Clinical test scheme design and multi-dimensional data construction analysis method

Abstract

The invention relates to the technical field of drug testing, in particular to a clinical test scheme design and multi-dimensional data construction analysis method. The method comprises the following steps: S1, designing a clinical test scheme, wherein a dosage scheme comprises an initial dosage, a maximum dosage, a titration period and a treatment maintaining period; s2, constructing a multi-dimensional data set: constructing the multi-dimensional data set based on the collected object, wherein the multi-dimensional data set comprises a total analysis set FAS, a security analysis set SS and a coincidence scheme set PPS; and S3, carrying out statistical analysis on the multi-dimensional data, wherein the statistical analysis comprises validity analysis and security analysis. By reasonably setting a plurality of visiting points such as dosage of a test group and a control group, a titration period, a treatment maintaining period, a screening period, a baseline period, a treatment period, a follow-up visit period and the like, a multi-dimensional data set containing abundant visiting point acquisition data is constructed; and the curative effect of the topiromilast tablet in patients with gout with hyperuricemia in China is accurately evaluated.

Description

Technical Field

[0001] This invention relates to the field of drug testing technology, specifically to a clinical trial protocol design and multi-dimensional data construction and analysis method. Background Technology

[0002] Hyperuricemia and gout, as systemic pathological states induced by purine metabolism disorders and affecting multiple systems, are closely related to the regulation of xanthine oxidoreductase (XOR) in their pathological mechanisms. XOR, as a key rate-limiting enzyme in the purine metabolism pathway, catalyzes reactive oxygen species and uric acid as its end products. Topiramate, by competitively inhibiting XOR activity at a Ki value of 5.1 nmol / L, effectively blocks the uric acid production pathway. Its mechanism of action falls within the same XOR inhibition category as febuxostat, a first-line treatment recommended in the American Guidelines for the Diagnosis and Treatment of Hyperuricemia and Gout. In terms of enzyme binding mode, both topiramate and febuxostat target the same hydrophobic cavity of XOR. However, topiramate is unique in that it can form a Mo-OC covalent bond with the molybdenum pterin center of the enzyme, thereby strongly blocking the formation of the enzyme-substrate complex and achieving an anti-gout effect. Of particular note is that the topiramate-XOR complex exhibits a long degradation half-life, giving it a sustained and stable uric acid-lowering effect. This characteristic is a significant advantage over febuxostat, indicating that topiramate tablets have broad prospects in clinical application.

[0003] Topiramate tablets have been used in multiple clinical trials in Japan and China for gout and hyperuricemia.

[0005] Given the differences in disease characteristics between hyperuricemia and gout patients in China and Japan, the original Japanese manufacturer failed to fully consider the treatment needs of Chinese patients when determining the starting dose, titration period, dosing regimen, and commonly used dose of the positive control drug for the clinical trials of this product. This makes it difficult to ensure the necessity and scientific rigor of the exploratory studies. Therefore, it is urgent to develop a treatment plan suitable for the Chinese population. Summary of the Invention

[0006] The technical problem to be solved by this invention is to overcome the shortcomings of the prior art and provide a method for clinical trial protocol design and multi-dimensional data construction and analysis.

[0007] The technical solution adopted in this invention is as follows: A clinical trial protocol design and multi-dimensional data construction and analysis method includes the following steps: S1. Clinical trial protocol design: Topiramate tablets were used as the experimental group and allopurinol tablets were used as the control group to explore the design of a dosage regimen for topiramate tablets based on the characteristics of the Chinese population. The dosage regimen included the starting dose, maximum dose, titration period, and maintenance treatment period. S2. Construction of a multidimensional dataset: Eight visit points were collected from subjects during the screening period, baseline period, treatment period, efficacy follow-up period, and safety follow-up period. The collected data included serum uric acid levels, number of gout attacks, and kidney injury indicators. A multidimensional dataset was constructed based on the collected data, which included the full analysis set FAS, the safety analysis set SS, and the compliance set PPS. S3. Statistical analysis of multidimensional data: Statistical analysis includes validity analysis and safety analysis of multidimensional datasets. Validity analysis includes primary endpoint indicators and secondary endpoint indicators; safety analysis includes adverse events, laboratory test data, and vital sign data.

[0008] This technical solution, through the construction of clinical trial protocol design and multi-dimensional data construction and analysis methods, without changing the basic characteristics of topirafil tablets as a potential treatment for gout with hyperuricemia, redesigns the clinical trial protocol for topirafil tablets specifically for the Chinese population. This is done by considering the differences in disease characteristics between the Chinese and Japanese populations of gout with hyperuricemia due to genetic, environmental, and lifestyle factors. This includes rationally setting the dosage, titration period, maintenance treatment period, and adopting appropriate trial design types for the experimental and control groups. A multi-dimensional dataset containing rich visitor data is constructed, and various scientific statistical analysis methods are used to comprehensively analyze the multi-dimensional data. This allows for a more accurate assessment of the efficacy and safety of topirafil tablets in treating Chinese patients with gout with hyperuricemia, and the exploration of a reasonable dosage suitable for the Chinese population. Therefore, this provides a more scientific basis for the rational clinical use of topirafil tablets in the Chinese population.Specifically, the topirafil tablets investigational drug was used to explore its efficacy and safety in treating gout with hyperuricemia in the Chinese population, and to determine a suitable dosage regimen for the Chinese population. Allopurinol tablets are a commonly used clinical drug for treating hyperuricemia; selecting them as a control provides a standard reference for known efficacy and safety. By comparing topirafil tablets with allopurinol tablets, the relative advantages and disadvantages of topirafil tablets can be more accurately assessed, determining whether topirafil tablets are competitive in terms of efficacy and safety. Developing a dosage regimen suitable for the Chinese population ensures that the study results more accurately reflect the efficacy and safety of topirafil tablets. To enhance the scientific rigor and reliability of the study, the actual efficacy of pyrazinol tablets in Chinese patients was investigated. Data collection was conducted at eight observation points throughout the study: screening, baseline, treatment, efficacy follow-up, and safety follow-up. This comprehensive and systematic monitoring of the subjects' condition changes, drug efficacy, and safety throughout the study was crucial. The screening period determined whether subjects met the inclusion criteria. The baseline period collected pre-treatment data. The treatment period observed the drug's therapeutic effect and adverse reactions. The efficacy and safety follow-up periods focused on... The study focuses on the long-term efficacy and safety of the drug, ensuring timely detection and handling of any issues. Data collection at eight visit points provides richer and more detailed information, improving data reliability. Data from different time points corroborates each other, more accurately reflecting the drug's characteristics and patterns of action. Data collected at each visit point reflects the subjects' physical condition and the drug's effects from multiple perspectives. By dividing the data into different datasets—including the full analysis set (FAS), the safety analysis set (SS), and the compliance set (PPS)—a comprehensive and accurate analysis of the data from different angles enhances the credibility of the research results. The primary endpoint is the most critical and direct indicator reflecting the drug's efficacy. Secondary endpoints supplement the primary endpoint, assessing drug efficacy from different angles, such as improvements in renal injury indicators. Adverse events are any adverse medical events occurring during the study, regardless of whether they are drug-related. Recording and analyzing adverse events helps to understand the various adverse reactions and their incidence rates associated with topiramate tablets during clinical use. Laboratory test data and vital sign data reflect the drug's impact on various bodily functions of the subjects.

[0009] In addition, the clinical trial protocol design and multi-dimensional data construction and analysis method proposed in this invention also have the following additional technical features: According to one embodiment of the present invention, in the design of the clinical trial protocol in step S1, the starting dose of topiramate tablets is 80 mg / day, and the maximum doses are 160 mg / day, 200 mg / day, and 240 mg / day, respectively; the starting dose of allopurinol tablets is 100 mg / day, and the maximum dose is 300 mg / day; the titration period is 4 weeks, and the maintenance treatment period is 8 weeks.

[0010] In this technical solution, topiramate tablets are used to treat gout with hyperuricemia. In the initial stage of clinical trials, to ensure the safety of subjects, a relatively low and safe starting dose of 80 mg / day is selected. Multiple maximum dose gradients are set to comprehensively explore the dose-response relationship of topiramate tablets in the Chinese population with gout and hyperuricemia. Different doses produce different degrees of uric acid-lowering effects and improvements in gout symptoms. By comparing efficacy indicators such as serum uric acid target achievement rate and the number of acute gout attacks in different maximum dose groups, the optimal effective dose range of the drug is determined. Doses of 160 mg / day, 200 mg / day, and 240 mg / day have been evaluated and found to significantly improve... While achieving therapeutic effects, adverse reactions remain within acceptable dosage levels. The 4-week titration cycle is based on the drug's onset time and the body's adaptation process to dosage adjustments. During this period, the drug has sufficient time to reach a relatively stable state in the body. Based on the patient's blood uric acid level and adverse reactions, the doctor rationally and gradually increases the drug dosage to gradually control the blood uric acid level within the target range, while reducing adverse reactions caused by excessively rapid dosage adjustments. The 8-week maintenance treatment cycle allows the drug to continue to exert its uric acid-lowering effect in the body, stabilizing blood uric acid levels within the target range, reducing the risk of acute gout attacks, and observing the drug's efficacy stability and safety over a longer period.

[0011] According to an embodiment of the present invention, in the construction of the multi-dimensional dataset in step S2, the 8 viewpoint visits include: The screening period, from day -21 to day -1, is defined as visit point V0; The baseline period, from day -1 to day 1, is defined as visit point V1. The treatment period, day 14±3, is defined as visit point V2; The treatment period, day 28±3, is defined as visit point V3; The treatment period, day 42±3, is defined as visit point V4; The treatment period, day 56±3, is defined as visit point V5; The effectiveness follow-up period was 84±5 days, defined as visit point V6; The safety follow-up period, day 98±5, is defined as visit point V7.

[0012] In this technical solution, the main purpose of the screening period is to comprehensively assess whether potential subjects meet the inclusion and exclusion criteria of the trial. Setting the screening period well in advance allows for the full identification of potential health problems or factors that may affect the trial results. The baseline period is the final comprehensive assessment of all indicators of the subjects before the start of the trial. Setting the baseline period close to the start of treatment (day -1 to day 1) minimizes the impact of changes in the subjects' physiological state over time on the trial results. Around day 14 after the start of treatment is an important time point for observing the early efficacy of the drug. For uric acid-lowering drugs such as topiramate, this period is used to initially assess whether the drug has begun to take effect and whether the blood uric acid level is showing a downward trend. Early visits also help to detect adverse reactions caused by the drug in a timely manner. As the treatment time extends, the efficacy of the drug is usually more obvious by day 28. At this time, a follow-up visit is conducted. The following follow-up procedures are performed: Day 42 follow-up to more accurately assess the uric acid-lowering effect of the drug and observe whether the decrease in serum uric acid levels reaches the expected target; Day 56 follow-up to observe the stability of the drug's efficacy over a longer period and promptly identify any fluctuations in efficacy; Day 56 follow-up to summarize the efficacy and safety during the mid-treatment period; By comprehensively analyzing the data from the previous follow-ups, the drug's effect and safety throughout the entire treatment period can be more comprehensively assessed; The efficacy follow-up period involves following up with subjects for a period of time after the end of treatment, mainly to assess the long-term efficacy of the drug; The follow-up around Day 84 provides important information about the long-term efficacy of the drug and determines whether the drug has a durable therapeutic effect; The safety follow-up period extends the observation time further after the efficacy follow-up period, mainly focusing on delayed adverse reactions caused by the drug; The follow-up around Day 98 increases the chance of detecting delayed adverse reactions and comprehensively assesses the safety of the drug.

[0013] According to one embodiment of the present invention, in the construction of the multidimensional dataset in step S2, the data collected at each visit includes: vital signs, 12-lead electrocardiogram, laboratory tests, and physical examination, and records adverse events, concomitant medications, and treatment of acute gout attacks; wherein, the laboratory tests include blood biochemistry, complete blood count, coagulation function, urinalysis, urine microalbumin / creatinine ratio, cystatin C, urine transferrin, α-1 microglobulin, β-2 microglobulin, and retinol-binding protein.

[0014] According to an embodiment of the present invention, in step S2, the construction of the multi-dimensional dataset includes: The full analysis set (FAS) includes all subjects who have received at least one treatment with the study drug after randomization and have at least one baseline efficacy assessment. The FAS is used to conduct demographic baseline analysis and efficacy endpoint analysis. If there is a randomization error or the wrong study drug is used, the efficacy endpoint analysis of the FAS population will be based on the data from the planned treatment group. The safety analysis set SS includes all subjects who received at least one treatment with the study drug after randomization and for whom safety assessment data are available; when conducting safety analysis of the SS population, data from the actual treatment group will be used. Eligible participants are those who have received at least one treatment with the study drug after randomization and have not committed any major protocol violations; the PPS is used for efficacy endpoint analysis; for participants excluded from the PPS, evaluation and confirmation will be conducted jointly by clinical experts, biostatisticians, and the sponsor during the blinded review phase.

[0015] In this technical approach, the FAS (Functional Assay) includes all subjects who, after randomization, received at least one treatment with the study drug and possess at least one post-baseline efficacy assessment. Randomization is a crucial means of ensuring inter-group balance in clinical trials, minimizing the impact of confounding factors on study results. The requirement of at least one treatment and post-baseline efficacy assessment ensures that included subjects can provide valid information for efficacy analysis, enabling the FAS to represent the basic situation of the entire study population in terms of drug efficacy. SS (Safety Spectrum) includes all subjects who, after randomization, received at least one treatment with the study drug and possess safety assessment data. Safety is a critical consideration in drug development; focusing on subjects who actually received drug treatment and can provide safety assessment data ensures that safety analysis is based on a population truly exposed to the drug. Therefore, SS accurately reflects the safety of the drug in actual use. The PPS includes all subjects who have received at least one treatment with the study drug after randomization and who have not committed any major protocol violations. Major protocol violations can affect the accuracy and reliability of the study results, such as subjects failing to take medication at the prescribed intervals or failing to complete the prescribed examinations. Subjects with these violations are excluded to ensure that the subjects in the PPS are strictly treated and evaluated in accordance with the trial protocol, so that the efficacy analysis results based on the PPS can more accurately reflect the efficacy of the drug under ideal treatment conditions.

[0016] According to an embodiment of the present invention, in the statistical analysis of multi-dimensional data in step S3, the validity analysis includes: The primary endpoint was the rate of serum uric acid ≤360 μmol / L at 12 weeks of treatment. The treatment efficacy rates of the experimental group and the control group were calculated, and statistical analysis was performed using the CMH test. Secondary endpoints included changes in serum uric acid levels from baseline at weeks 2, 4, 6, 8, and 12 of treatment, the average number of acute gout attacks within 12 weeks of treatment, and changes in renal injury indicators from baseline at 12 weeks of treatment. Wilcoxon rank-sum test or t-test was used for these endpoints.

[0017] In this technical protocol, the achievement rate of serum uric acid ≤360 μmol / L at 12 weeks of treatment was set as the primary endpoint because controlling serum uric acid levels is a key treatment goal for patients with gout and hyperuricemia. Maintaining serum uric acid at a low level (≤360 μmol / L) helps reduce urate crystal deposition, effectively preventing gout attacks, alleviating joint damage, and reducing the risk of complications such as kidney disease. The CMH test, after controlling for patient age and disease severity stratification, compares the treatment efficacy of the experimental and control groups, thus more accurately assessing the true efficacy of the drug, reducing confounding factors, and improving the reliability of statistical inference. The change in serum uric acid level from baseline at weeks 2, 4, 6, 8, and 12 of treatment (percentage change) was selected as a secondary endpoint to comprehensively understand the dynamic impact of the drug on serum uric acid levels during treatment. By observing changes at different time points, the onset time, speed and intensity of the drug's action, and whether it can sustainably and stably control serum uric acid levels were determined. In clinical trials, data such as changes in serum uric acid levels and changes in kidney injury indicators from baseline may not follow a normal distribution due to individual differences and measurement errors. In such cases, the Wilcoxon rank-sum test is more accurate for comparing two groups of data. When data such as the average number of acute gout attacks within 12 weeks of treatment meet the assumptions of the t-test, the t-test is used to obtain more accurate statistical results. The t-test has high statistical power and can detect differences between two groups of data with a small sample size.

[0018] According to an embodiment of the present invention, in the statistical analysis of multi-dimensional data in step S3, the security analysis includes: Adverse events are summarized and described according to the latest version of the Dictionary of Regulatory Activities for Medical Events, and graded into 1-5 severity levels according to the Common Adverse Event Evaluation Criteria. TEAEs, SAEs, TEAEs related to the investigational drug, and TEAEs leading to subject withdrawal are classified by system organ. The preferred terminology and treatment group are summarized, along with the number of cases, occurrences, and percentages. TEAEs of different severity are summarized according to SOC, PT, and drug group. Laboratory test data were analyzed using descriptive statistical methods, and cross-tabulated with vital signs data, physical examination data, and 12-lead electrocardiograms to summarize the changes in each indicator before and after treatment. Vital signs data will be analyzed using descriptive statistical methods, including descriptive statistics on observed values ​​and their changes relative to baseline. Changes in each indicator before and after treatment will be summarized using cross-tabulation methods, in conjunction with laboratory tests, physical examinations, and 12-lead electrocardiograms.

[0019] This technical solution uses the latest version of the Dictionary of Regulatory Activities for Medical Events (DRA) to summarize and describe adverse events, aiming to standardize and unify the terminology for adverse events. Adverse events are graded from 1 to 5 levels based on common adverse event evaluation criteria, enabling an objective and quantitative assessment of their impact on subjects. Different systems and organs in the human body have different physiological functions and structural characteristics; the occurrence of adverse events in different systems and organs reflects the potential effects of drugs on different tissues and organs. Based on the SOC classification, the solution further combines the preferred term (PT) and treatment group to summarize the number, occurrence, and percentage of adverse events. This multi-dimensional summary provides more detailed and comprehensive information on adverse events, facilitating in-depth analysis of drug safety issues. Laboratory test indicators, vital signs, physical examinations, and electrocardiogram data are all important information reflecting the subject's physical condition, and they are interconnected and correlated. By using cross-tabulation, these data are integrated for analysis, allowing for a more comprehensive assessment of the drug's multifaceted effects on the subject's body, identifying potential safety issues and drug mechanisms of action.

[0020] According to one embodiment of the present invention, in the statistical analysis of multi-dimensional data in step S3, all adverse events will be listed, and laboratory test data and vital sign data will be listed as subjects with abnormalities after treatment.

[0021] In this technical solution, clinical trials typically divide subjects into experimental and control groups. Displaying an adverse event list facilitates comparison of adverse event occurrences between the two groups. For example, comparing the incidence and severity distribution of a specific adverse event in the experimental and control groups allows for assessment of whether the investigational drug increases the risk of adverse events, and the nature and extent of that risk. The adverse event list is also arranged chronologically, facilitating analysis of trends over time. By listing subjects with abnormalities, individuals at risk are precisely identified, enabling further analysis of the causes of the abnormalities and their relationship to the drug. Analyzing the list of abnormal subjects allows researchers to identify problems in the trial, such as whether the drug dosage is appropriate or whether the inclusion criteria need adjustment. Based on this information, the trial protocol can be optimized and adjusted in a timely manner to improve the quality and safety of the trial.

[0022] According to an embodiment of the present invention, in the statistical analysis of multi-dimensional data in step S3, the security analysis further includes: Vital signs, including systolic and diastolic blood pressure, pulse, and body temperature; used to provide the number and percentage of subjects with normal, clinically insignificant, and clinically significant experiences categorized by treatment group and visit; and to provide a list of vital signs categorized by subject. Electrocardiograms (ECGs) were categorized into normal, abnormal with no clinical significance, and abnormal with clinical significance based on the examination results. The number and percentage of subjects were summarized according to treatment groups and visits. A list of ECG results categorized by subject was provided. Physical examinations were categorized into normal, clinically insignificant, and clinically significant abnormalities based on body systems, treatment groups, and visits; the number and percentage of subjects were summarized according to treatment groups and visits; and a list of physical examination results categorized by subject was provided.

[0023] This technical solution comprehensively assesses the impact of drugs or treatments on vital signs, including their degree of influence, trends, and individual characteristics, by statistically analyzing the number and percentage of subjects with abnormal vital signs according to treatment groups and visit classifications, and providing a list of vital signs categorized by subject. It also accurately evaluates the impact of drugs or treatments on cardiac electrical activity and individual differences by summarizing the number and percentage of subjects with abnormal electrocardiograms according to treatment groups and visit classifications, and providing a list of electrocardiogram results categorized by subject. Finally, it comprehensively analyzes the impact of drugs or treatments on various body systems and individual responses by summarizing the number and percentage of subjects with abnormal physical examination results categorized by body system, treatment group, and visit classifications, and providing a list of physical examination results categorized by subject. This results in a comprehensive, in-depth, and accurate safety analysis.

[0024] Compared with the prior art, the present invention has the following advantages: (1) Optimize clinical trial design: By reasonably setting the dosage, titration period, maintenance treatment period, and multiple visit points such as screening period, baseline period, treatment period, and follow-up period for the experimental group and the control group, we can ensure that the research results can accurately reflect the actual effect of the drug in Chinese patients; (2) Provide detailed data support: Construct a multi-dimensional dataset containing rich visit point collection data, and divide the dataset into different datasets for analysis to improve the reliability of the data; (3) Accurately assess drug efficacy: By setting primary and secondary endpoint indicators, such as serum uric acid target achievement rate and uric acid change value at different time points, combined with scientific statistical analysis methods, the efficacy of topiramate tablets in Chinese patients with gout and hyperuricemia can be accurately assessed. Attached Figure Description

[0025] Figure 1 This is a flowchart illustrating the principle of the present invention.

[0026] Figure 2 It is a design diagram of a clinical trial protocol. Detailed Implementation

[0027] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0028] Example 1 like Figure 1 As shown, this embodiment provides a clinical trial protocol design and multi-dimensional data construction and analysis method, including the following steps: S1. Clinical trial protocol design: Topiramate tablets were used as the experimental group and allopurinol tablets were used as the control group to explore the design of a dosage regimen for topiramate tablets based on the characteristics of the Chinese population. The dosage regimen included the starting dose, maximum dose, titration period, and maintenance treatment period. S2. Construction of a multidimensional dataset: Eight visit points were collected from subjects during the screening period, baseline period, treatment period, efficacy follow-up period, and safety follow-up period. The collected data included serum uric acid levels, number of gout attacks, and kidney injury indicators. A multidimensional dataset was constructed based on the collected data, which included the full analysis set FAS, the safety analysis set SS, and the compliance set PPS. S3. Statistical analysis of multidimensional data: Statistical analysis includes validity analysis and safety analysis of multidimensional datasets. Validity analysis includes primary endpoint indicators and secondary endpoint indicators; safety analysis includes adverse events, laboratory test data, and vital sign data.

[0029] This technical solution, through the construction of clinical trial protocol design and multi-dimensional data construction and analysis methods, without changing the basic characteristics of topirafil tablets as a potential treatment for gout with hyperuricemia, redesigns the clinical trial protocol for topirafil tablets specifically for the Chinese population. This is done by considering the differences in disease characteristics between the Chinese and Japanese populations of gout with hyperuricemia due to genetic, environmental, and lifestyle factors. This includes rationally setting the dosage, titration period, maintenance treatment period, and adopting appropriate trial design types for the experimental and control groups. A multi-dimensional dataset containing rich visitor data is constructed, and various scientific statistical analysis methods are used to comprehensively analyze the multi-dimensional data. This allows for a more accurate assessment of the efficacy and safety of topirafil tablets in treating Chinese patients with gout with hyperuricemia, and the exploration of a reasonable dosage suitable for the Chinese population. Therefore, this provides a more scientific basis for the rational clinical use of topirafil tablets in the Chinese population.Specifically, the topirafil tablets investigational drug was used to explore its efficacy and safety in treating gout with hyperuricemia in the Chinese population, and to determine a suitable dosage regimen for the Chinese population. Allopurinol tablets are a commonly used clinical drug for treating hyperuricemia; selecting them as a control provides a standard reference for known efficacy and safety. By comparing topirafil tablets with allopurinol tablets, the relative advantages and disadvantages of topirafil tablets can be more accurately assessed, determining whether topirafil tablets are competitive in terms of efficacy and safety. Developing a dosage regimen suitable for the Chinese population ensures that the study results more accurately reflect the efficacy and safety of topirafil tablets. To enhance the scientific rigor and reliability of the study, the actual efficacy of pyrazinol tablets in Chinese patients was investigated. Data collection was conducted at eight observation points throughout the study: screening, baseline, treatment, efficacy follow-up, and safety follow-up. This comprehensive and systematic monitoring of the subjects' condition changes, drug efficacy, and safety throughout the study was crucial. The screening period determined whether subjects met the inclusion criteria. The baseline period collected pre-treatment data. The treatment period observed the drug's therapeutic effect and adverse reactions. The efficacy and safety follow-up periods focused on... The study focuses on the long-term efficacy and safety of the drug, ensuring timely detection and handling of any issues. Data collection at eight visit points provides richer and more detailed information, improving data reliability. Data from different time points corroborates each other, more accurately reflecting the drug's characteristics and patterns of action. Data collected at each visit point reflects the subjects' physical condition and the drug's effects from multiple perspectives. By dividing the data into different datasets—including the full analysis set (FAS), the safety analysis set (SS), and the compliance set (PPS)—a comprehensive and accurate analysis of the data from different angles enhances the credibility of the research results. The primary endpoint is the most critical and direct indicator reflecting the drug's efficacy. Secondary endpoints supplement the primary endpoint, assessing drug efficacy from different angles, such as improvements in renal injury indicators. Adverse events are any adverse medical events occurring during the study, regardless of whether they are drug-related. Recording and analyzing adverse events helps to understand the various adverse reactions and their incidence rates associated with topiramate tablets during clinical use. Laboratory test data and vital sign data reflect the drug's impact on various bodily functions of the subjects.

[0030] In addition, the clinical trial protocol design and multi-dimensional data construction and analysis method proposed in this invention also have the following additional technical features: According to one embodiment of the present invention, in the design of the clinical trial protocol in step S1, the starting dose of topiramate tablets is 80 mg / day, and the maximum doses are 160 mg / day, 200 mg / day, and 240 mg / day, respectively; the starting dose of allopurinol tablets is 100 mg / day, and the maximum dose is 300 mg / day; the titration period is 4 weeks, and the maintenance treatment period is 8 weeks.

[0031] In this technical solution, topiramate tablets are used to treat gout with hyperuricemia. In the initial stage of clinical trials, to ensure the safety of subjects, a relatively low and safe starting dose of 80 mg / day is selected. Multiple maximum dose gradients are set to comprehensively explore the dose-response relationship of topiramate tablets in the Chinese population with gout and hyperuricemia. Different doses produce different degrees of uric acid-lowering effects and improvements in gout symptoms. By comparing efficacy indicators such as serum uric acid target achievement rate and the number of acute gout attacks in different maximum dose groups, the optimal effective dose range of the drug is determined. Doses of 160 mg / day, 200 mg / day, and 240 mg / day have been evaluated and found to significantly improve... While achieving therapeutic effects, adverse reactions remain within acceptable dosage levels. The 4-week titration cycle is based on the drug's onset time and the body's adaptation process to dosage adjustments. During this period, the drug has sufficient time to reach a relatively stable state in the body. Based on the patient's blood uric acid level and adverse reactions, the doctor rationally and gradually increases the drug dosage to gradually control the blood uric acid level within the target range, while reducing adverse reactions caused by excessively rapid dosage adjustments. The 8-week maintenance treatment cycle allows the drug to continue to exert its uric acid-lowering effect in the body, stabilizing blood uric acid levels within the target range, reducing the risk of acute gout attacks, and observing the drug's efficacy stability and safety over a longer period.

[0032] According to an embodiment of the present invention, in the construction of the multi-dimensional dataset in step S2, the 8 viewpoint visits include: The screening period, from day -21 to day -1, is defined as visit point V0; The baseline period, from day -1 to day 1, is defined as visit point V1. The treatment period, day 14±3, is defined as visit point V2; The treatment period, day 28±3, is defined as visit point V3; The treatment period, day 42±3, is defined as visit point V4; The treatment period, day 56±3, is defined as visit point V5; The effectiveness follow-up period was 84±5 days, defined as visit point V6; The safety follow-up period, day 98±5, is defined as visit point V7.

[0033] In this technical solution, the main purpose of the screening period is to comprehensively assess whether potential subjects meet the inclusion and exclusion criteria of the trial. Setting the screening period a considerable distance in advance allows for the full identification of potential health problems or factors that may affect the trial results. The baseline period is the final comprehensive assessment of all indicators of the subjects before the start of the trial. Setting the baseline period close to the start of treatment (days -1 to 1) minimizes the impact of changes in the subjects' physiological state over time on the trial results. Around day 14 after the start of treatment is an important time point for observing the early efficacy of the drug. For uric acid-lowering drugs such as topiramate, this period is used to initially assess whether the drug has begun to work and whether there is a downward trend in serum uric acid levels. Early visits also help to promptly detect adverse reactions caused by the drug. As the treatment duration increases, the efficacy of the drug is usually more obvious by day 28. A follow-up visit at this time allows for a more accurate assessment of the drug's uric acid-lowering effect and observation of whether the decrease in serum uric acid levels has reached the expected target. The first follow-up visit observes the drug's efficacy stability over a longer period, promptly identifying any fluctuations in efficacy. The second follow-up visit on day 56 summarizes the efficacy and safety during the mid-treatment period. By comprehensively analyzing data from previous visits, the drug's effect and safety throughout the entire treatment period are assessed more comprehensively. The efficacy follow-up period involves following up with subjects for a period after the end of treatment, primarily to assess the drug's long-term efficacy. The follow-up visit around day 84 provides important information about the drug's long-term efficacy, determining whether the drug has a durable therapeutic effect. The safety follow-up period extends the observation time further after the efficacy follow-up period, mainly focusing on delayed adverse reactions caused by the drug. The follow-up visit around day 98 increases the chance of detecting delayed adverse reactions and comprehensively assesses the drug's safety.

[0034] According to one embodiment of the present invention, in the construction of the multidimensional dataset in step S2, the data collected at each visit includes: vital signs, 12-lead electrocardiogram, laboratory tests, and physical examination, and records adverse events, concomitant medications, and treatment of acute gout attacks; wherein, the laboratory tests include blood biochemistry, complete blood count, coagulation function, urinalysis, urine microalbumin / creatinine ratio, cystatin C, urine transferrin, α-1 microglobulin, β-2 microglobulin, and retinol-binding protein.

[0035] According to an embodiment of the present invention, in step S2, the construction of the multi-dimensional dataset includes: The full analysis set (FAS) includes all subjects who have received at least one treatment with the study drug after randomization and have at least one baseline efficacy assessment. The FAS is used to conduct demographic baseline analysis and efficacy endpoint analysis. If there is a randomization error or the wrong study drug is used, the efficacy endpoint analysis of the FAS population will be based on the data from the planned treatment group. The safety analysis set SS includes all subjects who received at least one treatment with the study drug after randomization and for whom safety assessment data are available; when conducting safety analysis of the SS population, data from the actual treatment group will be used. Eligible participants are those who have received at least one treatment with the study drug after randomization and have not committed any major protocol violations; the PPS is used for efficacy endpoint analysis; for participants excluded from the PPS, evaluation and confirmation will be conducted jointly by clinical experts, biostatisticians, and the sponsor during the blinded review phase.

[0036] In this technical protocol, the FAS (Functional Assay) includes all subjects who, after randomization, received at least one treatment with the investigational drug and have at least one post-baseline efficacy assessment. Randomization is a crucial means of ensuring inter-group balance in clinical trials, minimizing the impact of confounding factors on study results. The requirement of at least one treatment and post-baseline efficacy assessment ensures that included subjects can provide valid information for efficacy analysis, enabling the FAS to represent the basic situation of the entire study population in terms of drug efficacy. SS (Safety Response) includes all subjects who, after randomization, received at least one treatment with the investigational drug and have safety evaluation data. Safety is a critical consideration in drug development, focusing on the actual treatment received. The study includes subjects who have received at least one treatment with the study drug after randomization and who have not committed any major protocol violations. Major protocol violations can affect the accuracy and reliability of the study results, such as subjects not taking medication at the prescribed intervals or not completing the prescribed examinations. Excluding subjects with these violations ensures that the subjects in the PPS are strictly treated and evaluated according to the trial protocol, so that the efficacy analysis results based on the PPS can more accurately reflect the efficacy of the drug under ideal treatment conditions.

[0037] According to an embodiment of the present invention, in the statistical analysis of multi-dimensional data in step S3, the validity analysis includes: The primary endpoint was the rate of serum uric acid ≤360 μmol / L at 12 weeks of treatment. The treatment efficacy rates of the experimental group and the control group were calculated, and statistical analysis was performed using the CMH test. Secondary endpoints included changes in serum uric acid levels from baseline at weeks 2, 4, 6, 8, and 12 of treatment, the average number of acute gout attacks within 12 weeks of treatment, and changes in renal injury indicators from baseline at 12 weeks of treatment. Wilcoxon rank-sum test or t-test was used for these endpoints.

[0038] In this technical protocol, the achievement rate of serum uric acid ≤360 μmol / L at 12 weeks of treatment was set as the primary endpoint because controlling serum uric acid levels is a key treatment goal for patients with gout and hyperuricemia. Maintaining serum uric acid at a low level (≤360 μmol / L) helps reduce urate crystal deposition, effectively preventing gout attacks, alleviating joint damage, and reducing the risk of complications such as kidney disease. The CMH test, after controlling for patient age and disease severity stratification, compares the treatment efficacy of the experimental and control groups, thus more accurately assessing the true efficacy of the drug, reducing confounding factors, and improving the reliability of statistical inference. The percentage change in serum uric acid levels from baseline at weeks 2, 4, 6, 8, and 12 of treatment were selected as the baseline value. Secondary endpoints are used to comprehensively understand the dynamic impact of drugs on serum uric acid levels during treatment. By observing changes at different time points, the timing, speed, and intensity of drug onset, as well as whether it can sustainably and stably control serum uric acid levels, are determined. In clinical trials, data such as changes in serum uric acid levels from baseline and changes in kidney injury indicators from baseline may not follow a normal distribution due to individual differences and measurement errors. In such cases, the Wilcoxon rank-sum test is used to more accurately compare the two groups of data. When data such as the average number of acute gout attacks within 12 weeks of treatment meet the assumptions of the t-test, the t-test is used to obtain more accurate statistical results. The t-test has high statistical power and can detect differences between two groups of data with a small sample size.

[0039] According to an embodiment of the present invention, in the statistical analysis of multi-dimensional data in step S3, the security analysis includes: Adverse events are summarized and described according to the latest version of the Dictionary of Regulatory Activities for Medical Events, and graded into 1-5 severity levels according to the Common Adverse Event Evaluation Criteria. TEAEs, SAEs, TEAEs related to the investigational drug, and TEAEs leading to subject withdrawal are classified by system organ. The preferred terminology and treatment group are summarized, along with the number of cases, occurrences, and percentages. TEAEs of different severity are summarized according to SOC, PT, and drug group. Laboratory test data were analyzed using descriptive statistical methods, and cross-tabulated with vital signs data, physical examination data, and 12-lead electrocardiograms to summarize the changes in each indicator before and after treatment. Vital signs data will be analyzed using descriptive statistical methods, including descriptive statistics on observed values ​​and their changes relative to baseline. Changes in each indicator before and after treatment will be summarized using cross-tabulation methods, in conjunction with laboratory tests, physical examinations, and 12-lead electrocardiograms.

[0040] This technical solution uses the latest version of the Regulatory Activity Medical Dictionary coding to summarize and describe adverse events, aiming to standardize and unify the terminology of adverse events. Adverse events are graded from 1 to 5 levels based on common adverse event evaluation criteria, enabling an objective and quantitative assessment of their impact on subjects. Different systems and organs in the human body have different physiological functions and structural characteristics; the occurrence of adverse events in different systems and organs reflects the potential effects of drugs on different tissues and organs. Based on the SOC classification, the solution further combines the preferred term (PT) and treatment group to summarize the number, occurrence, and percentage of adverse events. This multi-dimensional summary provides more detailed and comprehensive information on adverse events, facilitating in-depth analysis of drug safety issues. Laboratory test indicators, vital signs, physical examinations, and electrocardiogram data are all important information reflecting the subject's physical condition, and they are interconnected and correlated. By using cross-tabulation, these data are integrated for analysis, providing a more comprehensive assessment of the drug's multifaceted effects on the subject's body, identifying potential safety issues and drug mechanisms of action.

[0041] According to one embodiment of the present invention, in the statistical analysis of multi-dimensional data in step S3, all adverse events will be listed, and laboratory test data and vital sign data will be listed as subjects with abnormalities after treatment.

[0042] In this technical solution, clinical trials typically divide subjects into experimental and control groups. By displaying an adverse event list, the occurrence of adverse events between the two groups can be easily compared. For example, comparing the incidence and severity distribution of a specific adverse event in the experimental and control groups allows for the determination of whether the investigational drug increases the risk of adverse events, and the nature and extent of that risk. The adverse event list is also arranged chronologically, facilitating the analysis of trends over time. By listing subjects with abnormalities, individuals at risk can be precisely identified for further analysis of the causes of the abnormalities and their relationship to the drug. Analyzing the list of abnormal subjects allows researchers to identify problems in the trial, such as whether the drug dosage is appropriate or whether the inclusion criteria need adjustment. Based on this information, the trial protocol can be optimized and adjusted in a timely manner to improve the quality and safety of the trial.

[0043] According to an embodiment of the present invention, in the statistical analysis of multi-dimensional data in step S3, the security analysis further includes: Vital signs, including systolic and diastolic blood pressure, pulse, and body temperature; used to provide the number and percentage of subjects with normal, clinically insignificant, and clinically significant experiences categorized by treatment group and visit; and to provide a list of vital signs categorized by subject. Electrocardiograms (ECGs) were categorized into normal, abnormal with no clinical significance, and abnormal with clinical significance based on the examination results. The number and percentage of subjects were summarized according to treatment groups and visits. A list of ECG results categorized by subject was provided. Physical examinations were categorized into normal, clinically insignificant, and clinically significant abnormalities based on body systems, treatment groups, and visits; the number and percentage of subjects were summarized according to treatment groups and visits; and a list of physical examination results categorized by subject was provided.

[0044] This technical solution comprehensively assesses the impact of drugs or treatments on vital signs, including their degree of influence, trends, and individual characteristics, by statistically analyzing the number and percentage of subjects with abnormal vital signs according to treatment groups and visit classifications, and providing a list of vital signs categorized by subject. It also accurately evaluates the impact of drugs or treatments on cardiac electrical activity and individual differences by summarizing the number and percentage of subjects with abnormal electrocardiograms according to treatment groups and visit classifications, and providing a list of electrocardiogram results categorized by subject. Finally, it comprehensively analyzes the impact of drugs or treatments on various body systems and individual responses by summarizing the number and percentage of subjects with abnormal physical examination results categorized by body system, treatment group, and visit classifications, and providing a list of physical examination results categorized by subject. This results in a comprehensive, in-depth, and accurate safety analysis.

[0045] Example 2 Based on Example 1, such as Figure 2 As shown below, we present a multicenter, randomized, double-blind, double-dummy, active-drug parallel-controlled phase II clinical trial evaluating topiramate tablets for the treatment of gout with hyperuricemia: S1. Specific administration method: S11, the investigational drug group, consisted of 40 subjects who simultaneously took one of the following three topiramate tablet doses orally along with an allopurinol mimic tablet: Topiramate 160mg / day dosing group: Titration period (weeks 1 and 2): Topiramate 40mg (40mg x 1 tablet) orally every morning, and allopurinol mimic tablet orally once every evening; Maintenance period (weeks 3 and 4): Topiramate 80mg (40mg x 2 tablets) and allopurinol mimic tablet orally once every morning and evening; Maintenance period (weeks 5 to 12): Topiramate 80mg (40mg x 2 tablets), Topiramate mimic tablet 40mg (40mg x 1 tablet), Topiramate mimic tablet 20mg (20mg x 1 tablet), and allopurinol mimic tablet orally once every morning and evening, and allopurinol mimic tablet orally once every noon; Topiramate 200mg / day dose group: First titration period (weeks 1 and 2): Topiramate 40mg (40mg x 1 tablet) orally every morning, and allopurinol mimic tablet orally every evening; Second titration period (weeks 3 and 4): Topiramate 80mg (40mg x 2 tablets) and allopurinol mimic tablet orally once each morning and evening; Maintenance period (weeks 5 to 12): Topiramate 80mg (40mg x 2 tablets), Topiramate 20mg (20mg x 1 tablet), Topiramate mimic tablet 40mg (40mg x 1 tablet), and allopurinol mimic tablet orally once each morning and evening, and allopurinol mimic tablet orally at noon; Topiramate 240mg / day dose group: First titration period (weeks 1 and 2): 40mg topiramate tablets (40mg x 1 tablet) orally every morning, and 1 allopurinol mimic tablet orally every evening; Second titration period (weeks 3 and 4): 80mg topiramate tablets (40mg x 2 tablets) and 1 allopurinol mimic tablet orally every morning and evening; Maintenance period (weeks 5-12): 120mg topiramate tablets (40mg x 3 tablets), 20mg topiramate tablets (20mg x 1 tablet), and 1 allopurinol mimic tablet orally every morning and evening, and 1 allopurinol mimic tablet orally at noon.

[0046] S12, Positive control group, 40 subjects: First titration period (weeks 1 and 2): Take 40 mg of topiramate tablets (40 mg x 1 tablet) orally every morning, and 100 mg of allopurinol tablets orally every evening; Take 40 mg of topiramate tablets (40 mg x 1 tablet) orally every evening; Second titration period (weeks 3 and 4): Take 80 mg of topiramate tablets (40 mg x 2 tablets) orally every morning and evening, and 100 mg of allopurinol tablets orally once each; Maintenance period (weeks 5 to 12): Take 120 mg of topiramate tablets (40 mg x 3 tablets), 20 mg of topiramate tablets (20 mg x 1 tablet), and 100 mg of allopurinol tablets orally every morning and evening, and 100 mg of allopurinol tablets orally at noon.

[0047] S2, Data Acquisition Process: like Figure 2 As shown, this is a multicenter, randomized, double-blind, double-dummy, positive-drug-controlled phase II clinical trial, with a planned enrollment of 160 subjects. The trial will last 14 weeks and will be divided into three phases: screening (days -21 to -1), baseline (day 1), treatment (days 14 to 84), efficacy follow-up (day 84±5), and safety follow-up (day 98±5), with a total of 8 planned visits.

[0048] S21, Screening Period (Days -21 to -1): Visit V0. Participants are screened according to the trial's inclusion and exclusion criteria. Information is collected on gender, age, height, weight, past medical history, medication use, history of drug or alcohol abuse, and previous participation in clinical trials. Vital signs are measured, a 12-lead electrocardiogram is performed, and laboratory tests (blood biochemistry, complete blood count, coagulation function, urinalysis, glycated hemoglobin), imaging examinations (joint ultrasound and hand / foot X-ray), blood pregnancy tests for women of childbearing age, HLA-B*5801 gene testing, and a physical examination are conducted. Written informed consent is obtained before any protocol-specified evaluation. After completing Visit V0, eligible participants will avoid taking prohibited medications throughout the study. Concomitant medications / treatments are recorded.

[0049] S22, Baseline Period (Days -1 to 1): Visit point V1. Baseline data of subjects are collected one day prior to or on the day of drug administration, including vital signs, 12-lead electrocardiogram, laboratory tests (blood biochemistry, complete blood count, coagulation function, urinalysis, urine microalbumin / creatinine ratio, cystatin C, urine transferrin, α-1 microglobulin, β-2 microglobulin, retinol-binding protein), urine pregnancy test for women of childbearing age, and physical examination. If any test requires two or more examinations during this phase, the last baseline will be used. If the same test was performed at this hospital within 7 days prior to the baseline period, previous data will be used (except for pregnancy tests). The investigator will review the inclusion and exclusion criteria again, and eligible subjects will proceed to the next phase of the trial. The study drug, medication for acute gout attacks, and subject diary cards will be distributed to record adverse events, concomitant medications, and treatment of acute gout attacks.

[0050] S23. Treatment period visit (day 14±3): Visit point V2, conduct vital signs, 12-lead electrocardiogram, laboratory tests and physical examination as specified in the protocol, distribute / collect study drugs and diary cards, and record adverse events, concomitant medications and treatment of acute gout attacks. S24. Treatment period visit (day 28±3): Visit point V3, conduct vital signs, 12-lead electrocardiogram, laboratory tests and physical examination as specified in the protocol, distribute / collect study drugs and diary cards, and record adverse events, concomitant medications and treatment of acute gout attacks. S25. Treatment period visit (day 42±3): Visit point V4, conduct the vital signs, 12-lead electrocardiogram, laboratory tests, urine pregnancy test and physical examination of women of fertility as specified in the protocol, distribute / collect study drugs and diary cards, and record adverse events, concomitant medications and treatment of acute gout attacks. S26. Treatment period visit (day 56±3): Visit point V5, conduct vital signs, 12-lead electrocardiogram, laboratory tests and physical examination as specified in the protocol, distribute / collect study drugs and diary cards, and record adverse events, concomitant medications and treatment of acute gout attacks. S27. Efficacy Follow-up Period (Day 84±5): Visit point V6, perform the vital signs, 12-lead electrocardiogram, laboratory tests (blood biochemistry, complete blood count, coagulation function, urinalysis, urine microalbumin / creatinine ratio, cystatin C, urine transferrin, α-1 microglobulin, β-2 microglobulin, retinol-binding protein) and physical examination as specified in the protocol, collect the study drug and diary card, record adverse events, concomitant medications and treatment of acute gout attacks, and distribute the safety follow-up diary card; S28. Safety follow-up period (day 98±5): Visit point V7, perform the vital signs, 12-lead electrocardiogram, laboratory tests, urine pregnancy test for women of childbearing age, and physical examination as specified in the protocol, collect the safety follow-up diary card, and record adverse events and concomitant medications.

[0051] Subjects who have taken the investigational drug and withdrawn from the trial early must be followed up as required by the protocol, including monitoring vital signs, performing a 12-lead electrocardiogram, laboratory tests, urine pregnancy tests for women of childbearing age, and physical examinations. The investigational drug and diary card must be retrieved, and adverse events, concomitant medications, and treatment of acute gout attacks must be recorded.

[0052] S3. Statistical Analysis Methods S31. Validity Analysis: The validity analysis will be based on FAS and PPS.

[0053] S311. Primary endpoint: The rate of achieving serum uric acid ≤360 μmol / L (6.0 mg / dL) at 12 weeks of treatment: The rate of achieving serum uric acid at 12 weeks of treatment will be calculated according to the following formula: The rate of achieving serum uric acid at 12 weeks of treatment in each group (%) = Number of subjects in each group with serum uric acid ≤360 μmol / L (6.0 mg / dL) at 12 weeks of treatment / Total number of subjects in each group * 100.

[0054] Based on the target achievement rate of serum uric acid after 12 weeks of treatment, the difference in treatment efficacy between the experimental and control groups was tested according to the following null and alternative hypotheses: H0: Based on the target achievement rate of serum uric acid at 12 weeks of treatment, there was no difference between the experimental group and the control group. H1: Based on the achievement rate of serum uric acid targets at 12 weeks of treatment, there was a difference between the experimental group and the control group. The CMH test will be performed on the experimental and control groups at a 5% significance level: If the p-value is <= 0.05, then there is a difference between the experimental group and the control group.

[0055] If the p-value is greater than 0.05, then there is no difference between the experimental group and the control group.

[0056] Simultaneously, comparisons were made between the experimental groups.

[0057] Main analysis method: 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 response rate, the difference in rates between the experimental and control groups, and between experimental groups, the two-sided 95% confidence interval (CI) of the rate difference, and the p-value will be reported for each treatment group.

[0058] Sensitivity analysis: Chi-square test or Fisher's exact probability method will be used (stratification factors will not be considered in this analysis).

[0059] S312. Secondary endpoint indicators: The change values of serum uric acid levels at 2, 4, 6, 8, and 12 weeks of treatment compared with the baseline: Summarize the change values of serum uric acid levels at 2, 4, 6, 8, and 12 weeks of treatment by treatment group, including the number of cases, mean, standard deviation, median, Q1, Q3, minimum, and maximum. Wilcoxon signed-rank test will be used for comparison.

[0060] The percentage change of serum uric acid levels at 2, 4, 6, 8, and 12 weeks of treatment compared with the baseline. The percentage change of serum uric acid levels at each treatment week for each group compared with the baseline (%) = (serum uric acid result at each treatment week for each group - baseline serum uric acid result) / baseline serum uric acid result * 100%: Summarize the percentage change of serum uric acid levels at 2, 4, 6, 8, and 12 weeks of treatment by treatment group in the same way as above.

[0061] The average number of acute gout attacks within 12 weeks of treatment: Summarize the number of acute gout attacks within 12 weeks of treatment by treatment group in the same way as above.

[0062] The change values of kidney injury indicators (including serum cystatin C, urinary microalbumin / creatinine ratio, urinary transferrin, urinary α-1 microglobulin, urinary β-2 microglobulin, urinary retinol-binding protein) at 12 weeks of treatment compared with the baseline: Summarize the change values of kidney injury indicators (including serum cystatin C, urinary microalbumin / creatinine ratio, urinary transferrin, urinary α-1 microglobulin, urinary β-2 microglobulin, urinary retinol-binding protein) at 12 weeks of treatment by treatment group in the same way as above.

[0063] Unless otherwise specified, all confidence intervals will be two-sided with a confidence level of 95%. All statistical comparisons will be two-sided at the α = 0.05 level.

[0064] If the test result is reported as "<X" or ">X", X will be used as the result for statistical analysis, but it will be listed in the record form and presented as "<X" or ">X".

[0065] S313. Other analyses: The frequency of acute gout attacks at 2, 4, 6, 8, and 12 weeks of treatment: Summarize the frequency of acute gout attacks at 2, 4, 6, 8, and 12 weeks of treatment by treatment group, and use chi-square test or Fisher's exact probability method for comparison.

[0066] S32. Safety analysis: The safety analysis will be based on the SS for analysis.

[0067] S321. Adverse Events: Adverse events will be coded using the MedDRA (Medical Terminology Reference Intake) version 28.0 or later. Treatment-Extended Adverse Events (TEAEs) are defined as adverse events that begin or worsen on or after the date / time of first administration of the investigational drug. Pre-existing AEs that begin before the date / time of first administration of the investigational drug but whose severity has not worsened after the date of first administration will not be considered TEAEs. Investigational drug-related TEAEs are defined as TEAEs that are definitely related to, very related to, related to, or indeterminately related to the investigational drug. In the event of missing or partially missing dates, the adverse event will be considered a treatment-extended adverse event unless there is clear evidence (through comparison of partial dates) indicating that the adverse event began before the first administration of the investigational drug.

[0068] All AE summaries should provide the number of subjects who reported at least one AE and the total number of reported AE events. This will include the following summaries: the number and percentage of subjects who reported AEs, and summaries of AEs categorized by SOC and PT. The number and percentage of subjects who reported TEAEs, and summaries of TEAEs categorized by SOC and PT. The number and percentage of subjects who reported TEAEs, and summaries of TEAEs categorized by severity, SOC, and PT. The number and percentage of subjects who reported TEAEs, and summaries of TEAEs categorized by relationship to the investigational drug, SOC, and PT. The number and percentage of subjects who reported TEAEs, and summaries of TEAEs categorized by outcome, SOC, and PT. The number and percentage of subjects who reported TEAEs related to the investigational drug, and summaries of investigational drug-related TEAEs categorized by severity, SOC, and PT. The number and percentage of subjects who reported TEAEs related to the investigational drug, and summaries of investigational drug-related TEAEs categorized by outcome, SOC, and PT. Report the number and percentage of subjects with a treatment-associated adverse events (TEAEs) incidence >5% in the treatment group, as well as a summary of TEAEs categorized by SOC and PT. Report the number and percentage of subjects with a treatment-associated adverse events (TEAEs) incidence >5% in the treatment group, as well as a summary of investigational drug-related TEAEs categorized by SOC and PT.

[0069] For all AE tables, the number of participants is summarized. For SOC and PT categories, each participant is counted only once, even if the participant reports one or more events in each subcategory. To summarize the number of events, the number of AEs is calculated for each participant across all AEs in each SOC and PT category. Unless otherwise specified, the AE tables are sorted in descending order by the number of participants in each SOC category, and then in descending order by the number of participants in each PT category within the SOC category. If the frequencies are the same, they are sorted alphabetically.

[0070] For each adverse event (AE), the most severe event recorded will be summarized and used in the severity-based summary. Similarly, the relevance to the investigational drug will be summarized. If severity is missing, the most severe case will be classified as "Level 3". If relevance is missing, the worst causal relationship will be classified as "definitely related".

[0071] A list of all adverse events (including non-TEAEs) will be provided, categorized by treatment group and subject group. This list will include: center, subject ID, age, adverse event (SOC, PT, and report name), start date, end date, whether it occurred after the first dose, whether it was a serious adverse event, severity, relationship to the investigational drug, interventions taken, outcome, and whether the subject withdrew from the study due to the AE.

[0072] S322. Death, Serious Adverse Events: Serious adverse events (TESAEs) occurring during treatment are defined as SAEs that begin or worsen on or after the date / time of initial administration of the investigational drug. Investigational drug-related SAEs are defined as SAEs that are definitely related to the investigational drug, very related, related, or whose relationship with the investigational drug is uncertain.

[0073] The summary includes the following: The number and percentage of subjects who died during the study period, categorized by treatment group. A summary of SAE cases classified by SOC and PT. A summary of TESAE cases classified by SOC and PT. A summary of TESAE cases classified by severity, SOC, and PT. A summary of TESAE cases classified by relationship to the study drug, SOC, and PT. A summary of TESAE cases classified by outcome, SOC, and PT. A summary of study drug-related TESAE cases classified by severity, SOC, and PT. A summary of study drug-related TESAE cases classified by outcome, SOC, and PT. A summary of SAE cases leading to treatment discontinuation, categorized by SOC and PT.

[0074] The provided list should include the following: a list of all deaths (if any) that occurred during the study; a list of all SAEs; and a list of all AEs that led to the termination of the study. The list format should follow a similar format for AEs.

[0075] S323. Laboratory examination data: The summary classified 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 value after baseline), planned assessments, unscheduled assessments, and repeated assessments will be considered. All values outside the clinical reference range will be marked in the list. 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 abnormally clinically insignificant (NCS) or abnormally clinically significant (CS).

[0076] For test results reported as "<X" or ">X", X will be used for the pooled analysis, but will be listed in the recorded form, and the list will be presented as "<X" or ">X".

[0077] The following laboratory data summaries will be provided: The summary of alanine aminotransferase, aspartate aminotransferase, creatinine, total bilirubin, and direct bilirubin classified by treatment group and visit. The summary of the changes in alanine aminotransferase, aspartate aminotransferase, creatinine, total bilirubin, and direct bilirubin compared to baseline classified by treatment group and visit. The number and percentage of subjects who experienced normal, abnormally clinically insignificant (NCS), and abnormally clinically significant (CS) at baseline and the last study visit divided by laboratory examination indicators and treatment group using blood routine, blood biochemistry, urine routine, and coagulation function (cross-tabulation). A list of all treatment-related laboratory data classified by subject will be provided, including the center, subject identification number, age, gender, weight, visit, and date. The laboratory reference range will be listed.

[0078] S324. Vital signs: Vital signs include systolic blood pressure and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature (˚C). The following vital sign summaries will be provided: The number and percentage of subjects who experienced normal, abnormally clinically insignificant (NCS), and abnormally clinically significant (CS) classified by treatment group and visit. A list of vital signs classified by subject will be provided.

[0079] S325. Electrocardiogram: The number and percentage of subjects will be summarized by electrocardiogram (ECG) examination result categories (normal, abnormally clinically insignificant, and abnormally clinically significant), treatment group, and visit. A list of electrocardiogram results classified by subject will be provided.

[0080] S326. Physical examination: The summary of the number and percentage of subjects with normal, abnormally clinically insignificant, and abnormally clinically significant physical examination results classified by body system, treatment group, and visit. A list of physical examination results classified by subject will be provided.

[0081] Although the present invention has been described in detail with reference to the accompanying drawings and preferred embodiments, the invention is not limited thereto. Various equivalent modifications or substitutions can be made to the embodiments of the invention by those skilled in the art without departing from the spirit and essence of the invention, and such modifications or substitutions should all be within the scope of the invention. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the invention should also be covered within the protection scope of the invention. Therefore, the protection scope of the invention should be determined by the scope of the claims.

Claims

1. A clinical trial protocol design and multi-dimensional data construction and analysis method, characterized in that, The steps include: S1. Clinical trial protocol design: Topiramate tablets were used as the experimental group and allopurinol tablets were used as the control group to explore the design of a dosage regimen for topiramate tablets based on the characteristics of the Chinese population. The dosage regimen included the starting dose, maximum dose, titration period, and maintenance treatment period. S2. Construction of a multidimensional dataset: Eight visit points were collected from subjects during the screening period, baseline period, treatment period, efficacy follow-up period, and safety follow-up period. The collected data included serum uric acid levels, number of gout attacks, and kidney injury indicators. A multidimensional dataset was constructed based on the collected data, which included the full analysis set FAS, the safety analysis set SS, and the compliance set PPS. S3. Statistical analysis of multidimensional data: Statistical analysis includes validity analysis and safety analysis of multidimensional datasets. Validity analysis includes primary endpoint indicators and secondary endpoint indicators; safety analysis includes adverse events, laboratory test data, and vital sign data.

2. The clinical trial protocol design and multi-dimensional data construction and analysis method as described in claim 1, characterized in that, In the design of the clinical trial protocol in step S1, the starting dose of topiramate tablets was 80 mg / day, and the maximum doses were 160 mg / day, 200 mg / day, and 240 mg / day, respectively; the starting dose of allopurinol tablets was 100 mg / day, and the maximum dose was 300 mg / day; the titration period was 4 weeks, and the maintenance treatment period was 8 weeks.

3. The clinical trial protocol design and multi-dimensional data construction and analysis method as described in claim 1, characterized in that, In step S2, the construction of the multi-dimensional dataset includes 8 viewpoint visits: The screening period, from day -21 to day -1, is defined as visit point V0; The baseline period, from day -1 to day 1, is defined as visit point V1. The treatment period, day 14±3, is defined as visit point V2; The treatment period, day 28±3, is defined as visit point V3; The treatment period, day 42±3, is defined as visit point V4; The treatment period, day 56±3, is defined as visit point V5; The effectiveness follow-up period was 84±5 days, defined as visit point V6; The safety follow-up period, day 98±5, is defined as visit point V7.

4. The clinical trial protocol design and multi-dimensional data construction and analysis method as described in claim 1 or 3, characterized in that, In the construction of the multidimensional dataset in step S2, the data collected at each visit includes: vital signs, 12-lead electrocardiogram, laboratory tests, and physical examination, and records adverse events, combined medications, and treatment of acute gout attacks; among which, the laboratory tests include blood biochemistry, complete blood count, coagulation function, urinalysis, urine microalbumin / creatinine ratio, cystatin C, urine transferrin, α-1 microglobulin, β-2 microglobulin, and retinol-binding protein.

5. The clinical trial protocol design and multi-dimensional data construction and analysis method as described in claim 4, characterized in that, In step S2, the construction of the multi-dimensional dataset includes: The full analysis set (FAS) includes all subjects who have received at least one treatment with the study drug after randomization and have at least one baseline efficacy assessment. The FAS is used to conduct demographic baseline analysis and efficacy endpoint analysis. If there is a randomization error or the wrong study drug is used, the efficacy endpoint analysis of the FAS population will be based on the data from the planned treatment group. The safety analysis set SS includes all subjects who received at least one treatment with the study drug after randomization and for whom safety assessment data are available; when conducting safety analysis of the SS population, data from the actual treatment group will be used. Eligible participants are those who have received at least one treatment with the study drug after randomization and have not committed any major protocol violations; the PPS is used for efficacy endpoint analysis; for participants excluded from the PPS, evaluation and confirmation will be conducted jointly by clinical experts, biostatisticians, and the sponsor during the blinded review phase.

6. The clinical trial protocol design and multi-dimensional data construction and analysis method as described in claim 1, characterized in that, In the statistical analysis of the multi-dimensional data in step S3, the validity analysis includes: The primary endpoint was the rate of serum uric acid ≤360 μmol / L at 12 weeks of treatment. The treatment efficacy rates of the experimental group and the control group were calculated, and statistical analysis was performed using the CMH test. Secondary endpoints included changes in serum uric acid levels from baseline at weeks 2, 4, 6, 8, and 12 of treatment, the average number of acute gout attacks within 12 weeks of treatment, and changes in renal injury indicators from baseline at 12 weeks of treatment. Wilcoxon rank-sum test or t-test was used for these endpoints.

7. The clinical trial protocol design and multi-dimensional data construction and analysis method as described in claim 1 or 6, characterized in that, In the statistical analysis of multi-dimensional data in step S3, the security analysis includes: Adverse events are summarized and described according to the latest version of the Dictionary of Regulatory Activities for Medical Events, and graded into 1-5 severity levels according to the Common Adverse Event Evaluation Criteria. TEAEs, SAEs, TEAEs related to the investigational drug, and TEAEs leading to subject withdrawal are classified by system organ. The preferred terminology and treatment group are summarized, along with the number of cases, occurrences, and percentages. TEAEs of different severity are summarized according to SOC, PT, and drug group. Laboratory test data were analyzed using descriptive statistical methods, and cross-tabulated with vital signs data, physical examination data, and 12-lead electrocardiograms to summarize the changes in each indicator before and after treatment. Vital signs data will be analyzed using descriptive statistical methods, including descriptive statistics on observed values ​​and their changes relative to baseline. Changes in each indicator before and after treatment will be summarized using cross-tabulation methods, in conjunction with laboratory tests, physical examinations, and 12-lead electrocardiograms.

8. The clinical trial protocol design and multi-dimensional data construction and analysis method as described in claim 7, characterized in that, In the statistical analysis of multi-dimensional data in step S3, all adverse events will be listed, and laboratory test data and vital sign data will be listed in a list of subjects with abnormalities after treatment.

9. The clinical trial protocol design and multi-dimensional data construction and analysis method as described in claim 7, characterized in that, In the statistical analysis of multi-dimensional data in step S3, the security analysis also includes: Vital signs, including systolic and diastolic blood pressure, pulse, and body temperature; used to provide the number and percentage of subjects with normal, clinically insignificant, and clinically significant experiences categorized by treatment group and visit; and to provide a list of vital signs categorized by subject. Electrocardiograms (ECGs) were categorized into normal, abnormal with no clinical significance, and abnormal with clinical significance based on the examination results. The number and percentage of subjects were summarized according to treatment groups and visits. A list of ECG results categorized by subject was provided. Physical examinations were categorized into normal, clinically insignificant, and clinically significant abnormalities based on body systems, treatment groups, and visits; the number and percentage of subjects were summarized according to treatment groups and visits; and a list of physical examination results categorized by subject was provided.

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