A combined traditional chinese and western medicine and its use

Abstract

The present application relates to the technical field of medicine, and especially relates to a combined Chinese and western medicine composition and application thereof, wherein the combined Chinese and western medicine composition comprises Chinese patent medicine and western medicine; the raw material of the Chinese patent medicine comprises Strychnos seed powder, Earthworm, Codonopsis, Poria cocos, Atractylodes, Chuanxiong, Salvia miltiorrhiza, Panax notoginseng, Radix et Rhizoma Bovis, and Radix Glycyrrhizae; and the effective component of the western medicine is diclofenac; the application of the combined Chinese and western medicine composition in preparation of a lumbar pain medicine; the application is for preparation of intervertebral disc-derived lumbar pain medicines of different syndromes; the syndrome is preferably qi and blood deficiency syndrome; the combined Chinese and western medicine composition can effectively treat intervertebral disc-derived lumbar pain of different syndromes through mutual cooperation between the Chinese patent medicine and the western medicine, and the curative effect is more obvious for intervertebral disc-derived lumbar pain of qi and blood deficiency syndrome.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a combination of traditional Chinese and Western medicine and its application. Background Technology

[0002] Chronic low back pain is one of the leading causes of disability worldwide, with over 40% of cases diagnosed as discogenic low back pain (DLBP). DLBP is caused by intradiscal disturbances, such as inflammation, degeneration, and damage to the annulus fibrosus, which stimulate pain receptors within the intervertebral disc. It is often not accompanied by radicular symptoms, but its specific pathophysiological mechanisms remain unclear. Patients typically present with chronic low back pain, which worsens when sitting and may be accompanied by leg pain. If left untreated, it can severely impact a patient's quality of life and increase the social burden.

[0003] In Traditional Chinese Medicine (TCM), DLBP is classified as "lower back pain" and "Bi syndrome." The earliest record in the *Huangdi Neijing* states, "The lower back is the residence of the kidneys; if it cannot turn and move, the kidneys are exhausted," indicating that kidney deficiency is the core pathogenesis of lower back pain. TCM considers the lower back to be "the residence of the kidneys." The *Suwen* (Plain Questions) states, "When affected by cold, the patient's joints become stiff, and the lower back and ribs ache," suggesting that wind, cold, and dampness affecting the body, particularly the lower back, obstructs the meridians in the lower back and legs, leading to poor blood circulation and lower back pain. This disease is mainly caused by external pathogens such as wind, cold, dampness, and heat, physical weakness, old age, falls, sprains, and overexertion, leading to obstructed meridians, poor blood circulation, and malnourishment of the lower back. It primarily stems from liver and kidney deficiency, poor nutrition of the muscles and bones, poor blood circulation, and obstructed meridians.

[0004] Currently, the treatment of deep vein thrombosis (DLBP) mainly includes a step-by-step approach: conservative treatment, interventional treatment, minimally invasive treatment, and surgical treatment. Most DLBP patients can achieve some efficacy with conservative treatment, which is inexpensive and non-invasive, making it a viable first-stage treatment option. However, conservative treatment has drawbacks such as slow onset of action and high recurrence rate. For DLBP patients who do not respond to conservative treatment or whose efficacy is not significant, interventional and minimally invasive surgical treatments, which are less invasive, have faster recovery, and better efficacy, can be considered. However, these methods have limitations such as a narrow range of applications. Open surgery takes various forms and is currently the preferred treatment for DLBP, but this method is highly invasive and prone to complications such as neurovascular damage, intervertebral disc height loss, and infection. In recent years, more and more TCM scholars have discovered that TCM treatment can achieve certain efficacy in treating this disease. Shen Xingchao et al. found that TCM treatment for DLBP is more effective than Western medicine and has higher safety. Guo Tuanmao et al.'s research found that compared with ibuprofen, a modified version of Du Huo Ji Sheng Tang is particularly suitable for patients who cannot tolerate surgery, showing better results in improving patient symptoms and alleviating negative emotions, while also significantly reducing gastrointestinal reactions with long-term use.

[0005] Although nonsteroidal anti-inflammatory drugs (NSAIDs) can relieve pain by inhibiting the biosynthesis of cyclooxygenase and thus the production of prostaglandins, and have become the first-line drugs for the treatment of acute low back pain, their drug treatment also carries certain risks of toxic side effects such as liver and kidney damage.

[0006] Therefore, the search for a combination of traditional Chinese and Western medicines that can treat discogenic low back pain has become a research hotspot. Summary of the Invention

[0007] In order to solve at least one of the above-mentioned technical problems, the present invention provides a combination of Chinese and Western medicine and its application, which can treat different types of discogenic low back pain.

[0008] In one aspect, the present invention provides a combination of traditional Chinese and Western medicine, which includes traditional Chinese medicine and Western medicine; wherein the traditional Chinese medicine is Biqi capsules; and the active ingredient of the Western medicine is diclofenac or diclofenac salt.

[0009] In some embodiments of the present invention, the combination of Chinese and Western medicines can take the form of any one of physical combination, chemical combination, and formulation combination.

[0010] In some embodiments of the present invention, the dosage of the traditional Chinese medicine in the combination of Chinese and Western medicine is 2.4-3.6g per day, and the dosage of the Western medicine is 100mg per day.

[0011] In some embodiments of the present invention, the Western medicine includes at least one of diclofenac, diclofenac sodium, and diclofenac sodium sustained-release tablets.

[0012] In some embodiments of the present invention, the combination of traditional Chinese and Western medicine comprises: the traditional Chinese medicine being Biqi capsules; and the Western medicine being diclofenac.

[0013] In some embodiments of the present invention, the combination of traditional Chinese and Western medicine comprises: the traditional Chinese medicine being Biqi capsules; and the Western medicine being diclofenac sodium sustained-release tablets.

[0014] In another aspect, the present invention provides an application of the above-mentioned combination of Chinese and Western medicines in the preparation of a medicine for treating lower back pain.

[0015] In some embodiments of the present invention, the low back pain is discogenic low back pain.

[0016] In some embodiments of the present invention, the symptoms of discogenic low back pain include at least one of the following: deficiency of qi and blood, deficiency of liver and kidney, and cold-dampness obstruction syndrome.

[0017] In some embodiments of the present invention, the preferred symptom type is qi and blood deficiency syndrome.

[0018] The technical solution provided by this invention has the following advantages: The combination of traditional Chinese and Western medicines in this invention, and its application, effectively treats different types of discogenic low back pain through the synergistic effect of traditional Chinese medicine and Western medicine. The efficacy is particularly pronounced for discogenic low back pain with a qi and blood deficiency pattern. Specifically, the traditional Chinese medicine, Biqi Capsules, has the functions of "tonifying qi and nourishing blood, dispelling wind and dampness, promoting blood circulation and relieving pain." The active ingredient in the Western medicine, diclofenac, has the effect of treating "low back pain." Detailed Implementation

[0019] To better understand the above-mentioned objectives, features, and advantages of the present invention, the solutions of the present invention will be further described below. It should be noted that, unless otherwise specified, the embodiments of the present invention and the features thereof can be combined with each other.

[0020] Many specific details are set forth in the following description in order to provide a full understanding of the invention, but the invention may also be practiced in other ways different from those described herein; obviously, the embodiments in the specification are only some embodiments of the invention, and not all embodiments.

[0021] 1. Research Plan 1.1 Overall Research Design and Planning This study adopted a randomized, open-label, positive-drug parallel-controlled clinical trial design.

[0022] 1.2 Selection of the study population 1.2.1 Western Medicine Diagnosis Based on Practical Orthopedics (4th Edition) and other literature, and referring to the clinical symptoms and imaging manifestations of discogenic low back pain, the following guidelines were developed: (1) Has a history of recurrent lower back pain for more than 4 weeks.

[0023] (2) Persistent and recurrent low back pain, with or without lower limb symptoms, symptoms worsen after increased longitudinal load on the spine and cannot be relieved immediately after rest; physical examination generally shows no tenderness in the spinous process and paraspinous process, and the femoral nerve traction test and straight leg raise test are usually negative.

[0024] (3) MRI shows decreased signal of the intervertebral disc on T2-WI images, also known as "dark disc" signal shadow, with or without a small round or oval high intensity zone (HIZ) at the midline of the posterior side of the intervertebral disc adjacent to the superior endplate of the next vertebral body on T2-WI sagittal images.

[12] .

[0025] 1.2.2 Traditional Chinese Medicine Diagnosis This diagnosis falls under the categories of "low back pain" or "bi syndrome" in Traditional Chinese Medicine.

[0026] 1.2.3 Syndrome Classification (1) Qi and Blood Deficiency Syndrome: Symptoms include aversion to cold, cold limbs, spontaneous sweating, fatigue and weakness, dull pain that is not fixed in one place, which is relieved after rest and aggravated after exertion, pale and sallow complexion. Pale tongue with thin coating, weak or deep and feeble pulse.

[0027] (2) Liver and kidney deficiency syndrome: Symptoms include soreness and weakness in the lower back and knees, and fatigue. Bone and joint pain may be present, with the pain varying in intensity. The tongue is thin and slender, with little or no coating, and the pulse is deep and thready.

[0028] (3) Cold-dampness obstruction syndrome: Symptoms include cold pain and heaviness in the joints, waist and back, with fixed location of pain, aggravated by cold and relieved by warmth, and persistent pain. The tongue is swollen and pale with teeth marks, the coating is white and greasy, and the pulse is wiry and tight or soft.

[0029] If a complex syndrome exists, the syndrome with the primary syndrome as the primary syndrome should be included in the group based on the primary and secondary manifestations of the primary syndrome, and the complex syndrome should be recorded in the case report form.

[0030] 1.2.4 Number of subjects This study plans to include 360 ​​subjects with the target indication. They will be divided into three groups: a traditional Chinese medicine monotherapy group, a Western medicine monotherapy group, and a combined traditional Chinese and Western medicine group, with 40 subjects in each group, designed in a 1:1:1 ratio, and 120 subjects in each syndrome type.

[0031] 1.2.5 Selection Criteria Subjects must meet all of the following criteria to be enrolled: (1) Meets the Western medicine diagnosis, traditional Chinese medicine diagnosis and traditional Chinese medicine syndrome classification of intervertebral discogenic low back pain ("Qi and blood deficiency syndrome" or "liver and kidney deficiency syndrome" or "cold and dampness obstruction syndrome"). (2) Age between 18 and 60 years old, gender not limited; (3) Visual analog scale (VAS) score ≥5 for discogenic low back pain; (4) Voluntarily sign the informed consent form.

[0032] 2. Treatment 2.1 Basic Drug Information test drug [Drug Name] Generic Name: Biqi Capsules

Ingredients

[0033]

Specifications

[0034] [Dosage and administration] Take 4 capsules orally, 2-3 times a day.

[0035] [Manufacturer] Tianjin Darentang Jingwanhong (Tianjin) Pharmaceutical Co., Ltd.

[0036] control drug [Drug Name] Regimen Drug Name: Diclofenac; Generic Name: Diclofenac Sodium Extended-Release Tablets (V) Product Name: Tianxinlide [Specifications] 50mg [Dosage and Administration] Oral administration: 1 tablet (50mg) twice a day, or as directed by your doctor. Take with warm water after meals. Swallow the tablet whole; do not crush or chew it.

[0037] [Manufacturer] Tianjin Zhongxin Pharmaceutical Group Co., Ltd., Xinxin Pharmaceutical Factory.

[0038] 2.2 Treatment of Subjects 2.2.1 Administration method (1) Single Chinese patent medicine group: Biqi capsules Produced by Tianjin Darentang Jingwanhong (Tianjin) Pharmaceutical Co., Ltd., for oral administration, take 4 capsules (0.3g) each time, 3 times a day.

[0039] (2) Western medicine single-drug group: diclofenac Produced by Tianjin Zhongxin Pharmaceutical Group Co., Ltd. Xinxin Pharmaceutical Factory. Oral administration after meals, one tablet (50mg) at a time, twice a day; (3) Integrated Traditional Chinese and Western Medicine Group: Biqi Capsules + Diclofenac Biqi Capsules (produced by Tianjin Darentang Jingwanhong (Tianjin) Pharmaceutical Co., Ltd.), oral administration, 4 capsules (0.3g) each time, 3 times a day + diclofenac, oral administration after meals, 1 tablet (50mg) each time, twice a day; 2.2.2 Treatment Course Clinical efficacy was observed after all subjects received the medication for 30 consecutive days. During the entire study period, no other medications for treating discogenic low back pain were added to the above treatment. If other comorbidities were present, the corresponding medications were permitted.

[0040] 3. Efficacy assessment 3.1 Therapeutic indicators: 3.1.1 Main therapeutic indicators Changes in VAS score for the primary symptom, discogenic low back pain, 30 days after treatment compared to baseline.

[0041] 3.1.2 Secondary efficacy indicators The reduction rate of TCM syndrome scores after 30 days of treatment compared to baseline; Clinical efficacy based on TCM syndrome scores before and 30 days after medication.

[0042] 3.1.3 Exploratory Indicators The differences in serum inflammatory markers between the groups before and 30 days after medication were compared, including C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor (TNF-α), and prostaglandin E2 (PGE2). The differences in bone turnover markers between the groups before and 30 days after medication were compared, including the levels of bone-specific alkaline phosphatase (B-ALP), total type I collagen N-terminal elongated peptide (T-PINP), and β-collagen specific sequence (β-CTX). (Fasting venous blood was collected during the screening period and at 8:00 AM on day 30. After centrifugation, the supernatant was collected for testing.) Explore the differences in imaging findings among different syndrome subtypes and the changes in imaging findings before and after treatment.

[0043] 3.2 Criteria for Evaluating Therapeutic Effect 3.2.1 VAS score The visual analog scale (VAS) for pain was used, in which patients marked the corresponding locations on a 10 cm scale that represented the severity of their condition ("0 cm" indicates no symptoms, and "10 cm" indicates the most severe).

[0044] Instructions for use: This experiment uses a 10 cm ruler with 10 graduations on one side and 0 and 10 markings at both ends. 0 represents no pain, and 10 represents the most severe pain. The subject faces the unmarked side of the ruler and draws a cross line on the ruler at the position that best represents the current pain level. The researcher observes the marked side and records the pain level numerically, avoiding any hints or suggestions during the process. The same method is used for assessment and recording before and after treatment.

[0045] 3.2.2 Traditional Chinese Medicine Syndrome Scoring Standard Referring to the 2002 edition of the "Guiding Principles for Clinical Research of New Traditional Chinese Medicine Drugs," the TCM classification of discogenic low back pain, and clinical practice, a TCM syndrome scoring scale for discogenic low back pain was developed. The scoring scale quantifies the clinical symptoms of the syndrome type according to the severity of primary and secondary symptoms, tongue and pulse, etc. Researchers recorded the TCM syndrome scores of patients before treatment and on day 30 after treatment. The TCM syndrome efficacy index was calculated. Primary symptoms were divided into four levels according to severity, scored as 0, 2, 4, and 6 points respectively; secondary symptoms were also divided into four levels according to severity, scored as 0, 1, 2, and 3 points respectively; tongue and pulse were scored as 0 and 1 points respectively for presence and absence. The calculation formula is: Score reduction rate = [(Total score before treatment - Total score after treatment) ÷ Score before treatment] × 100%.

[0046] 3.2.3 Traditional Chinese Medicine Syndrome Score Determination Referring to the "Guiding Principles for Clinical Research of New Traditional Chinese Medicine Drugs" and the "Standards for Diagnosis and Efficacy of Diseases and Syndromes in Traditional Chinese Medicine," efficacy was evaluated according to a four-level efficacy standard (nimodipine method), categorized as clinically cured, significantly effective, effective, and ineffective. The overall effective rate is the proportion of the clinically cured, significantly effective, and effective groups in the total patient population.

[0047] The formula for calculating nimodipine is: [(pre-treatment score - post-treatment score) ÷ pre-treatment score] × 100% 1) Clinical cure: Disappearance of lower back pain symptoms, free movement of the lower back, and a reduction in the score by ≥95% 2) Significant effect: No lower back pain symptoms, basic recovery of lumbar mobility, 70% ≤ score reduction < 95%; 3) Effective: Lower back pain symptoms are relatively eliminated, and lumbar mobility is slightly limited; scores decrease by 30% ≤ < 70%. 4) Ineffective: There is no significant improvement in low back pain and lumbar mobility, and the score decreases by <30%.

[0048] 3.2.4 Serum inflammatory markers Changes in CRP, interleukin-6 (IL-6), tumor necrosis factor (TNF-α), and prostaglandin E2 (PGE2) before and after the study.

[0049] 3.2.5 Bone turnover markers The study investigated changes in the levels of bone-specific alkaline phosphatase (B-ALP), total type I collagen N-terminal elongated peptide (T-PINP), and β-collagen specific sequence (β-CTX) before and after the study. (Fasting venous blood was collected during the screening period and at 8:00 AM on day 30. After centrifugation, the supernatant was collected for analysis.)

[0050] 4. The statistical methods and sample size determined in the research plan. 4.1 Statistical Analysis Plan Statistical analysis was performed using SAS 9.4 or later.

[0051] 4.2 General Introduction to Summary and Analysis For quantitative indicators, descriptive statistics include the number of cases, mean, standard deviation, median, upper and lower quartiles, minimum, and maximum values. T-tests or Wilcoxon rank-sum tests will be used for inter-group comparisons.

[0052] For qualitative indicators, descriptive statistics include the number of cases and percentages, with 95% confidence intervals added if necessary. Generally, missing values ​​are not included in the percentage calculation. Chi-square tests or Fisher's exact test will be used for between-group comparisons.

[0053] The difference test will be a two-tailed test. Unless otherwise specified, P ≤ 0.05 will be used as the criterion for judging the difference as statistically significant. The confidence level of all confidence intervals is taken as 95%.

[0054] The minimum and maximum values ​​are rounded to the same number of decimal places as the original data recorded in the database. The mean and median are rounded to one more decimal place than the original data recorded in the database, and the standard deviation is rounded to two more decimal places. Percentages are rounded to one decimal place; frequencies of 0 are not reported as percentages, and percentages of 100 are reported as 100 without rounding. All statistical data are rounded to a maximum of four decimal places. In statistical tests, p-values ​​greater than or equal to 0.0001 are rounded to four decimal places; p-values ​​less than 0.0001 are indicated by "<0.0001", and p-values ​​greater than 0.9999 are indicated by ">0.9999".

[0055] 4.3 Hypothesis Testing The primary objective of this study was to evaluate the changes in VAS scores for the main symptom, discogenic low back pain, after 30 days of treatment. This study hypothesized that the combination of Biqi capsules and diclofenac was superior to diclofenac monotherapy; if this hypothesis holds true, then Biqi capsules monotherapy was superior to diclofenac monotherapy.

[0056] The null and alternative hypotheses used for hypothesis testing are as follows: H10: δ 痹褀胶囊和双氯芬酸联合用药组 - δ 双氯芬酸单药组 = 0 H11: δ 痹褀胶囊和双氯芬酸联合用药组 - δ 双氯芬酸单药组 ≠ 0 Where, δ 痹褀胶囊和双氯芬酸联合用药组 and δ 双氯芬酸单药组 The values ​​represent the differences between baseline VAS scores and VAS scores after 30 days of treatment in the Biqi capsule and diclofenac combination therapy group and the diclofenac monotherapy group, respectively. Hypothesis testing was performed using analysis of covariance. If P ≤ 0.05, and the difference between the baseline VAS score and the score after 30 days of treatment in the Biqi capsule and diclofenac combination therapy group is greater than the difference between the baseline VAS score and the score after 30 days of treatment in the diclofenac monotherapy group, then the Biqi capsule and diclofenac combination therapy group can be considered superior to the diclofenac monotherapy group.

[0057] H2O: δ 痹褀胶囊单药组 - δ 双氯芬酸单药组 = 0 H21: δ 痹褀胶囊单药组 - δ 双氯芬酸单药组 ≠ 0 Where, δ 痹褀胶囊单药组 and δ 双氯芬酸单药组The values ​​represent the differences between baseline VAS scores and VAS scores after 30 days of treatment in the Biqi capsule monotherapy group and the diclofenac monotherapy group, respectively. Hypothesis testing was performed using analysis of covariance. If P ≤ 0.05, and the difference between the baseline VAS score and the score after 30 days of treatment in the Biqi capsule monotherapy group is greater than the difference between the baseline VAS score and the score after 30 days of treatment in the diclofenac monotherapy group, then the Biqi capsule monotherapy group can be considered superior to the diclofenac monotherapy group.

[0058] 4.4 Multiplicity Adjustment This study used a fixed-ranking, descending-ranking method to compare the combination of Biqi capsules and diclofenac + diclofenac monotherapy, as well as the Biqi capsules monotherapy + diclofenac monotherapy group. In this case, the significance level for each hypothesis test is α, which does not need to be adjusted, and the overall Type I error remains α.

[0059] 4.5 Baseline Unless otherwise specified, the baseline is defined as the last non-missing measurement taken before the subject first uses the study drug.

[0060] 4.6 Explanation of Adjustments to Statistical Analysis Methods Considering that the data collected in this study may contain some unforeseen circumstances during the protocol design phase, appropriate adjustments need to be made to the selection of statistical analysis methods. For continuous indicators (such as VAS scores) involving changes between baseline and post-treatment, analysis of covariance (ANCOVA) is more suitable than the t-test. The reasons are explained below: (1) The t-test is usually used to compare the difference in means between two independent groups, but it assumes that the differences between the groups at baseline are small or there is no significant baseline difference. Since the baseline data of different treatment groups in a study may differ, the t-test cannot accurately assess the treatment effect.

[0061] (2) Analysis of covariance (ANCOVA) takes into account baseline differences during the analysis. That is, it not only compares the differences in efficacy between groups after treatment, but also adjusts and controls the influence of baseline values. Therefore, ANCOVA can effectively control baseline differences, adjust for other confounding factors, eliminate the interference of baseline differences on the results, improve statistical power, and thus provide a more accurate and reliable assessment of treatment efficacy.

[0062] 4.7 Subject Distribution Summarize the distribution of subjects in each center, the total number of screening cases, the number of screening failure cases, and the number and percentage of subjects for each reason of screening failure.

[0063] Calculate the number of enrolled subjects, subjects who completed the study, subjects who completed treatment (i.e., those who did not fill out the treatment termination form), and the number and percentage of subjects who terminated treatment (i.e., those who filled out the treatment termination date on the treatment termination form). Also summarize the number and percentage of each category of reasons for not completing the study and reasons for treatment termination.

[0064] Calculate the number and percentage of subjects entering the randomized subject set, the adjusted intention-to-treat analysis set, the protocol compliance set, and the safety analysis set.

[0065] List the subjects who failed the screening, the reasons for the failure, and the distribution of the subjects. Also list the subjects who were not included in each analysis set.

[0066] 4.8 Efficacy Analysis The primary and secondary efficacy endpoints will be analyzed using both mITT and PPS. Statistical conclusions for the primary efficacy endpoint will be based primarily on the results of the PPS analysis. Comparisons between the two analyses will be described in the statistical analysis report and the clinical study report.

[0067] 4.8.1 Main therapeutic indicators The primary efficacy endpoint was the change in VAS score for the main symptom, discogenic low back pain, after 30 days of treatment compared to baseline. The score was defined as the difference between the subject's baseline VAS score and their VAS score after 30 days of treatment.

[0068] The Visual Analogue Scale / Score (VAS) for pain: Subjective pain is quantitatively graded on a scale of 0 to 10, where 0 indicates no pain, 10 indicates unbearable pain, and other grades are assessed on a 0 to 10 cm scale based on the subject's own pain level: 0 to 3 indicates mild pain that is relatively tolerable and sleep is not affected by pain; 4 to 6 indicates mild pain that affects sleep quality but is still tolerable; 7 to 10 indicates severe pain that is unbearable and makes it impossible to get sleep.

[0069] Descriptive summaries were compiled for baseline VAS scores, VAS scores after 30 days of treatment, and changes in scores relative to baseline, categorized by treatment group. Mean, standard deviation, median, upper and lower quartiles, minimum, and maximum values ​​were reported. Inter-group comparisons were performed based on an analysis of covariance model (baseline scores as covariates). A fixed-ranking, descending-order method was used to compare the Biqi capsule and diclofenac combination therapy + diclofenac monotherapy group, and the Biqi capsule monotherapy + diclofenac monotherapy group. In this case, the significance level for each hypothesis test was α, requiring no adjustment, and the overall Type I error remained α. Comparisons between the Biqi capsule monotherapy group and the diclofenac monotherapy group were only performed when the Biqi capsule and diclofenac combination therapy was superior to the diclofenac monotherapy group (i.e., P ≤ 0.05). If the comparison between the combination of Biqi capsules and diclofenac versus diclofenac monotherapy is negative (i.e., P>0.05), then the comparison between Biqi capsule monotherapy and diclofenac monotherapy will not be performed.

[0070] Provide a detailed list of VAS rating scales.

[0071] 4.8.2 Secondary efficacy indicators Reduction rate of TCM syndrome scores Defined as the reduction rate of TCM syndrome scores (including Qi and Blood Deficiency Syndrome, Liver and Kidney Deficiency Syndrome, and Cold-Dampness Obstruction Syndrome) after 30 days of treatment.

[0072] Referring to the 2002 edition of the "Guiding Principles for Clinical Research of New Traditional Chinese Medicine Drugs," the TCM classification of discogenic low back pain, and clinical practice, a TCM syndrome scoring scale for discogenic low back pain was developed. The scoring scale quantifies the clinical symptoms of each syndrome type according to the severity of primary and secondary symptoms, tongue and pulse, etc. Researchers recorded the TCM syndrome scores of subjects before treatment and on day 30 after treatment. The TCM syndrome efficacy index was calculated. Primary symptoms were divided into four levels according to severity, scored as 0, 2, 4, and 6 points respectively; secondary symptoms were also divided into four levels according to severity, scored as 0, 1, 2, and 3 points respectively; tongue and pulse abnormalities were scored as 0 and 1 points respectively. The calculation formula is as follows: Points reduction rate = [(Total points before treatment - Total points after treatment) ÷ Points before treatment] × 100%.

[0073] The reduction rates of scores for Qi and Blood Deficiency Syndrome, Liver and Kidney Deficiency Syndrome, and Cold-Dampness Obstruction Syndrome were descriptively summarized according to treatment groups, reporting the mean, standard deviation, median, upper and lower quartiles, minimum, and maximum values. Inter-group comparisons were conducted based on an analysis of covariance model (baseline scores as covariates). A fixed-ranking, stepwise descending method was used to compare the Biqi Capsule and Diclofenac combination therapy + Diclofenac monotherapy group and the Biqi Capsule monotherapy + Diclofenac monotherapy group. A comparison between the Biqi Capsule monotherapy group and the Diclofenac monotherapy group was only conducted when the Biqi Capsule and Diclofenac combination therapy was superior to the Diclofenac monotherapy group (i.e., P ≤ 0.05). If the comparison between the Biqi Capsule and Diclofenac combination therapy and the Diclofenac monotherapy group was negative (i.e., P > 0.05), the comparison between the Biqi Capsule monotherapy group and the Diclofenac monotherapy group was not conducted.

[0074] Clinical efficacy rate of TCM syndrome scoring The clinical efficacy rate is defined as the score based on traditional Chinese medicine syndromes (including Qi and Blood Deficiency Syndrome, Liver and Kidney Deficiency Syndrome, and Cold-Dampness Obstruction Syndrome) before and 30 days after medication. The judgment criteria are as follows: Referring to the "Guiding Principles for Clinical Research of New Traditional Chinese Medicine Drugs" and the "Standards for Diagnosis and Efficacy of Diseases and Syndromes in Traditional Chinese Medicine," efficacy was evaluated according to a four-level efficacy standard (nimodipine method), categorized as clinically cured, significantly effective, effective, and ineffective. The overall effective rate is the proportion of the clinically cured, significantly effective, and effective groups in the total patient population.

[0075] The formula for calculating nimodipine is: [(pre-treatment score - post-treatment score) ÷ pre-treatment score] × 100% 1) Clinical cure: Disappearance of lower back pain symptoms, free movement of the lower back, and a reduction in the score by ≥95% 2) Significant effect: No lower back pain symptoms, basic recovery of lumbar mobility, 70% ≤ score reduction < 95%; 3) Effective: Lower back pain symptoms are relatively eliminated, and lumbar mobility is slightly limited; scores decrease by 30% ≤ < 70%. 4) Ineffective: There is no significant improvement in low back pain and lumbar mobility, and the score decreases by <30%.

[0076] At the end of the descriptive statistical study, the number and percentage of subjects with clinical cure, significant effect, effective, ineffective, and total effective (clinical cure + significant effect + effective) scores for Qi and Blood Deficiency Syndrome, Liver and Kidney Deficiency Syndrome, and Cold-Dampness Obstruction Syndrome were calculated for each group. The 95% confidence interval for the percentages was estimated using the Clopper-Pearson method. The difference in total clinical effective rate between groups was compared using the chi-square test or Fisher's exact test. A fixed-ranking, descending-order method was used to compare the Biqi Capsule and Diclofenac combination therapy + Diclofenac monotherapy group and the Biqi Capsule monotherapy + Diclofenac monotherapy group. A comparison between the Biqi Capsule monotherapy group and the Diclofenac monotherapy group was only conducted when the Biqi Capsule and Diclofenac combination therapy was superior to the Diclofenac monotherapy group (i.e., P ≤ 0.05). If the comparison between the combination of Biqi capsules and diclofenac versus diclofenac monotherapy is negative (i.e., P>0.05), then the comparison between Biqi capsule monotherapy and diclofenac monotherapy will not be performed.

[0077] 4.9 Exploratory Indicators (1) Changes in serum inflammatory markers before and after treatment The indicators were defined as the differences between serum inflammatory markers before and 30 days after medication, including C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor (TNF-α), and prostaglandin E2 (PGE2).

[0078] Descriptive summaries were compiled for baseline measurements, measurements after 30 days of treatment, and changes relative to baseline measurements of various serum inflammatory markers according to treatment groups. Mean, standard deviation, median, upper and lower quartiles, minimum, and maximum values ​​were reported. Inter-group comparisons were performed based on an analysis of covariance model (baseline scores as covariates). A fixed-ranking, descending-order method was used to compare the Biqi capsule and diclofenac combination therapy + diclofenac monotherapy group and the Biqi capsule monotherapy + diclofenac monotherapy group. A comparison between the Biqi capsule monotherapy group and the diclofenac monotherapy group was only performed when the Biqi capsule and diclofenac combination therapy was superior to the diclofenac monotherapy group (i.e., P ≤ 0.05). If the comparison between the Biqi capsule and diclofenac combination therapy group and the diclofenac monotherapy group was negative (i.e., P > 0.05), the comparison between the Biqi capsule monotherapy group and the diclofenac monotherapy group was not performed.

[0079] (2) Changes in bone turnover markers before and after treatment The indicators were defined as the differences between various bone turnover markers before and 30 days after medication, including the levels of bone-specific alkaline phosphatase (B-ALP), total type I collagen N-terminal elongated peptide (T-PINP), and β-collagen specific sequence (β-CTX).

[0080] Baseline measurements, measurements after 30 days of treatment, and changes relative to baseline measurements for all bone turnover markers were descriptively summarized according to treatment groups. Mean, standard deviation, median, upper and lower quartiles, minimum, and maximum values ​​were reported. Inter-group comparisons were performed based on an analysis of covariance model (baseline scores as covariates). A fixed-ranking, descending-order method was used to compare the Biqi capsule and diclofenac combination therapy + diclofenac monotherapy group and the Biqi capsule monotherapy + diclofenac monotherapy group. A comparison between the Biqi capsule monotherapy group and the diclofenac monotherapy group was only performed when the Biqi capsule and diclofenac combination therapy was superior to the diclofenac monotherapy group (i.e., P ≤ 0.05). If the comparison between the Biqi capsule and diclofenac combination therapy group and the diclofenac monotherapy group was negative (i.e., P > 0.05), the comparison between the Biqi capsule monotherapy group and the diclofenac monotherapy group was not performed.

[0081] (3) Explore the differences in imaging of different syndrome types and the changes in imaging before and after treatment.

[0082] 4.10 Determining the Sample Size The sample size was estimated based on the change in the visual analog scale (VAS) score of the primary symptom, discogenic low back pain, after 30 days of treatment, the main efficacy endpoint of this study. This study hypothesized that the combination of Biqi capsules and diclofenac was superior to diclofenac monotherapy. Assuming a bilateral alpha of 0.05 and a standard deviation of 1.4, then with 32 subjects in each group, there was an 80% power to observe a difference of 1.0 in the VAS score change between groups after 30 days of treatment. Considering a 20% dropout rate, the sample size was planned to be 40 subjects per group, with a 1:1:1 design, i.e., 120 cases per syndrome type, for a total of 360 cases.

[0083] 5. Study patients 5.1 Study on the management of patients The first participant screening for this study began on November 16, 2022, and the first participant was enrolled on November 23, 2022. The last participant was enrolled on July 23, 2024, and the follow-up period for the last participant ended on September 10, 2024. A total of 393 participants were screened, and 360 were successfully enrolled, divided into three groups: a combined traditional Chinese and Western medicine group, a Biqi capsule monotherapy group, and a diclofenac monotherapy group, with 120 participants in each group.

[0084] Of the 393 participants screened, 360 (91.6%) were successfully enrolled, while 33 (8.4%) failed the screening. The main reasons for screening failure were: not meeting the inclusion / exclusion criteria (19 cases, 57.6%), which was the highest proportion; withdrawal of informed consent (10 cases, 30.3%); and other reasons (4 cases, 12.1%).

[0085] Of the 360 ​​enrolled participants, 29 (8.1%) did not complete the study, and 331 (91.9%) completed it. The number of participants who did not complete the study in the three groups were 11 (9.2%), 10 (8.3%), and 8 (6.7%), respectively. The main reasons for not completing the study were: loss to follow-up (including participants withdrawing voluntarily) in 25 cases (86.2%); adverse events in 2 cases (6.9%), both in the integrated traditional Chinese and Western medicine group; and other reasons in 2 cases (6.9%).

[0086] Of the 360 ​​enrolled subjects, 325 (90.3%) completed treatment, 34 (9.4%) discontinued treatment, and 1 patient voluntarily withdrew before receiving treatment. The number of patients discontinuing treatment in the three groups were 12 (10.0%), 13 (10.8%), and 9 (7.5%), respectively. The main reasons for treatment discontinuation were: voluntary withdrawal from the study in 16 cases (47.1%); other reasons in 9 cases (26.5%); loss to follow-up in 6 cases (17.6%); and adverse events in 3 cases (8.8%).

[0087] 5.2 Analyzing the dataset Based on the analysis set division, the randomized subjects analysis set (RSS) had 120 participants in all three groups; the modified intention-to-treat (mITT) analysis sets (mITT) for the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group had 117, 119, and 118 participants, respectively; the protocol compliance set (PPS) for the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group had 104 participants; and the safety analysis set (SAS) had 119, 120, and 118 participants, respectively.

[0088] 5.3 Disease Diagnosis Analysis In the study, all participants were diagnosed with discogenic low back pain. The combined TCM and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group all had 104 participants (100%). TCM syndromes were categorized into Qi and Blood Deficiency Syndrome, Liver and Kidney Deficiency Syndrome, and Cold-Dampness Obstruction Syndrome. The Qi and Blood Deficiency Syndrome group had 32 (30.8%), 38 (36.5%), and 26 (25.0%) participants, respectively; the Liver and Kidney Deficiency Syndrome group had 29 (27.9%), 22 (21.2%), and 30 (28.8%) participants, respectively; and the Cold-Dampness Obstruction Syndrome group had 43 (41.3%), 44 (42.3%), and 48 (46.2%) participants, respectively. There were no statistically significant differences in the distribution of each syndrome type among the three groups (P > 0.05), and no compound syndromes were found, suggesting that the distribution of TCM syndrome types was essentially consistent across the three groups.

[0089] In the adjusted intention-to-treat set, all subjects presented with discogenic low back pain. The number of subjects in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were 117 (100%), 119 (100%), and 118 (100%), respectively. The distribution of TCM syndrome types was similar to that in the protocol-compliant set. The number of subjects with Qi and Blood Deficiency syndrome was 34 (29.1%), 42 (35.3%), and 31 (26.3%) in the three groups, respectively; the number of subjects with Liver and Kidney Deficiency syndrome was 36 (30.8%), 26 (21.8%), and 34 (28.8%), respectively; and the number of subjects with Cold-Dampness Obstruction syndrome was 47 (40.2%), 51 (42.9%), and 53 (44.9%), respectively. The p-values ​​for intergroup comparisons were all greater than 0.05, and no composite syndromes were found, indicating that the distribution of TCM syndrome types among the three groups was basically consistent.

[0090] 6. Efficacy Analysis 6.1 Analysis of VAS score changes after 30 days of treatment In the protocol-compliant analysis set, the baseline VAS scores of the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were similar, at 5.97±0.910, 5.99±0.829, and 6.03±0.877, respectively. After 30 days of treatment, the mean changes in VAS scores from baseline for the three groups were -3.88±1.931, -3.87±1.821, and -3.78±1.916, respectively. The adjusted mean (LSmean) changes in VAS scores from baseline after 30 days of treatment for the three groups were -3.91 (95% CI: [ -4.221, -3.592]), -3.88 (95% CI: [ -4.194, -3.566]), and -3.74 (95% CI: [ -4.058, -3.426]), respectively. The corrected mean difference in VAS scores between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was -0.16, with a 95% CI of (-0.668, 0.338), indicating no statistically significant difference between the groups (P = 0.6868). Since the comparison between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group, and between the Biqi capsule monotherapy group and the diclofenac monotherapy group, was conducted sequentially using a fixed-rank descending method, the result for the integrated traditional Chinese and Western medicine group versus the diclofenac monotherapy group was negative (P > 0.05). Therefore, the comparison between the Biqi capsule monotherapy group and the diclofenac monotherapy group was not performed further.

[0091] In the adjusted intention-to-treat analysis set, the baseline VAS scores of the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were similar, at 5.99±0.967, 6.01±0.834, and 6.05±0.903, respectively. After 30 days of treatment, the mean changes in VAS scores from baseline for the three groups were -3.95±1.957, -3.85±1.776, and -3.83±1.926, respectively. The adjusted mean (LSMean) changes in VAS scores from baseline after 30 days of treatment for the three groups were -3.94 (95% CI: [-4.242, -3.635]), -3.89 (95% CI: [-4.191, -3.586]), and -3.80 (95% CI: [-4.106, -3.501]), respectively. The adjusted mean difference in VAS scores between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was -0.13, with a 95% CI of (-0.619, 0.349), indicating no statistically significant difference between the groups (P = 0.7608). Since the comparisons between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group, and between the Biqi capsule monotherapy group and the diclofenac monotherapy group, were performed sequentially using a fixed-rank descending method, and the integrated traditional Chinese and Western medicine group vs. the diclofenac monotherapy group yielded a negative result (P > 0.05), the comparison between the Biqi capsule monotherapy group and the diclofenac monotherapy group was not performed. The results were consistent with the protocol analysis set, suggesting that the improvement in VAS scores was comparable among the three groups.

[0092] The changes in VAS scores of the subjects after 30 days of treatment are shown in Tables 1 and 2.

[0093] Table 1. Analysis of VAS score changes after 30 days of treatment – ​​Consistent protocol analysis set Note: A fixed-order descending method was used to compare the Biqi capsules and diclofenac combination therapy + diclofenac monotherapy group, and the Biqi capsules monotherapy + diclofenac monotherapy group. In this case, the significance level for each hypothesis test is α, which does not need to be adjusted, and the total Type I error remains α. The comparison between the Biqi capsules and diclofenac combination therapy and the diclofenac monotherapy group is only performed when the Biqi capsules and diclofenac combination therapy is superior to the diclofenac monotherapy group (i.e., P ≤ 0.05). If the comparison between the Biqi capsules and diclofenac combination therapy and the diclofenac monotherapy group is negative (i.e., P > 0.05), the comparison between the Biqi capsules and diclofenac monotherapy group and the diclofenac monotherapy group is not performed.

[0094] Table 2. Analysis of VAS score changes after 30 days of treatment – ​​Adjusted intention-to-treat analysis set Note 1: A fixed-order descending method was used to compare the Biqi capsules and diclofenac combination therapy + diclofenac monotherapy group, and the Biqi capsules monotherapy + diclofenac monotherapy group. In this case, the significance level for each hypothesis test is α, which does not need to be adjusted, and the total Type I error remains α. The comparison between the Biqi capsules and diclofenac combination therapy and the diclofenac monotherapy group is only performed when the Biqi capsules and diclofenac combination therapy is superior to the diclofenac monotherapy group (i.e., P ≤ 0.05). If the comparison between the Biqi capsules and diclofenac combination therapy and the diclofenac monotherapy group is negative (i.e., P > 0.05), the comparison between the Biqi capsules and diclofenac monotherapy group and the diclofenac monotherapy group is not performed. Note 2: Data with missing primary efficacy endpoints after baseline will be filled using the corresponding primary efficacy endpoint measurement from the last baseline period prior to the missing data (LOCF).

[0095] 6.2 Analysis of the reduction rate of TCM syndrome scores In the protocol-compliant analysis set, the baseline TCM syndrome scores of the integrated TCM and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were similar, at 8.59±3.543, 8.09±3.066, and 8.58±3.437, respectively. The mean reduction rates of TCM syndrome scores after 30 days of treatment in the three groups were 47.24%±30.707%, 37.59%±44.570%, and 41.91%±24.561%, respectively. The adjusted mean (LSMean) of the reduction rates of TCM syndrome scores after 30 days of treatment in the three groups were 47.10% (95% CI: [42.442%, 51.750%]), 37.87% (95% CI: [33.208%, 42.528%]), and 41.77% (95% CI: [37.092%, 46.446%]), respectively. The adjusted mean difference in the reduction rate of TCM syndrome scores between the integrated TCM and Western medicine group and the diclofenac monotherapy group was 5.33%, with 95% CI of -2.119% and 12.773%, respectively, indicating no statistically significant difference between the groups (P=0.1970). Since the comparisons between the integrated TCM and Western medicine group and the diclofenac monotherapy group, and between the Biqi capsule monotherapy group and the diclofenac monotherapy group, were conducted sequentially using a fixed-ranking descending method, and the results for the integrated TCM and Western medicine group versus the diclofenac monotherapy group were negative (P>0.05), the comparison between the Biqi capsule monotherapy group and the diclofenac monotherapy group was not performed.

[0096] Subgroup analysis showed that there were no statistically significant differences in the scores and reduction rates of Qi and Blood Deficiency Syndrome, Liver and Kidney Deficiency Syndrome, and Cold-Dampness Obstruction Syndrome among the three groups (P values ​​were all greater than 0.05). Only the reduction rate of Qi and Blood Deficiency Syndrome score in the integrated traditional Chinese and Western medicine group showed a difference of 0.0391 compared with that in the diclofenac monotherapy group, but overall, there was no significant difference in the improvement effect among the three groups.

[0097] In the adjusted intention-to-treat analysis set, the baseline TCM syndrome scores of the integrated TCM and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were similar, at 8.52±3.447, 8.25±3.149, and 8.53±3.374, respectively. The mean reduction rates of TCM syndrome scores after 30 days of treatment in the three groups were 46.91%±31.116%, 37.70%±43.691%, and 43.46%±24.821%, respectively. The adjusted mean (LSMean) of the reduction rates of TCM syndrome scores after 30 days of treatment in the three groups were 46.89% (95% CI: [42.373%, 51.408%]), 37.85% (95% CI: [33.355%, 42.354%]), and 43.32% (95% CI: [38.824%, 47.823%]), respectively. The adjusted mean difference in the reduction rate of TCM syndrome scores between the integrated TCM and Western medicine group and the diclofenac monotherapy group was 3.57%, with a 95% CI of (-3.631%, 10.765%), indicating no statistically significant difference between the groups (P=0.4397). Since a fixed-ranking, descending-order comparison was used to compare the integrated TCM and Western medicine group versus the diclofenac monotherapy group, and the comparison between the Biqi capsule monotherapy group and the diclofenac monotherapy group was negative (P>0.05), no further comparison was made between the Biqi capsule monotherapy group and the diclofenac monotherapy group. Consistent with the results of the protocol analysis set, this suggests no significant difference in the improvement of TCM syndrome scores among the three groups.

[0098] Subgroup analysis showed that there were no statistically significant differences in the scores and score reduction rates of Qi and Blood Deficiency Syndrome, Liver and Kidney Deficiency Syndrome, and Cold-Dampness Obstruction Syndrome among the three groups (P values ​​were all greater than 0.05).

[0099] The results of the analysis of the reduction rate of TCM syndrome scores are detailed in Tables 3 and 4.

[0100] Table 3. Analysis of the reduction rate of different TCM syndrome scores – Consistent scheme analysis set Note 1: The formula for calculating the lower score rate is: [(Pre-treatment score - Post-treatment score) ÷ Pre-treatment score] × 100%; Note 2: A fixed-order, descending-step method was used to compare the Biqi capsules and diclofenac combination therapy + diclofenac monotherapy group, and the Biqi capsules monotherapy + diclofenac monotherapy group. In this case, the significance level for each hypothesis test is α, which does not need to be adjusted, and the total Type I error remains α. The comparison between the Biqi capsules and diclofenac combination therapy and the diclofenac monotherapy group is only performed when the Biqi capsules and diclofenac combination therapy is superior to the diclofenac monotherapy group (i.e., P ≤ 0.05). If the comparison between the Biqi capsules and diclofenac combination therapy and the diclofenac monotherapy group is negative (i.e., P > 0.05), the comparison between the Biqi capsules and diclofenac monotherapy group and the diclofenac monotherapy group is not performed.

[0101] Table 4. Analysis of the reduction rate of different TCM syndrome scores – Adjusted intention-to-treat analysis set Note 1: The formula for calculating the lower score rate is: [(Pre-treatment score - Post-treatment score) ÷ Pre-treatment score] × 100%; Note 2: A fixed-order, descending-step method was used to compare the Biqi capsules and diclofenac combination therapy + diclofenac monotherapy group, and the Biqi capsules monotherapy + diclofenac monotherapy group. In this case, the significance level for each hypothesis test is α, which does not need to be adjusted, and the total Type I error remains α. The comparison between the Biqi capsules and diclofenac combination therapy and the diclofenac monotherapy group is only performed when the Biqi capsules and diclofenac combination therapy is superior to the diclofenac monotherapy group (i.e., P ≤ 0.05). If the comparison between the Biqi capsules and diclofenac combination therapy and the diclofenac monotherapy group is negative (i.e., P > 0.05), the comparison between the Biqi capsules and diclofenac monotherapy group and the diclofenac monotherapy group is not performed.

[0102] 6.3 Analysis of changes in serum inflammatory markers before and after treatment 6.3.1 Compliant Scheme Analysis Set For the inflammatory marker C-reactive protein (CRP), the mean changes from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were 1.06±7.776 mg / L, 0.20±2.267 mg / L, and 0.58±5.343 mg / L, respectively. Intergroup comparisons were conducted using an analysis of covariance model with group (diclofenac monotherapy group as the reference group) as the independent variable and baseline CRP level as the covariate. The corrected mean (LSMean) of the changes from baseline in CRP levels after 30 days of treatment in the three groups were 1.07 (95% CI: [-0.031, 2.180]), 0.17 (95% CI: [-0.913, 1.243]), and 0.60 (95% CI: [-0.490, 1.687]), respectively. The adjusted mean difference in CRP levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was 0.48, with a 95% CI of (-1.276, 2.229), indicating no statistically significant difference between the groups (P = 0.7704). Since the comparisons between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group, and between the Biqi capsule monotherapy group and the diclofenac monotherapy group, were performed sequentially using a fixed-rank descending method, and the results for the integrated traditional Chinese and Western medicine group versus the diclofenac monotherapy group were negative (P > 0.05), no further comparisons were made between the Biqi capsule monotherapy group and the diclofenac monotherapy group.

[0103] For the validation endpoint of interleukin-6 (IL-6), the mean changes from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were -0.05±5.347 pg / mL, -1.44±8.333 pg / mL, and 0.18±1.552 pg / mL, respectively. Intergroup comparisons were performed using an analysis of covariance model with group (the reference group being the diclofenac monotherapy group) as the independent variable and baseline IL-6 levels as the covariate. The corrected mean (LSMean) of the changes from baseline in IL-6 levels after 30 days of treatment in the three groups were 0.16 (95% CI: [-0.460, 0.787]), -0.92 (95% CI: [-1.552, -0.280]), and -0.59 (95% CI: [-1.240, 0.057]), respectively. The adjusted mean difference in IL-6 levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was 0.75, with a 95% CI of (-0.262, 1.771), indicating no statistically significant difference between the groups (P = 0.1747). Since the comparisons between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group, and between the Biqi capsule monotherapy group and the diclofenac monotherapy group, were performed sequentially using a fixed-rank descending method, and the results for the integrated traditional Chinese and Western medicine group versus the diclofenac monotherapy group were negative (P > 0.05), no further comparisons were made between the Biqi capsule monotherapy group and the diclofenac monotherapy group.

[0104] For tumor necrosis factor-α (TNF-α) levels, the mean changes from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were 3.50±14.801 pg / mL, 1.91±5.970 pg / mL, and 2.41±6.551 pg / mL, respectively. Intergroup comparisons were performed using an analysis of covariance model with group (diclofenac monotherapy group as the reference group) as the independent variable and baseline TNF-α levels as the covariate. The corrected mean (LSMean) of the changes from baseline in TNF-α levels after 30 days of treatment in the three groups were 3.54 (95% CI: [1.154, 5.934]), 1.86 (95% CI: [-0.605, 4.323]), and 2.42 (95% CI: [-0.025, 4.864]), respectively. The corrected mean difference in TNF-α levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was 1.12, with a 95% CI of (-2.737, 4.986), indicating no statistically significant difference between the groups (P = 0.7406). Since the comparisons between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group, and between the Biqi capsule monotherapy group and the diclofenac monotherapy group, were performed sequentially using a fixed-rank descending method, and the results for the integrated traditional Chinese and Western medicine group versus the diclofenac monotherapy group were negative (P > 0.05), the comparison between the Biqi capsule monotherapy group and the diclofenac monotherapy group was not performed.

[0105] For prostaglandin E2 (PGE2) levels, the mean changes from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were -0.51±14.717, 2.29±15.443, and 0.98±13.414, respectively. Intergroup comparisons were conducted using an analysis of covariance model with group (diclofenac monotherapy group as the reference group) as the independent variable and baseline PGE2 levels as the covariate. The corrected mean (LSMean) of the changes from baseline in PGE2 levels after 30 days of treatment in the three groups were -0.95 (95% CI: [-6.704, 4.809]), 2.56 (95% CI: [-3.796, 8.919]), and 1.24 (95% CI: [-4.967, 7.455]), respectively. The adjusted mean difference in PGE2 levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was -2.19, with a 95% CI of (-11.83, 7.449), indicating no statistically significant difference between the groups (P=0.8265). Since the comparisons between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group, and between the Biqi capsule monotherapy group and the diclofenac monotherapy group, were performed sequentially using a fixed-ranking descending method, and the results for the integrated traditional Chinese and Western medicine group versus the diclofenac monotherapy group were negative (P>0.05), the comparison between the Biqi capsule monotherapy group and the diclofenac monotherapy group was not performed.

[0106] In summary, the intergroup comparisons of changes in serum inflammatory markers (CRP, IL-6, TNF-α, PGE2) after 30 days of treatment were all greater than 0.05, indicating that the three groups had comparable effects in improving serum inflammatory markers.

[0107] 6.3.2 Adjusted Intention-to-Treatment Analysis Set For C-reactive protein (CRP) levels, the mean changes from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were 0.99±7.556 mg / L, 0.26±2.349 mg / L, and 0.46±5.213 mg / L, respectively. Intergroup comparisons were performed using an analysis of covariance model with group (diclofenac monotherapy group as the reference group) as the independent variable and baseline CRP levels as the covariate. (Data with missing post-baseline indicators were imputed using the last post-baseline measurement prior to the missing data (LOCF)). The adjusted mean (LSMean) changes in CRP levels from baseline after 30 days of treatment in the three groups were 1.01 (95% CI: [-0.031, 2.061]), 0.21 (95% CI: [-0.816, 1.229]), and 0.49 (95% CI: [-0.538, 1.514]), respectively. The adjusted mean difference in CRP levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was 0.53, with a 95% CI of (-1.128, 2.181), indicating no statistically significant difference between the groups (P = 0.7020). Since the comparisons between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group, and between the Biqi capsule monotherapy group and the diclofenac monotherapy group were conducted sequentially using a fixed ranking descending method, and the results of the integrated traditional Chinese and Western medicine group vs. the diclofenac monotherapy group were negative (P>0.05), the comparison between the Biqi capsule monotherapy group and the diclofenac monotherapy group was no longer conducted.

[0108] For the interleukin-6 (IL-6) level, the mean changes from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were -0.17±5.299 pg / mL, -1.35±8.054 pg / mL, and 0.17±1.534 pg / mL, respectively. Intergroup comparisons were performed using an analysis of covariance model with group (diclofenac monotherapy group as the reference group) as the independent variable and baseline IL-6 level as the covariate. (Data with missing post-baseline indicators were imputed using the last post-baseline measurement prior to the missing data (LOCF)). The corrected mean (LSMean) changes in IL-6 levels from baseline after 30 days of treatment in the three groups were 0.11 (95% CI: [-0.484, 0.709]), -0.92 (95% CI: [-1.519, -0.318]), and -0.60 (95% CI: [-1.228, 0.026]), respectively. The corrected mean difference in IL-6 levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was 0.71, with a 95% CI of (-0.264, 1.691), indicating no statistically significant difference between the groups (P = 0.1835). Since the comparisons between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group, and between the Biqi capsule monotherapy group and the diclofenac monotherapy group were conducted sequentially using a fixed ranking descending method, and the comparison between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group yielded negative results (P>0.05), the comparison between the Biqi capsule monotherapy group and the diclofenac monotherapy group was no longer performed.

[0109] For the tumor necrosis factor-α (TNF-α) level, the mean changes from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were 3.35±14.409 pg / mL, 2.08±6.407 pg / mL, and 3.36±9.128 pg / mL, respectively. Intergroup comparisons were performed using an analysis of covariance model with group (diclofenac monotherapy group as the reference group) as the independent variable and baseline TNF-α level as the covariate. (Data with missing post-baseline indicators were imputed using the last post-baseline measurement prior to the missing data (LOCF)). The corrected mean (LSMean) changes in TNF-α levels from baseline after 30 days of treatment in the three groups were 3.43 (95% CI: [0.978, 5.874]), 1.98 (95% CI: [-0.538, 4.502]), and 3.38 (95% CI: [0.846, 5.920]), respectively. The corrected mean difference in TNF-α levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was 0.04, with a 95% CI of (-3.938, 4.023), indicating no statistically significant difference between the groups (P = 0.9996). Since the comparisons between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group, and between the Biqi capsule monotherapy group and the diclofenac monotherapy group were conducted sequentially using a fixed ranking descending method, and the results of the integrated traditional Chinese and Western medicine group vs. the diclofenac monotherapy group were negative (P>0.05), the comparison between the Biqi capsule monotherapy group and the diclofenac monotherapy group was no longer conducted.

[0110] For prostaglandin E2 (PGE2) levels, the mean changes from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were 0.42±15.397, 2.29±15.443, and 0.98±13.414, respectively. Intergroup comparisons were conducted using an analysis of covariance model with group (diclofenac monotherapy group as the reference group) as the independent variable and baseline PGE2 levels as the covariate (data with missing post-baseline indicators were imputed using the last post-baseline measurement prior to the missing data (LOCF)). The corrected mean (LSMean) of the changes from baseline in PGE2 levels after 30 days of treatment in the three groups were -0.09 (95% CI: [-5.723, 5.534]), 2.63 (95% CI: [-3.821, 9.086]), and 1.31 (95% CI: [-4.992, 7.618]), respectively. The adjusted mean difference in PGE2 levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was -1.41, with a 95% CI of (-11.02, 8.209), indicating no statistically significant difference between the groups (P=0.9229). Since a fixed-ranking, descending-order comparison was used sequentially between the combined use of Biqi capsules and diclofenac versus diclofenac monotherapy, and between Biqi capsules monotherapy and diclofenac monotherapy, and the comparison between the integrated traditional Chinese and Western medicine group and diclofenac monotherapy was negative (P>0.05), no further comparison was made between Biqi capsules monotherapy and diclofenac monotherapy.

[0111] In summary, the intergroup comparisons of changes in serum inflammatory markers (CRP, IL-6, TNF-α, PGE2) after 30 days of treatment from baseline showed P values ​​greater than 0.05, consistent with the results of the protocol analysis set, suggesting that there was no significant difference in the improvement of serum inflammatory markers among the three groups.

[0112] The results of the analysis of changes in serum inflammatory markers before and after treatment are detailed in Tables 5 and 6.

[0113] Table 5. Analysis of changes in serum inflammatory markers before and after treatment – ​​Consistent protocol analysis set Note: A fixed-order descending method was used to compare the Biqi capsules and diclofenac combination therapy + diclofenac monotherapy group, and the Biqi capsules monotherapy + diclofenac monotherapy group. In this case, the significance level for each hypothesis test is α, which does not need to be adjusted, and the total Type I error remains α. The comparison between the Biqi capsules and diclofenac combination therapy and the diclofenac monotherapy group is only performed when the Biqi capsules and diclofenac combination therapy is superior to the diclofenac monotherapy group (i.e., P ≤ 0.05). If the comparison between the Biqi capsules and diclofenac combination therapy and the diclofenac monotherapy group is negative (i.e., P > 0.05), the comparison between the Biqi capsules and diclofenac monotherapy group and the diclofenac monotherapy group is not performed.

[0114] Table 6. Analysis of changes in serum inflammatory markers before and after treatment – ​​Adjusted intention-to-treat analysis set Note: A fixed-order descending method was used to compare the Biqi capsules and diclofenac combination therapy + diclofenac monotherapy group, and the Biqi capsules monotherapy + diclofenac monotherapy group. In this case, the significance level for each hypothesis test is α, which does not need to be adjusted, and the total Type I error remains α. The comparison between the Biqi capsules and diclofenac combination therapy and the diclofenac monotherapy group is only performed when the Biqi capsules and diclofenac combination therapy is superior to the diclofenac monotherapy group (i.e., P ≤ 0.05). If the comparison between the Biqi capsules and diclofenac combination therapy and the diclofenac monotherapy group is negative (i.e., P > 0.05), the comparison between the Biqi capsules and diclofenac monotherapy group and the diclofenac monotherapy group is not performed.

[0115] 6.4 Analysis of changes in bone turnover markers before and after treatment 6.4.1 Set of compliant scheme analysis For bone-specific alkaline phosphatase (B-ALP), the mean changes from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were -0.58±2.618ug / L, -0.02±1.700ug / L, and -0.12±1.870ug / L, respectively. Intergroup comparisons were conducted using an analysis of covariance model with group (diclofenac monotherapy group as the reference group) as the independent variable and baseline B-ALP level as the covariate. The corrected mean (LSMean) of the changes from baseline in B-ALP levels after 30 days of treatment in the three groups were -0.54 (95% CI: [-1.325, 0.249]), 0.16 (95% CI: [-0.741, 1.068]), and -0.33 (95% CI: [-1.193, 0.537]), respectively. The corrected mean difference in B-ALP levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was -0.21, with a 95% CI of (-1.536, 1.115), indicating no statistically significant difference between the groups (P = 0.9097). Since the comparisons between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group, and between the Biqi capsule monotherapy group and the diclofenac monotherapy group, were performed sequentially using a fixed-ranking descending method, and the integrated traditional Chinese and Western medicine group vs. the diclofenac monotherapy group yielded negative results (P > 0.05), the comparison between the Biqi capsule monotherapy group and the diclofenac monotherapy group was not further performed.

[0116] For the total type I collagen N-terminal extended peptide (T-PINP) index, the mean changes from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were -0.44±12.133 ng / mL, 2.43±10.082 ng / mL, and 1.44±8.374 ng / mL, respectively. Intergroup comparisons were conducted using an analysis of covariance model with group (diclofenac monotherapy group as the reference group) as the independent variable and baseline T-PINP levels as the covariate. The corrected mean (LSMean) of the changes from baseline in T-PINP levels after 30 days of treatment in the three groups were -0.45 (95% CI: [-2.692, 1.782]), 2.55 (95% CI: [0.236, 4.859]), and 1.34 (95% CI: [-0.971, 3.651]), respectively. The corrected mean difference in T-PINP levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was -1.80, with a 95% CI of (-5.427, 1.836), indicating no statistically significant difference between the groups (P = 0.4386). Since the comparisons between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group, and between the Biqi capsule monotherapy group and the diclofenac monotherapy group, were performed sequentially using a fixed-rank descending method, and the comparison between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group yielded negative results (P > 0.05), no further comparisons were made between the Biqi capsule monotherapy group and the diclofenac monotherapy group.

[0117] For the β-collagen specific sequence (β-CTX) index, the mean changes from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were -2.48±21.884 ng / mL, -3.46±30.094 ng / mL, and 0.00±0.117 ng / mL, respectively. Intergroup comparisons were performed using an analysis of covariance model with group (diclofenac monotherapy group as the reference group) as the independent variable and baseline β-CTX levels as the covariate. The corrected mean (LSMean) of the changes from baseline in β-CTX levels after 30 days of treatment in the three groups were -2.05 (95% CI: [-2.096, -1.995]), -1.98 (95% CI: [-2.034, -1.931]), and -2.01 (95% CI: [-2.060, -1.955]), respectively. The corrected mean difference in β-CTX levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was -0.04, with a 95% CI of (-0.120, 0.045), indicating no statistically significant difference between the groups (P = 0.4930). Since the comparisons between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group, and between the Biqi capsule monotherapy group and the diclofenac monotherapy group, were performed sequentially using a fixed-ranking descending method, and the results for the integrated traditional Chinese and Western medicine group versus the diclofenac monotherapy group were negative (P > 0.05), the comparison between the Biqi capsule monotherapy group and the diclofenac monotherapy group was not performed.

[0118] In summary, the intergroup comparisons of changes from baseline after 30 days of treatment with the three groups of bone turnover markers (B-ALP, T-PINP, and β-CTX) all showed P values ​​greater than 0.05, indicating that there was no significant difference in the effects of the three groups on bone turnover markers.

[0119] 6.4.2 Adjusted Intention-to-Treatment Analysis Set For bone-specific alkaline phosphatase (B-ALP), the mean changes from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were -0.45±2.602ug / L, -0.02±1.700ug / L, and -0.12±1.870ug / L, respectively. Intergroup comparisons were performed using an analysis of covariance model with group (diclofenac monotherapy group as the reference group) as the independent variable and baseline B-ALP level as the covariate. (Data with missing post-baseline indicators were imputed using the last post-baseline measurement prior to the missing data (LOCF)). The corrected mean (LSMean) changes in B-ALP levels from baseline after 30 days of treatment in the three groups were -0.43 (95% CI: [-1.192, 0.327]), 0.18 (95% CI: [-0.725, 1.087]), and -0.32 (95% CI: [-1.184, 0.545]), respectively. The corrected mean difference in B-ALP levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was -0.11, with a 95% CI of (-1.415, 1.189), indicating no statistically significant difference between the groups (P = 0.9717). Since the comparisons between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group, and between the Biqi capsule monotherapy group and the diclofenac monotherapy group were conducted sequentially using a fixed ranking descending method, and the results of the integrated traditional Chinese and Western medicine group vs. the diclofenac monotherapy group were negative (P>0.05), the comparison between the Biqi capsule monotherapy group and the diclofenac monotherapy group was no longer conducted.

[0120] For the total type I collagen N-terminal extended peptide (T-PINP) index, the mean changes from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were -0.54±12.097 ng / mL, 3.34±10.338 ng / mL, and 1.54±8.357 ng / mL, respectively. Intergroup comparisons were performed using an analysis of covariance model with group (diclofenac monotherapy group as the reference group) as the independent variable and baseline T-PINP level as the covariate (data with missing post-baseline indicators were imputed using the last post-baseline measurement prior to the missing data (LOCF)). The corrected mean (LSMean) changes in T-PINP levels from baseline after 30 days of treatment in the three groups were -0.51 (95% CI: [-2.721, 1.703]), 3.41 (95% CI: [1.179, 5.631]), and 1.43 (95% CI: [-0.835, 3.702]), respectively. The corrected mean difference in T-PINP levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was -1.94, with a 95% CI of (-5.520, 1.635), indicating no statistically significant difference between the groups (P = 0.3745). Since the comparisons between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group, and between the Biqi capsule monotherapy group and the diclofenac monotherapy group were conducted sequentially using a fixed ranking descending method, and the results of the integrated traditional Chinese and Western medicine group vs. the diclofenac monotherapy group were negative (P>0.05), the comparison between the Biqi capsule monotherapy group and the diclofenac monotherapy group was no longer conducted.

[0121] For the β-collagen specific sequence (β-CTX) index, the mean changes from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were -2.39±21.475 ng / mL, -3.21±28.972 ng / mL, and 0.00±0.115 ng / mL, respectively. Intergroup comparisons were performed using an analysis of covariance model with group (diclofenac monotherapy group as the reference group) as the independent variable and baseline β-CTX level as the covariate (data with missing post-baseline indicators were imputed using the last post-baseline measurement prior to the missing data (LOCF)). The corrected mean (LSMean) changes in β-CTX levels from baseline after 30 days of treatment in the three groups were -1.94 (95% CI: [-1.985, -1.887]), -1.89 (95% CI: [-1.938, -1.840]), and -1.91 (95% CI: [-1.960, -1.858]), respectively. The corrected mean difference in β-CTX levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was -0.03, with a 95% CI of (-0.107, 0.053), indicating no statistically significant difference between the groups (P = 0.6721). Since the comparisons between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group, and between the Biqi capsule monotherapy group and the diclofenac monotherapy group were conducted sequentially using a fixed ranking descending method, and the results of the integrated traditional Chinese and Western medicine group vs. the diclofenac monotherapy group were negative (P>0.05), the comparison between the Biqi capsule monotherapy group and the diclofenac monotherapy group was no longer conducted.

[0122] In summary, the intergroup comparisons of changes from baseline after 30 days of treatment for the three bone turnover markers (B-ALP, T-PINP, and β-CTX) all showed P values ​​greater than 0.05, consistent with the results of the protocol analysis set, suggesting that there were no significant differences among the three groups in their effects on bone turnover markers.

[0123] The changes in bone turnover markers before and after treatment are detailed in Tables 7 and 8.

[0124] Table 7. Analysis of changes in bone turnover markers before and after treatment – ​​Consistent protocol analysis set Note: A fixed-order descending method was used to compare the Biqi capsules and diclofenac combination therapy + diclofenac monotherapy group, and the Biqi capsules monotherapy + diclofenac monotherapy group. In this case, the significance level for each hypothesis test is α, which does not need to be adjusted, and the total Type I error remains α. The comparison between the Biqi capsules and diclofenac combination therapy and the diclofenac monotherapy group is only performed when the Biqi capsules and diclofenac combination therapy is superior to the diclofenac monotherapy group (i.e., P ≤ 0.05). If the comparison between the Biqi capsules and diclofenac combination therapy and the diclofenac monotherapy group is negative (i.e., P > 0.05), the comparison between the Biqi capsules and diclofenac monotherapy group and the diclofenac monotherapy group is not performed.

[0125] Table 8. Analysis of changes in bone turnover markers before and after treatment – ​​Adjusted intention-to-treat analysis set Note: A fixed-order descending method was used to compare the Biqi capsules and diclofenac combination therapy + diclofenac monotherapy group, and the Biqi capsules monotherapy + diclofenac monotherapy group. In this case, the significance level for each hypothesis test is α, which does not need to be adjusted, and the total Type I error remains α. The comparison between the Biqi capsules and diclofenac combination therapy and the diclofenac monotherapy group is only performed when the Biqi capsules and diclofenac combination therapy is superior to the diclofenac monotherapy group (i.e., P ≤ 0.05). If the comparison between the Biqi capsules and diclofenac combination therapy and the diclofenac monotherapy group is negative (i.e., P > 0.05), the comparison between the Biqi capsules and diclofenac monotherapy group and the diclofenac monotherapy group is not performed.

[0126] 6.5 Conclusion on Therapeutic Effect A total of 360 patients were enrolled (120 in the integrated traditional Chinese and Western medicine group, 120 in the Biqi capsule monotherapy group, and 120 in the diclofenac monotherapy group). The adjusted intention-to-treat (mITT) sets were 117, 119, and 118, respectively. The protocol compliance (PPS) sets were 104 in each of the three groups. The main reason for exclusion was a major protocol deviation that resulted in the absence of the primary efficacy endpoint.

[0127] The primary efficacy endpoint analysis showed that, within the protocol-compliant analysis set, the baseline VAS scores of the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were similar. After 30 days of treatment, the mean changes in VAS scores from baseline for the three groups were -3.88±1.931, -3.87±1.821, and -3.78±1.916, respectively. The adjusted mean (LSmean) changes in VAS scores from baseline after 30 days of treatment for the three groups were -3.91 (95% CI: [-4.221, -3.592]), -3.88 (95% CI: [-4.194, -3.566]), and -3.74 (95% CI: [-4.058, -3.426]), respectively. The adjusted mean difference in VAS scores between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was -0.16, with a 95% CI of (-0.668, 0.338), indicating no statistically significant difference between the groups (P=0.6868). The results of the adjusted intention-to-treat analysis set were similar to those of the compliance analysis set.

[0128] Secondary efficacy endpoint analysis showed: (1) In the protocol-compliant analysis set, the adjusted mean (LSMean) of the reduction rate of TCM syndrome scores after 30 days of treatment in the integrated TCM and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were 47.10% (95% CI: [42.442%, 51.750%]), 37.87% (95% CI: [33.208%, 42.528%]), and 41.77% (95% CI: [37.092%, 46.446%]), respectively. The difference in the adjusted mean of the reduction rate of TCM syndrome scores between the integrated TCM and Western medicine group and the diclofenac monotherapy group was 5.33%, with a 95% CI of -2.119% and 12.773%, respectively, indicating no statistically significant difference between the groups (P=0.1970). The results of the adjusted intention-to-treat analysis set were similar to those of the protocol-compliant analysis set. Subgroup analysis showed that there were no statistically significant differences in the scores and reduction rates of Qi and Blood Deficiency Syndrome, Liver and Kidney Deficiency Syndrome, and Cold-Dampness Obstruction Syndrome among the three groups (P values ​​were all greater than 0.05). Only the reduction rate of Qi and Blood Deficiency Syndrome score in the integrated traditional Chinese and Western medicine group showed a difference of 0.0391 compared with that in the diclofenac monotherapy group, but overall, there was no significant difference in the improvement effect among the three groups.

[0129] (2) In the protocol-compliant analysis set, the clinical efficacy rates of the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were 74.0%, 62.5%, and 67.3%, respectively. There was no statistically significant difference in the total clinical efficacy rate between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group (P>0.05). The results of the adjusted intention-to-treat analysis set were similar to those of the protocol-compliant analysis set.

[0130] (3) In the protocol-compliant analysis set, for the C-reactive protein (CRP) index, the adjusted mean (LSMean) of CRP levels after 30 days of treatment compared to baseline in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were 1.07 (95% CI: [-0.031, 2.180]), 0.17 (95% CI: [-0.913, 1.243]), and 0.60 (95% CI: [-0.490, 1.687]), respectively. The adjusted mean difference in CRP levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was 0.48, with a 95% CI of (-1.276, 2.229), indicating no statistically significant difference between the groups (P=0.7704). For the interleukin-6 (IL-6) index, the corrected mean (LSMean) of the change in IL-6 levels from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were 0.16 (95% CI: [-0.460, 0.787]), -0.92 (95% CI: [-1.552, -0.280]), and -0.59 (95% CI: [-1.240, 0.057]), respectively. The corrected mean difference in IL-6 levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was 0.75, with a 95% CI of (-0.262, 1.771), indicating no statistically significant difference between the groups (P=0.1747). For the tumor necrosis factor-α (TNF-α) index, the corrected mean (LSMean) of the change in TNF-α levels from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were 3.54 (95% CI: [1.154, 5.934]), 1.86 (95% CI: [-0.605, 4.323]), and 2.42 (95% CI: [-0.025, 4.864]), respectively. The corrected mean difference in TNF-α levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was 1.12, with a 95% CI of (-2.737, 4.986), indicating no statistically significant difference between the groups (P=0.7406). For prostaglandin E2 (PGE2) levels, the corrected mean (LSMean) of the changes in PGE2 levels from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were -0.95 (95% CI: [-6.704, 4.809]), 2.56 (95% CI: [-3.796, 8.919]), and 1.24 (95% CI: [-4.967, 7.455]), respectively.The adjusted mean difference in PGE2 levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was -2.19, with a 95% CI of (-11.83, 7.449), indicating no statistically significant difference between the groups (P=0.8265). The results of the adjusted intention-to-treat analysis set were similar to those of the compliance analysis set.

[0131] (4) In the protocol-compliant analysis set, for bone-specific alkaline phosphatase (B-ALP) levels, the corrected mean (LSMean) of the changes in B-ALP levels from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were -0.54 (95% CI: [-1.325, 0.249]), 0.16 (95% CI: [-0.741, 1.068]), and -0.33 (95% CI: [-1.193, 0.537]), respectively. The corrected mean difference in B-ALP levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was -0.21, with a 95% CI of (-1.536, 1.115), indicating no statistically significant difference between the groups (P=0.9097). For the total type I collagen N-terminal extended peptide (T-PINP) index, the corrected mean (LSMean) of the change in T-PINP levels from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were -0.45 (95% CI: [-2.692, 1.782]), 2.55 (95% CI: [0.236, 4.859]), and 1.34 (95% CI: [-0.971, 3.651]), respectively. The corrected mean difference in T-PINP levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was -1.80, with a 95% CI of (-5.427, 1.836), indicating no statistically significant difference between the groups (P = 0.4386). For the β-collagen-specific sequence (β-CTX) index, the adjusted mean (LSMean) of the change in β-CTX levels from baseline after 30 days of treatment in the integrated traditional Chinese and Western medicine group, the Biqi capsule monotherapy group, and the diclofenac monotherapy group were -2.05 (95% CI: [-2.096, -1.995]), -1.98 (95% CI: [-2.034, -1.931]), and -2.01 (95% CI: [-2.060, -1.955]), respectively. The adjusted mean difference in β-CTX levels between the integrated traditional Chinese and Western medicine group and the diclofenac monotherapy group was -0.04, with a 95% CI of (-0.120, 0.045), indicating no statistically significant difference between the groups (P=0.4930). The results of the adjusted intention-to-treat analysis set were similar to those of the conformity analysis set.

[0132] In summary, the combination of Biqi capsules and diclofenac significantly improved VAS scores, TCM syndrome scores, serum inflammatory markers, and bone turnover markers. In particular, in patients with Qi and Blood Deficiency syndrome type of discogenic low back pain, the TCM score reduction rate of the combined TCM and Western medicine group was better than that of the diclofenac monotherapy group, indicating that the combined use of Biqi capsules and diclofenac has a more significant therapeutic effect on Qi and Blood Deficiency syndrome type of discogenic low back pain.

[0133] 7. Conclusion Biqi capsules combined with diclofenac significantly improved VAS scores, TCM syndrome scores, serum inflammatory markers, and bone turnover markers. Particularly in patients with Qi and Blood Deficiency syndrome-type discogenic low back pain, the combined TCM and Western medicine group showed a greater improvement in TCM score reduction than the diclofenac monotherapy group, indicating that the combined use of Biqi capsules and diclofenac has a more significant therapeutic effect on Qi and Blood Deficiency syndrome-type discogenic low back pain. However, given the current sample size and data, the combined use of Biqi capsules and diclofenac, Biqi capsules alone, and diclofenac monotherapy for different syndrome types of discogenic low back pain cannot yet prove that the combined TCM and Western medicine group was superior to the diclofenac monotherapy group in terms of the primary endpoint of 30 days of treatment for the main symptoms of low back pain.

[0134] Regarding safety, the incidence of adverse events was similar when Biqi capsules were used in combination with diclofenac, when Biqi capsules were used alone, and when diclofenac was used alone to treat different types of discogenic low back pain. No new safety issues were found, so the safety is controllable.

[0135] It should be noted that, in this document, relational terms such as "first" and "second" are used merely to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0136] The above description is merely a specific embodiment of the present invention, enabling those skilled in the art to understand or implement the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the present invention is not to be limited to the embodiments described herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A combination of traditional Chinese and Western medicine, characterized in that, The combination of Chinese and Western medicines includes both traditional Chinese medicine and Western medicine. The traditional Chinese medicine mentioned is Biqi Capsules; The active ingredient of the Western medicine is diclofenac or diclofenac salt.

2. The combination of traditional Chinese and Western medicines according to claim 1, characterized in that, In the aforementioned combination of Chinese and Western medicines, the dosage of the Chinese patent medicine is 2.4-3.6g per day, and the dosage of the Western medicine is 100mg per day.

3. The combination of traditional Chinese and Western medicines according to claim 1 or 2, characterized in that, The Western medicine includes at least one of diclofenac, diclofenac sodium, and diclofenac sodium sustained-release tablets.

4. The combination of traditional Chinese and Western medicines according to any one of claims 1 to 3, characterized in that, The combination of traditional Chinese and Western medicines includes: The traditional Chinese medicine mentioned is Biqi Capsules; The Western medicine in question is diclofenac.

5. The combination of traditional Chinese and Western medicines according to any one of claims 1 to 4, characterized in that, The combination of traditional Chinese and Western medicines includes: The traditional Chinese medicine mentioned is Biqi Capsules; The Western medicine in question is diclofenac sodium sustained-release tablets.

6. The use of the combination of traditional Chinese and Western medicine as described in any one of claims 1 to 5 in the preparation of a medicine for treating low back pain.

7. The application according to claim 6, characterized in that, The lower back pain described is discogenic lower back pain.

8. The application according to claim 7, characterized in that, The symptoms of discogenic low back pain include at least one of the following: deficiency of qi and blood, deficiency of liver and kidney, and cold-dampness obstruction.

9. The application according to claim 8, characterized in that, The preferred syndrome type is Qi and Blood Deficiency Syndrome.

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