A PhaseⅡ/ Ⅲ Seamless Study to Evaluate Efficacy and Safety of Paracetamol Injection as Adjuvant to Morphine-based Postoperative Analgesia

Study Overview
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Brief Summary
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Paracetamol,a classical analgesic agent,constitutes an essential component of multi-modal analgesia. This medication is generally safe, well tolerated and effective within recommended daily dose.The purpose of the study is to evaluate the efficacy and safety of Paracetamol Injection as adjuvant to morphine-based post-operative analgesia, as well as to explore the reasonable dosage of paracetamol among Chinese population under above-mentioned circumstance.

Official Title
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A PhaseⅡ/ Ⅲ Seamless Study to Evaluate Efficacy and Safety of Paracetamol Injection as Adjuvant to Morphine-based Postoperative Analgesia-Multicentered, Randomized, Double-blind, Placebo-controlled Clinical Trial

Conditions
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Post-operative Analgesia

Intervention / Treatment
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* Drug: Paracetamol injection
* Drug: Normal Saline injection
* Drug: Morhpine PCA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged from 18 to 70 years inclusively, male or female; Patients scheduled for open abdominal surgery(such as gall bladder, lower abdominal investigative surgery), gynecologic surgery(such as trans-abdominal hysterectomy), orthopedic surgery(such as replacement and reconstruction of knee, hip or shoulder joint), with anticipated need for post-operative iv. morphine analgesia≥24h; 18kg/m2≤BMI≤30 kg/m2; Classified as ASA risk class I, II according to the American Society of Anesthesiologists; Able to understand the study procedures and the use of the pain scales, able to operate a patient controlled analgesia (PCA) device and to communicate meaningfully with the study observer and staff; Patients free of any contraindication to the study drugs, morphine and to the standardized anesthesia protocol; Clearly understand the procedure of study, voluntarily participate and provided written consent form. Exclusion Criteria: Impaired liver function (ALT and/or AST > 2 x upper limit of normal range, or TBIL≥1.5 x upper limit of normal range); Impaired renal function(Serum Creatinine >176μmoL/L), or undergoing dialysis within 28 days before surgery; Patients at high risk for bleeding, including congenital hemorrhagic disease(such as Hemophilia), Thrombocytopenia(CBC PLT<30×109/L), Qualitative Plateletdefects(such as ITP, DIC, congenital abonormal platelet), or clinically significant active bleeding; Abnormal resting ECG, judged as not eligible for entry by investigator; Hypertensive patients not achieving satisfactory BP control under hypertensive medication(Sitting SBP≥160mm Hg, and/or DBP≥105mm Hg during screen period); Sitting SBP≤90mm Hg during screening period; Diabetic Patients not achieving satisfactory blood glucose control(FBG≥11.1moL/L during screening period); Known history of bronchial asthma, pulmonary heart disease or heart failure; Participation in other trials within 30 days; Pregnant women or women in lactation; Patients not eligible due to other reasons judged by the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Experimental:Paracetamol Injection<br>325mg(32.5mL)or 500mg(50mL) iv q6h according to assignment | Drug: Paracetamol injection<br>* 325mg(32.5mL) or 500mg(50mL) iv q6h,4 doses in 24h.Infushion time≥15min.<br>Drug: Morhpine PCA<br>* Morphine PCA will be connected upon the first dose of study drug(roughly 30min prior to the completion of would suture). Morphine PCA is set as follows:1mg bolus every 5min with background infusion of 0.25mg/h and maximal dose<25mg/4h.<br>|
| Placebo Comparator: Placebo:Normal Saline Injcetion<br>32.5mLor 50mL iv q6h according to assignment. | Drug: Normal Saline injection<br>* 32.5mL or 50mL iv q6h,4 doses in 24h.Infushion time≥15min.<br>Drug: Morhpine PCA<br>* Morphine PCA will be connected upon the first dose of study drug(roughly 30min prior to the completion of would suture). Morphine PCA is set as follows:1mg bolus every 5min with background infusion of 0.25mg/h and maximal dose<25mg/4h.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total morphine use in 24 hours | Total morhpine use(including PCA and emergency morphine use)in 24 hours. | 24h after the 1st dose of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain Intensity VAS AUC(0-24h) at rest |  | 0-24h PI VAS AUC(mesured at 1h、3h、6h、12h、24h after the 1st dose of study drug) | 
| Pain Intensity VAS AUC(0-24h) at movement |  | 0-24h PI VAS AUC(mesured at 1h、3h、6h、12h、24h after the 1st dose of study drug) | 
| Incidence of mophine-related ADR |  | 0-24h after the 1st dose of study drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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paracetamol, post-operative analgesia