A Multicentre, Randomised, Double-blind, Positive-drug-controlled Phase III Clinical Trial on the Efficacy and Safety of CZ1S Peroneal Nerve Block Combined With Popliteal Artery and Posterior Capsule Gap Block for Postoperative Analgesia in Total Knee Arthroplasty.

A Multicentre, Randomised, Double-blind, Positive-drug-controlled Phase III Clinical Trial on the Efficacy and Safety of CZ1S Peroneal Nerve Block Combined With Popliteal Artery and Posterior Capsule Gap Block for Postoperative Analgesia in Total Knee Arthroplasty.

This is a multicentre, randomised, double-blind, positive-drug-controlled confirmatory clinical trial designed to evaluate the efficacy and safety of CZ1S injection for femoral nerve block (FNB) combined with the interspace between the popliteal artery and the capsule of the knee (IPACK) block for postoperative analgesia following total knee arthroplasty (TKA).

1. The subjects are able to understand the procedures and methods of this clinical trial (including pain intensity assessment methods), and voluntarily sign the informed consent form after being fully informed.
2. Male or female aged 18-75 years; body mass index (BMI) within the range of [18.0-32.0] kg/m2 (including boundary values).
3. Subjects scheduled for elective primary unilateral total knee arthroplasty under general anaesthesia.
4. American Society of Anesthesiologists (ASA) classification I-III.
5. Possess mobility and are able to walk 20 metres without assistance (only a four-legged walker may be used for balance).
6. Normal pain and temperature sensation in the surgical limb.
7. Female or male subjects of reproductive potential must agree to use effective contraception from the time of signing the informed consent form until 30 days after administration of the investigational medicinal product, for themselves and, in the case of male subjects, their partners.

Exclusion criteria: Subjects meeting any of the following criteria cannot be enrolled in this study:

1. Subjects with pain unrelated to the indications for total knee arthroplasty, which the investigator judges may confound postoperative assessment (e.g., pain caused by lumbar nerve disease).

2. Subjects planning to undergo surgery on other sites simultaneously.

3. Subjects with a history of any of the following serious clinical diseases or currently suffering from serious diseases:

   1. Respiratory diseases: such as acute or bronchial asthma, pulmonary heart disease, other chronic lung diseases, or a history of respiratory depression;
   2. Circulatory system diseases: such as unstable angina and/or myocardial infarction within the past 6 months, patients with heart failure (New York Heart Association [NYHA] Class III-IV), atrial fibrillation, ventricular fibrillation, prolonged QTcF interval (12-lead ECG examination): males ≥450ms, females ≥470ms (if initially abnormal, may retest three times and take the average); poorly controlled hypertension (resting seated systolic blood pressure ≥160mmHg for two or more consecutive readings, or diastolic blood pressure ≥100mmHg);
   3. Blood system diseases: bleeding disorders caused by clotting factor deficiencies or other coagulation abnormalities;
   4. Tumours: history of malignant tumour within the past year, except for non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin or local cervical carcinoma in situ;
   5. Digestive system diseases: known gastrointestinal bleeding, gastrointestinal obstruction or perforation, or other diseases that may pose a risk to the gastrointestinal tract; f) Presence of other diseases that may significantly affect the evaluation of the investigational drug efficacy or metabolism in the body.

4. Diagnosed progressive femoral nerve dysfunction or chronic neuromuscular injury.

5. Subjects experiencing vomiting during the screening period or with a history of severe, refractory postoperative nausea and vomiting.

6. Subjects with screening laboratory results meeting the following criteria: a) Liver function: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2 times the upper limit of normal (ULN) or total bilirubin (TBIL) ≥1.5×ULN; b) Renal function: serum creatinine (Cr) ≥1.5×ULN; c) Coagulation function: prothrombin time (PT) >3s above the upper limit of normal and/or activated partial thromboplastin time (APTT) >10s above the upper limit of normal; d) Random blood glucose ≥11.1mmol/L.

7. Individuals allergic to any component of the investigational medicinal product, general anaesthesia regimen drugs, rescue analgesics, or antiemetic medications, or with other contraindications.

8. Use or anticipated use of opioids, NSAIDs, sedatives, anaesthetics, local anaesthetics, glucocorticoids, antiepileptics, anxiolytics, antidepressants, traditional Chinese medicines with analgesic effects, class III antiarrhythmic drugs, potent CYP1A2 inhibitors, CYP1A2 highly sensitive substrates, potent CYP3A4 inhibitors, CYP3A4 highly sensitive substrates, potent CYP3A4 inducers within five half-lives before randomisation (based on the actual drug label; if half-life is unknown, washout period should be at least 48 hours), except as specified in the protocol. (See Appendix 1 for prohibited concomitant drugs/non-drug treatments)

9. Regular alcohol consumption within the 3 months (90 days) prior to screening, defined as more than 14 units per week (1 unit = 360 mL of beer, or 45 mL of 40% spirit, or 150 mL of wine).

10. Participation in a drug or device clinical trial within the 3 months (90 days) prior to screening, with use of investigational medicinal products or devices. Previous participation in clinical trials of this study drug or similar analgesics (including but not limited to Exparel ®, HYR-PB21, Aihengping®).

11. History of drug abuse or substance abuse within 1 year prior to screening.

12. Positive pregnancy test during the screening period, currently breastfeeding, or currently not breastfeeding but less than 6 months postpartum.

13. Individuals deemed by the investigator to be unable to evaluate efficacy or unable to complete the trial.