Efficacy and Safety of HSK21542 in Inducing Postoperative Analgesia in Undergoing Elective Laparoscopic Surgery

Study Overview
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Brief Summary
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This is a multicenter, randomized, double-blind, placebo-controlled, two-stage phase II clinical study. The main objective is to evaluate the efficacy and safety of HSK21542 injection and explore the recommended dose and administration frequency for subsequent Phase II studies in conjunction with the pharmacodynamic (PD) and pharmacokinetic (PK) characteristics.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Two-stage Phase II Study Evaluating the Efficacy and Safety of HSK21542 in Inducing Postoperative Analgesia in Subjects Undergoing Elective Laparoscopic Surgery Under General Anesthesia

Conditions
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Analgesia

Intervention / Treatment
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* Drug: Experimental: stage I：HSK21542 0.4 μg/kg
* Drug: Experimental: stage I：HSK21542 1 μg/kg
* Drug: Experimental: stage I：HSK21542 0.5μg/kg
* Drug: Experimental: stage I：HSK21542 1μg/kg
* Drug: Experimental: stage II：HSK21542 0.5μg/kg
* Drug: Experimental: stage II：HSK21542 1μg/kg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 ≤ age ≤ 65 years old, with no gender requirement American Society of Anesthesiologists (ASA) Class I-II 18 kg/m^2 ≤ BMI ≤ 30 kg/m^2 Subjects undergoing elective laparoscopic surgery under general anesthesia with an expected surgery duration of 1-5 h (inclusive) Agree to participate in this trial and voluntarily sign the informed consent form; Exclusion Criteria: History of allergy to opioids, such as urticaria, or allergic to the intraoperative anesthetics prescribed in the protocol; History or evidence of any one of the following diseases prior to screening: History of cardiovascular diseases: Uncontrolled hypertension (systolic blood pressure [SBP] ≥ 170 mmHg and/or diastolic blood pressure [DBP] ≥ 105 without antihypertensive treatment, or SBP > 160 mmHg and/or DBP > 100 mmHg despite antihypertensive treatment), aneurysm, severe arrhythmia, heart failure, Adams-Stokes syndrome, New York Heart Association (NYHA) Class ≥ III, severe superior vena caval syndrome, pericardial effusion, acute myocardial ischemia, unstable angina, myocardial infarction in the last 6 months before screening, history of tachycardia/bradycardia requiring medication, and II-III degree atrioventricular block (excluding patients with pacemakers); History of respiratory disorder: Severe chronic obstructive pulmonary disease, acute exacerbation of chronic obstructive pulmonary disease, severe bronchostenosis, throat mass, history of (bronchial) tracheoesophageal fistula or airway tear, and severe respiratory tract infection in the last 2 weeks before screening; History of disorders in the nervous and psychiatric system: History of craniocerebral injury, possible convulsions, intracranial hypertension, cerebral aneurysms, and history of cerebrovascular accidents; history of schizophrenia, mania, mental aberration, long-term use of psychotropic drugs, and cognitive disorder; history of depression, anxiety, and epilepsy, etc.; Underwent major surgery within 3 months before screening and was judged by the investigator to have potential effect on the postoperative pain evaluation; Any of the following airway management risks during screening: Acute asthma attacks; Sleep apnea syndrome; History or family history of malignant hyperthermia; History of failed tracheal intubation; Difficult airway (modified Mallampati score ≥ III) as determined by the investigator; In receipt of any of the following drugs or therapies during the screening period: The time between randomization and the last dose of opioid or non-opioid (such as acetaminophen, aspirin [daily dose of > 100 mg], indomethacin, diclofenac, parecoxib sodium and other non-steroidal anti-inflammatory drugs) analgesics is shorter than 5 half-lives of the drug or the duration of drug efficacy (whichever is longer); Continuous use of opioid analgesics for more than 10 days for any reason within 3 months before screening; Use of drugs that affect the analgesic effect within 14 days before randomization, including but not limited to: Sedative hypnotics (benzodiazepines [triazolam, diazepam, midazolam, etc.], non-benzodiazepines [zolpidem, zopiclone, zaleplon, etc.]), sedative anesthetics (sevoflurane, anesthesia ether, nitrous oxide, thiopental, ketamine, etomidate, etc.), glucocorticoids (dexamethasone hydrochloride , methylprednisolone, etc.), anti-epilepsy drugs (carbamazepine, sodium valproate, etc.), anxiolytics (carbamazepine, diazepam, etc.), antidepressants (imipramine, amitriptyline, etc.), and Chinese herbal medicines or Chinese patent medicines with analgesic and sedative effects; Expected to receive anti-tumor drugs and treatments during the period from 14 days before randomization to the end of the follow-up period, including but not limited to chemotherapeutic drugs, targeted drugs, and Chinese herbal medicines. The time between randomization and the last use of diuretics and compound drugs containing diuretic components is shorter than 5 half-lives of the drug or the duration of drug efficacy (whichever is longer); Laboratory test parameters meet one of the following criteria in the screening period and is confirmed by retests: White blood cell count < 3.0 x 10^9/L; Platelet count < 80 x 10^9/L; Hemoglobin < 80 g/L; Prothrombin time > 1.5 x ULN; Activated partial thromboplastin time > 1.5 x ULN; Alanine aminotransferase and/or aspartate aminotransferase > 2 x ULN; Total bilirubin > 1.5 x ULN; Blood creatinine > 1.5 x ULN; Fasting blood glucose ≥ 11.1 mmol/L; Without oxygen supplement during the screening period, the pulse oxygen saturation is < 92%; During the screening period, the virological examination for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCVAb), treponema pallidum antibody, or human immunodeficiency virus (HIV) antibody is positive; History of drug abuse, narcotics use and/or alcohol abuse within 3 months before screening. Alcohol abuse is defined as > 2 units of alcohol consumption per day (1 unit = 360 mL of beer containing 5% alcohol, 45 mL of liquor containing 40% alcohol, or 150 mL of wine); Donated or lost ≥ 400 mL of blood within 3 months before screening; Participated in any drug clinical trials within 3 months before screening (defined as the administration of the investigational product or placebo); Women who are pregnant or breastfeeding; fertile women or men who are unwilling to use contraception during the trial; subjects who are planning pregnancy within 3 month after the completion of the trial (including male subjects); Subjects determined by the investigator to be unsuitable for participating in this clinical study for any other reason.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: stage I：HSK21542 0.4 μg/kg<br>Preoperative:0.4 μg/kg Postoperative:0.2 μg/kg； intravenous injection | Drug: Experimental: stage I：HSK21542 0.4 μg/kg<br>* Once preoperative and once each at 0, 8, and 16 h postoperative, for a total of 4 administrations<br>|
| Experimental: stage I：HSK21542 1 μg/kg<br>Preoperative:1 μg/kg Postoperative:0.5 μg/kg；intravenous injection | Drug: Experimental: stage I：HSK21542 1 μg/kg<br>* Once preoperative and once each at 0, 8, and 16 h postoperative, for a total of 4 administrations<br>|
| Experimental: stage I：HSK21542 0.5μg/kg<br>Postoperative: 0.5μg/kg；intravenous injection | Drug: Experimental: stage I：HSK21542 0.5μg/kg<br>* once each at 0, 8, and 16 h postoperative, for a total of 3 administrations<br>|
| Experimental: stage I：HSK21542 1μg/kg<br>Postoperative: 1μg/kg；intravenous injection | Drug: Experimental: stage I：HSK21542 1μg/kg<br>* once each at 0, 8, and 16 h postoperative, for a total of 3 administrations<br>|
| Experimental: stage II：HSK21542 0.5μg/kg<br>Postoperative: 0.5μg/kg；intravenous injection | Drug: Experimental: stage II：HSK21542 0.5μg/kg<br>* once each at 0, 8, and 16 h postoperative, for a total of 3 administrations<br>|
| Experimental: stage II：HSK21542 1μg/kg<br>Postoperative: 1μg/kg；intravenous injection | Drug: Experimental: stage II：HSK21542 1μg/kg<br>* once each at 0, 8, and 16 h postoperative, for a total of 3 administrations<br>|
| Placebo Comparator: Postoperative: Placebo<br>Placebo；intravenous injection | Drug: Placebo<br>* once each at 0, 8, and 16 h postoperative, for a total of 3 administrations<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence and severity of AEs | Adverse event/serious adverse event | From screening up to 4 weeks | 
| Vital signs: Systolic and Diastolic Blood Pressure | Vital signs (Systolic and Diastolic Blood Pressure) will be collected in subjects. | From screening up to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sum of Pain Intensity Differences (SPID) | The time-weighted sum of pain intensity differences of the rest pain in each group within 0-12 h and 0-24 h after the first postoperative dose | Frome administration until 24 hours after administration | 
| Use of remedial analgesics | Cumulative dose of remedial analgesics (mg of morphine injection) in each group within 0-12 h and 0-24 h after the first postoperative dose, the percentage of subjects in each group who have not used remedial analgesics, and the time to start using remedial analgesics | Frome administration until 24 hours after administration | 
| The proportion of subjects with a NRS of ≤ 3 | The proportion of subjects in each group with a resting pain NRS of ≤ 3 at 12 h and 24 h after the first postoperative dose | Frome administration until 24 hours after administration | 
| The plasma concentration |  | -30 minutes before administration until 24 hours after administration |