the data of the embodiments. Without departing from the spirit and essence of the present invention, a person of ordinary skill in the art may make various equivalent modifications or replacements to the embodiments of the present invention, and these modifications or replacements should all be within the scope of the present invention. Any person skilled in the art who is familiar with the present invention can easily think of changes or replacements within the technical scope disclosed by the present invention, and they should all be within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. A use of topiramate in the preparation of a medicament for treating hyperuricemia / gout with hyperuricemia, characterized in that: The drug is administered continuously according to the following dosage regimen: (a) Initial dose: 40-80 mg / day for 2-4 weeks; (b) First adjusted dose: 120-160 mg / day for 2-4 weeks; (c) Maximum dose: 160-320 mg / day for at least 8 weeks.

2. Use of topiramate according to claim 1 in the preparation of a medicament for treating hyperuricemia / gout with hyperuricemia, characterized in that: The drug is administered continuously according to the following dosage regimen: (a) Initial dose: 60-80 mg / day for 2-4 weeks; (b) First adjusted dose: 140-160 mg / day for 2-4 weeks; (c) Maximum dose: 160-240 mg / day for at least 8 weeks.

3. Use of topiralast according to claim 1 in the preparation of a medicament for treating hyperuricemia / gout with hyperuricemia, characterized in that: The drug is administered continuously according to the following dosage regimen: (a) Starting dose: 80 mg / day for 2 weeks; (b) First adjusted dose: 160 mg / day for 2 weeks; (c) Maximum dose: 160 mg / day for 8 weeks.

4. Use of topiralast according to claim 1 in the preparation of a medicament for treating hyperuricemia / gout with hyperuricemia, characterized in that: The drug is administered continuously according to the following dosage regimen: (a) Starting dose: 80 mg / day for 2 weeks; (b) First adjusted dose: 160 mg / day for 2 weeks; (c) Maximum dose: 200 mg / day for 8 weeks.

5. Use of topiralast according to claim 1 in the preparation of a medicament for treating hyperuricemia / gout with hyperuricemia, characterized in that: The drug is administered continuously according to the following dosage regimen: (a) Starting dose: 80 mg / day for 2 weeks; (b) First adjusted dose: 160 mg / day for 2 weeks; (c) Maximum dose: 240 mg / day for 8 weeks.

6. Use of topiralast according to claim 1 in the preparation of a medicament for treating hyperuricemia / gout with hyperuricemia, characterized in that: Suitable for people with renal insufficiency.

7. Use of the topiramate according to any one of claims 1 to 6 in the preparation of a medicament for treating hyperuricemia / gout with hyperuricemia, characterized in that: After the drug is administered according to the dosage regimen, the renal injury indicators at 12 weeks of treatment are evaluated by improvement of at least one of serum cystatin C, urine microalbumin / urine creatinine ratio, urine transferrin, urine α-1 microglobulin, urine β-2 microglobulin, and urine retinol-binding protein.

8. A pharmaceutical composition, characterized in that: The drug according to any one of items 1 to 6 is administered in a therapeutically effective amount of topiramate according to the dosage regimen.

9. The pharmaceutical composition according to claim 8, characterized in that: The drug is a topiramate tablet, each tablet containing 40 mg or 20 mg of topiramate.

10. A method for reducing serum uric acid levels in gout patients, characterized by: The drug according to any one of items 1-6 is administered according to the dosage regimen, wherein the serum uric acid level is reduced to ≤360 μmol / L after 12 weeks of treatment.

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