Knee Pain Ejiao Paste for Knee Osteoarthritis

Overall Design: This study employs a randomized, double-blind, internal and external dual-control clinical trial design. Trial Procedures: The trial consists of a screening/baseline period and a 12-week treatment period, with an End-of-Study (EOS) or End-of-Treatment (EOT) visit conducted after 12 weeks of administration. Randomization and Blinding: A stratified block randomization method will be used to assign participants to each group in a 1:1 ratio, with competitive enrollment across all centers and a double-blind design. External Control: Literature-based data. Data Collection: Electronic Data Capture (EDC) system and Electronic Patient-Reported Outcome (ePRO) system.

• Knee Pain Ejiao Paste (Drug): By comparing Knee Pain Ejiao Paste with the base formula, Knee Pain Ejiao-free Clear Paste, this study minimizes confounding factors such as dosage form, administration method, and matrix components. This approach allows for a precise evaluation of the incremental therapeutic benefits contributed by the addition of Ejiao, thereby providing direct evidence for the medicinal value of Colla Corii Asini.
• Knee Pain Ejiao-free Clear Paste (Drug): Using an Ejiao-free clear paste as a parallel control.

Primary outcomes

• Change from baseline in Numerical Rating Scale (NRS) score for target knee pain at Week 12 [Screening Period/Baseline, Week 12]: Selection of the target knee joint: For participants with unilateral involvement, the affected knee is designated as the target knee. In cases of bilateral involvement, the knee with the higher Numerical Rating Scale (NRS) pain score will be selected as the target knee. If the pain NRS scores are identical for both knees, the right knee joint will be chosen as the target knee.

Secondary outcomes

• Patient Electronic Diary (ePRO) Joint Pain NRS Score [Baseline to Week 12]: During the treatment period, subjects will complete the NRS score for target knee pain and other records on ePRO daily.
• Change from baseline in NRS score for target knee pain at Weeks 4 and 8 [Screening Period/Baseline, Week 4, and Week 8]: Selection of the target knee joint: For participants with unilateral involvement, the affected knee is designated as the target knee. In cases of bilateral involvement, the knee with the higher Numerical Rating Scale (NRS) pain score will be selected as the target knee. If the pain NRS scores are identical for both knees, the right knee joint will be chosen as the target knee.
• Pain relief rate of target knee pain at Weeks 4, 8, and 12 post-treatment [Screening Period/Baseline, Week 4, Week 8, and Week 12]: Effectiveness is defined as a ≥ 50% decrease in the target knee pain NRS score relative to baseline, where the reduction rate = \[(Pre-trearment score - Post-treatment score) ÷ Pre-trearment score\] × 100%.
• Time to onset of target knee pain relief [Baseline to Week 12]: Time (in days) to the first ≥ 25% reduction from baseline in target knee pain NRS score (as recorded in the diary card).
• Change from baseline in WOMAC total score for the target knee at Weeks 4, 8, and 12 post-treatment [Screening Period/Baseline, Week 4, Week 8, and Week 12]: Comparison of the change from baseline in WOMAC total score between groups at Weeks 4, 8, and 12 post-treatment.
• Changes from baseline in WOMAC subscale scores (Pain, Stiffness, and Physical Function) for the target knee at Weeks 4, 8, and 12 post-treatment [Screening Period/Baseline, Week 4, Week 8, and Week 12]: Comparison of the change from baseline in WOMAC subscale scores (Pain, Stiffness, and Physical Function) between groups at Weeks 4, 8, and 12 post-treatment.
• Comparison of MOAKS scores for joint effusion in the target knee at Week 12 post-treatment [Screening Period/Baseline, Week 12]: Comparison of the change from baseline in MOAKS joint effusion scores between groups at Week 12 post-treatment.
• Change from baseline in subject satisfaction scores at Week 12 post-treatment [Screening Period/Baseline, Week 4, Week 8, and Week 12]: Comparison of the change from baseline in subject satisfaction scores between groups at Weeks 4, 8, and 12, as well as the proportion of satisfied subjects between groups.
• Change from baseline in investigator satisfaction scores at Week 12 post-treatment [Screening Period/Baseline, Week 4, Week 8, and Week 12]: Comparison of the change from baseline in investigator satisfaction scores between groups at Weeks 4, 8, and 12 post-treatment, as well as the proportion of investigator-rated satisfaction between groups.
• Consumption of rescue medication during the treatment period [Baseline to Week 12]: Comparison of the consumption of Celecoxib tablets as rescue medication between groups during the study period.
• Effective rate of TCM syndrome at Weeks 4, 8, and 12 post-treatment [Screening Period/Baseline, Week 4, Week 8, and Week 12]: Comparison of the between-group differences in the effective rate at Weeks 4, 8, and 12 post-treatment. Based on the results of the TCM Syndrome Quantitative Rating Scale, TCM syndrome scores are calculated before and after treatment, and the efficacy is evaluated according to the following criteria: Effective: A reduction in TCM syndrome score of ≥ 50% Ineffective: A reduction in TCM syndrome score of less than 50% The reduction rate of TCM syndrome score is caculated as: Reduction Rate = \[(Pre-trearment score - Post-treatment score) ÷ Pre-trearment score\] × 100%.
• Changes from baseline in TCM syndrome total scores and individual symptom scores at Weeks 4, 8, and 12 post-treatment [Screening Period/Baseline, Week 4, Week 8, and Week 12]: Comparison of the change from baseline in TCM syndrome total scores and individual symptom scores between groups at Weeks 4, 8, and 12 post-treatment.

Other outcomes

• Adverse Event (AE) [Week 4, Week 8, and Week 12]: Adverse events will be evaluated and recorded based on their type, incidence, severity, timing, and causality (relationship to the study drug).
• Vital Signs (Body Temperature) [Screening Period/Baseline, Week 4, Week 8, and Week 12]: Body temperature (°C) is measured under standardized conditions (rest ≥5 minutes, using calibrated equipment) by trained study personnel.
• Vital Signs (Pulse Rate) [Screening Period/Baseline, Week 4, Week 8, and Week 12]: Pulse rate (beats per minute, bpm) is measured under standardized conditions (rest ≥5 minutes, using calibrated equipment) by trained study personnel.
• Vital Signs (Respiratory Rate) [Screening Period/Baseline, Week 4, Week 8, and Week 12]: Respiratory rate (breaths per minute) is measured under standardized conditions (rest ≥5 minutes, using calibrated equipment) by trained study personnel.
• Vital Signs (Blood Pressure) [Screening Period/Baseline, Week 4, Week 8, and Week 12]: Blood pressure (systolic and diastolic, mmHg) is measured under standardized conditions (rest ≥5 minutes, using calibrated equipment) by trained study personnel. Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) are recorded and reported separately.
• Laboratory Parameters (Hematology-Red Blood Cell count) [Screening Period/Baseline, Week 12]: Laboratory tests are performed as part of routine safety monitoring to evaluate potential hematological, hepatic, renal, or urinary effects of the investigational treatment. Hematology (Blood Routine): Red Blood Cell count (RBC) Unit: ×10¹²/L (Number of red blood cells per liter of blood × 10¹²)
• Laboratory Parameters (Hematology-White Blood Cell count) [Screening Period/Baseline, Week 12]: Laboratory tests are performed as part of routine safety monitoring to evaluate potential hematological, hepatic, renal, or urinary effects of the investigational treatment. Hematology (Blood Routine): White Blood Cell count (WBC) Unit: ×10⁹/L (Number of white blood cells per liter of blood × 10⁹)
• Laboratory Parameters (Hematology- Platelet count) [Screening Period/Baseline, Week 12]: Laboratory tests are performed as part of routine safety monitoring to evaluate potential hematological, hepatic, renal, or urinary effects of the investigational treatment. Hematology (Blood Routine): Platelet count (PLT) Unit: ×10⁹/L (Number of platelets per liter of blood × 10⁹)
• Laboratory Parameters (Hematology-Hemoglobin ) [Screening Period/Baseline, Week 12]: Laboratory tests are performed as part of routine safety monitoring to evaluate potential hematological, hepatic, renal, or urinary effects of the investigational treatment. Hematology (Blood Routine): Hemoglobin (HGB)-Hemoglobin Concentration Unit: g/L (grams per liter) or g/dL
• Laboratory Parameters (Hematology-Neutrophil percentage ) [Screening Period/Baseline, Week 12]: Laboratory tests are performed as part of routine safety monitoring to evaluate potential hematological, hepatic, renal, or urinary effects of the investigational treatment. Hematology (Blood Routine): Neutrophil percentage (NEUT%) Unit: % (Percentage of neutrophils among total white blood cells)
• Laboratory Parameters (Liver Function-Alanine Aminotransferase) [Screening Period/Baseline, Week 12]: Laboratory tests are performed as part of routine safety monitoring to evaluate potential hematological, hepatic, renal, or urinary effects of the investigational treatment. Liver Function: Alanine Aminotransferase (ALT) Unit: U/L (units per liter)
• Laboratory Parameters (Liver Function- Aspartate Aminotransferase) [Screening Period/Baseline, Week 12]: Laboratory tests are performed as part of routine safety monitoring to evaluate potential hematological, hepatic, renal, or urinary effects of the investigational treatment. Liver Function: Aspartate Aminotransferase (AST) Unit: U/L (units per liter)
• Laboratory Parameters (Liver Function-Total Bilirubin) [Screening Period/Baseline, Week 12]: Laboratory tests are performed as part of routine safety monitoring to evaluate potential hematological, hepatic, renal, or urinary effects of the investigational treatment. Liver Function: Total Bilirubin (TBIL) Unit: μmol/L (micromoles per liter)
• Laboratory Parameters (Liver Function-Alkaline Phosphatase) [Screening Period/Baseline, Week 12]: Laboratory tests are performed as part of routine safety monitoring to evaluate potential hematological, hepatic, renal, or urinary effects of the investigational treatment. Liver Function:Alkaline Phosphatase (ALP) Unit: U/L (units per liter)
• Laboratory Parameters (Liver Function-γ-Glutamyl Transferase) [Screening Period/Baseline, Week 12]: Laboratory tests are performed as part of routine safety monitoring to evaluate potential hematological, hepatic, renal, or urinary effects of the investigational treatment. Liver Function: γ-Glutamyl Transferase (GGT) Unit: U/L (units per liter)
• Laboratory Parameters (Renal Function- Serum Creatinine ) [Screening Period/Baseline, Week 12]: Laboratory tests are performed as part of routine safety monitoring to evaluate potential hematological, hepatic, renal, or urinary effects of the investigational treatment. Renal Function: Serum Creatinine (Scr) Unit: μmol/L (micromoles per liter) or mg/dL
• Laboratory Parameters (Renal Function- Blood Urea Nitrogen) [Screening Period/Baseline, Week 12]: Laboratory tests are performed as part of routine safety monitoring to evaluate potential hematological, hepatic, renal, or urinary effects of the investigational treatment. Renal Function: Blood Urea Nitrogen (BUN) / Urea Unit: mmol/L (millimoles per liter) or mg/dL
• Laboratory Parameters (Renal Function- Estimated Glomerular Filtration Rate) [Screening Period/Baseline, Week 12]: Laboratory tests are performed as part of routine safety monitoring to evaluate potential hematological, hepatic, renal, or urinary effects of the investigational treatment. Renal Function: Estimated Glomerular Filtration Rate (eGFR) Unit: mL/min/1.73m² (milliliters per minute per 1.73 square meters)
• Laboratory Parameters (Renal Function- Urine Albumin-Creatinine Ratio) [Screening Period/Baseline, Week 12]: Laboratory tests are performed as part of routine safety monitoring to evaluate potential hematological, hepatic, renal, or urinary effects of the investigational treatment. Renal Function: Urine Albumin-Creatinine Ratio (UACR) Unit: mg/g (milligrams per gram) or mg/mmol
• Laboratory Parameters (Urinalysis-Protein ) [Screening Period/Baseline, Week 12]: Laboratory tests are performed as part of routine safety monitoring to evaluate potential hematological, hepatic, renal, or urinary effects of the investigational treatment. Urinalysis (Urine Routine): Protein (PRO) Unit: Qualitative/Semi-quantitative, typically reported as: Negative (-), Trace (±), +, ++, +++, ++++ (or mg/dL, g/L)
• Laboratory Parameters (Urinalysis-Glucose ) [Screening Period/Baseline, Week 12]: Laboratory tests are performed as part of routine safety monitoring to evaluate potential hematological, hepatic, renal, or urinary effects of the investigational treatment. Urinalysis (Urine Routine): Glucose (GLU) Unit: Qualitative/Semi-quantitative, typically reported as: Negative (-), Trace (±), +, ++, +++, ++++ (or mmol/L, mg/dL)
• Laboratory Parameters (Urinalysis-Red Blood Cells) [Screening Period/Baseline, Week 12]: Laboratory tests are performed as part of routine safety monitoring to evaluate potential hematological, hepatic, renal, or urinary effects of the investigational treatment. Urinalysis (Urine Sediment Microscopy): Red Blood Cells (RBC) Unit: per high-power field (/HPF) or per microliter (μL) (microscope count)
• Laboratory Parameters (Urinalysis-Leukocytes) [Screening Period/Baseline, Week 12]: Laboratory tests are performed as part of routine safety monitoring to evaluate potential hematological, hepatic, renal, or urinary effects of the investigational treatment. Urinalysis (Urine Routine): Leukocytes (LEU) Unit: per high-power field (/HPF) or per microliter (μL) (microscope count)
• Blood Glucose [Screening Period/Baseline, Week 12]: Measuring Fasting Blood Glucose (FBG), which is the blood glucose level measured after fasting for 8 to 12 hours.
• Blood Lipids [Screening Period/Baseline, Week 12]: Measuring fasting Total Cholesterol (TC), Low-Density Lipoprotein Cholesterol (LDL-C), High-Density Lipoprotein Cholesterol (HDL-C), and Triglycerides (TG).
• Heart Rate on 12-lead electrocardiogram [Screening Period/Baseline, Week 12]: Heart rate (beats per minute) is measured from a standard 12-lead electrocardiogram recorded after at least 5 minutes of rest in a supine position, using calibrated equipment. Measurements are performed by trained personnel and interpreted by qualified investigators or cardiologists. Unit of Measure: beats per minute (bpm)
• PR Interval on 12-lead electrocardiogram [Screening Period/Baseline, Week 12]: PR interval (milliseconds) is measured from a standard 12-lead electrocardiogram recorded after at least 5 minutes of rest in a supine position, using calibrated equipment. Measurements are performed by trained personnel and interpreted by qualified investigators or cardiologists. Unit of Measure: milliseconds (ms)
• QRS Duration on 12-lead electrocardiogram [Screening Period/Baseline, Week 12]: QRS duration (milliseconds) is measured from a standard 12-lead electrocardiogram recorded after at least 5 minutes of rest in a supine position, using calibrated equipment. Measurements are performed by trained personnel and interpreted by qualified investigators or cardiologists. Monitored for potential ventricular conduction abnormalities. Unit of Measure: milliseconds (ms)
• QT Interval on 12-lead electrocardiogram [Screening Period/Baseline, Week 12]: QT interval (milliseconds) is measured from a standard 12-lead electrocardiogram recorded after at least 5 minutes of rest in a supine position, using calibrated equipment. Measurements are performed by trained personnel and interpreted by qualified investigators or cardiologists. Unit of Measure: milliseconds (ms)
• Corrected QT Interval (QTc) on 12-lead electrocardiogram [Screening Period/Baseline, Week 12]: Corrected QT interval (QTc, milliseconds) is calculated from the QT interval on a standard 12-lead electrocardiogram (recorded after ≥5 minutes rest, supine position, calibrated equipment) using Bazett or Fridericia formula as specified in the protocol. Interpreted by qualified cardiologists or trained investigators. Unit of Measure: milliseconds (ms)
• Pharmacokinetic (PK) Parameters-Plasma Maximum Observed Concentration (Cmax) [Screening Period/Baseline, Week 4, Week 8, and Week 12]: Plasma concentration measured from blood samples collected at Baseline, Weeks 4, 8, and 12( or early out of study).The exact time of blood collection and the time of the dose most recent to the collection must be recorded for each visit. Cmax is the maximum observed concentration post-dose. Parameters estimated using non-compartmental analysis or population PK modeling due to sparse sampling. Geometric mean and variability reported. Assessed as an exploratory pharmacokinetic biomarker. Unit of Measure: ng/mL (or appropriate unit, e.g., nmol/L)
• Pharmacokinetic (PK) Parameters-Plasma Trough Concentration (Ctrough) [Screening Period/Baseline, Week 4, Week 8, and Week 12]: Plasma concentration measured from blood samples collected at Baseline, Weeks 4, 8, and 12( or early out of study).The exact time of blood collection and the time of the dose most recent to the collection must be recorded for each visit. Ctrough is the observed minimum concentration at the end of the dosing interval. Reported as geometric mean and variability. Exploratory pharmacokinetic endpoint focusing on steady-state trough exposure. Unit of Measure: ng/mL (or nmol/L, adjust based on drug)
• Pharmacokinetic (PK) Parameters-Time Curve (AUC0-last) [Screening Period/Baseline, Week 4, Week 8, and Week 12]: Area under the concentration-time curve from time zero to the last measurable concentration (AUC0-last), estimated using population PK methods. Geometric mean reported. Exploratory PK biomarker of exposure. Unit of Measure: h·ng/mL (or appropriate, e.g., h·nmol/L)
• Gut Microbial Alpha-diversity [Screening Period/Baseline, Week 12]: Evaluation of microbial richness and evenness within fecal samples using 16S rRNA sequencing. Alpha-diversity represents the biological variety within a single sample. Unit of Measure: Shannon Diversity Index (a calculated score typically ranging from 0 to 5, where higher values indicate greater diversity).
• Gut Microbial Relative Abundance [Screening Period/Baseline, Week 12]: Assessment of the taxonomic composition of the gut microbiota at the genus and species levels via metagenomic sequencing. Unit of Measure: Percentage of total sequences (%).
• Fecal Metabolomic Profiles [Screening Period/Baseline, Week 12]: Untargeted metabolomics analysis using LC-MS/GC-MS to identify global metabolic shifts and differential metabolites induced by the treatment. Unit of Measure: Normalized peak intensity (arbitrary units).
• Fecal Short-Chain Fatty Acid (SCFA) [Screening Period/Baseline, Week 12]: Quantitative analysis of major SCFAs (acetate, propionate, and butyrate) using GC-MS. The sum of these concentrations will be reported. Unit of Measure: μ mol/g of feces.
• Plasma Concentration of Cartilage Oligomeric Matrix Protein (COMP) [Screening Period/Baseline, Week 4, Week 8, and Week 12]: Evaluation of cartilage turnover and degradation levels. COMP is a key structural protein of the cartilage matrix, and its plasma concentration reflects the rate of cartilage breakdown in patients with knee osteoarthritis. Measured using Enzyme-Linked Immunosorbent Assay (ELISA). Unit of Measure: ng/mL
• Plasma Level of C-Terminal Cross-Linked Telopeptide of Type II Collagen (CTX-II) [Screening Period/Baseline, Week 4, Week 8, and Week 12]: Assessment of cartilage collagen degradation. CTX-II is a specific biomarker for the degradation of type II collagen, the primary collagen found in articular cartilage. Higher levels are associated with increased radiographic progression of knee osteoarthritis. Measured using high-sensitivity immunoassay. Unit of Measure: pg/mL
• Plasma Concentration of Tryptophan [Screening Period/Baseline, Week 4, Week 8, and Week 12]: Assessment of systemic amino acid metabolism and inflammatory signaling. Tryptophan is an essential amino acid whose metabolic pathways (such as the kynurenine pathway) are often altered by chronic inflammation in knee osteoarthritis. Changes in tryptophan levels can reflect the metabolic impact of treatment on systemic inflammation and pain-related pathways. Measured using Liquid Chromatography-Mass Spectrometry (LC-MS). Unit of Measure: nmol/L

Sex: All, ages: 40 Years to 75 Years

Inclusion Criteria:

1. Meets the diagnostic criteria for knee osteoarthritis (OA), with unilateral or bilateral knee involvement
2. Prior to randomization, the NRS pain score of the target knee joint ≥4, and the NRS score of the contralateral knee joint is not higher than that of the target knee joint; among the 5 pain items on the WOMAC, at least 1 item scores ≥40 mm
3. Body Mass Index (BMI) ≤32 kg/m²
4. Meets the diagnostic criteria for Qi and Blood Deficiency Pattern
5. Age between 40 and 75 years inclusive (40 years ≤ age ≤ 75 years), male or female
6. The Kellgren-Lawrence grading of the target knee joint is grade I-III, and the Kellgren-Lawrence grading of the contralateral knee joint is not higher than that of the target knee joint (in cases of unilateral disease, the affected side is the target knee joint; in cases of bilateral disease, the target knee joint must satisfy the above criteria)
7. Voluntarily participates in this clinical trial, provides informed consent, and signs the informed consent form

Exclusion Criteria:

1. Other conditions exist that may confound the assessment of function and pain in the target knee joint, such as: systemic diseases that may involve the joints (e.g., gouty arthritis, rheumatoid arthritis, etc.), chronic inflammatory or connective tissue diseases, neurological disorders, Paget's disease involving the knee, localized pain resulting from radicular lumbar compression, and any other conditions that may interfere with the efficacy assessment
2. Use of other Chinese or Western medicines or therapies for osteoarthritis within one week prior to screening (excluding celecoxib tablets): such as non-steroidal anti-inflammatory drugs (excluding aspirin at no more than 325mg daily for cardiovascular disease prevention) , analgesics (including opioids, non-steroidal anti-inflammatory drugs, cyclooxygenase-2 (COX-2) inhibitors, tramadol, ketamine, clonidine, gabapentin, pregabalin and/or cannabinoids), or traditional Chinese medicine formulations with similar therapeutic indications to Knee Pain Ejiao Paste (i.e., those possessing qi-tonifying and blood-nourishing effects)
3. Use within 4 weeks prior to screening of drugs that relieve osteoarthritis (OA) symptoms (such as glucosamine, chondroitin sulfate, diacerein, etc.), any nutritional supplements with potential activity on articular cartilage, systemic corticosteroids or immunosuppressive drugs (subjects requiring only inhaled corticosteroids for asthma treatment may be enrolled)
4. Receipt of biological products or intra-articular drug injection therapy (e.g., glucocorticoids, sodium hyaluronate, medical chitosan, growth factors, platelet-rich plasma, stem cell therapy, etc.) within 3 months prior to screening
5. Invasive procedures such as arthroscopy or lavage of the target knee joint within 6 months before screening or planned during the study period
6. Previous or planned target knee joint replacement (partial or total), autologous osteochondral mosaicplasty, microfracture, meniscectomy, osteotomy or other surgery during the study period
7. Planned change or new use of mobility aids (e.g., wheelchair, walker, cane or crutch) or need for lower limb prosthesis and/or structural knee brace during the study period
8. Investigator-judged serious comorbid cardiovascular, cerebrovascular, gastrointestinal diseases, poorly controlled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg), or other conditions that could affect the assessment of the investigational product's efficacy and safety
9. Laboratory abnormalities: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5 times the upper limit of normal (ULN), or creatinine (Cr) >ULN
10. Known or suspected allergy to the investigational product, rescue medication, or any of their components
11. Pregnant or lactating women, or women of childbearing potential planning pregnancy from enrollment through 3 months after the end of the study
12. Known or suspected history of alcohol or drug abuse
13. Intellectual disability, psychosis, or neurosis
14. Subjects who participated in any interventional drug clinical trial and received the investigational drug within 3 months prior to enrollment, or who are within 5 half-lives (whichever is longer) of any other clinical trial drug

• Yuelong Cao, Ph.D, Principal investigator, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine