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

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

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.

Study Overview

• Status: Completed
• Conditions: Analgesia
• Intervention / Treatment: 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

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Hangzhou, China
    • Second Affiliated Hospital of Zhejiang University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 18 ≤ age ≤ 65 years old, with no gender requirement
2. American Society of Anesthesiologists (ASA) Class I-II
3. 18 kg/m^2 ≤ BMI ≤ 30 kg/m^2
4. Subjects undergoing elective laparoscopic surgery under general anesthesia with an expected surgery duration of 1-5 h (inclusive)
5. Agree to participate in this trial and voluntarily sign the informed consent form;

Exclusion Criteria:

1. History of allergy to opioids, such as urticaria, or allergic to the intraoperative anesthetics prescribed in the protocol;

2. History or evidence of any one of the following diseases prior to screening:

   1. 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);
   2. 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;
   3. 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.;
   4. Underwent major surgery within 3 months before screening and was judged by the investigator to have potential effect on the postoperative pain evaluation;

3. Any of the following airway management risks during screening:

   1. Acute asthma attacks;
   2. Sleep apnea syndrome;
   3. History or family history of malignant hyperthermia;
   4. History of failed tracheal intubation;
   5. Difficult airway (modified Mallampati score ≥ III) as determined by the investigator;

4. In receipt of any of the following drugs or therapies during the screening period:

   1. 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);
   2. Continuous use of opioid analgesics for more than 10 days for any reason within 3 months before screening;
   3. 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;
   4. 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.
   5. 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);

5. Laboratory test parameters meet one of the following criteria in the screening period and is confirmed by retests:

   1. White blood cell count < 3.0 x 10^9/L;
   2. Platelet count < 80 x 10^9/L;
   3. Hemoglobin < 80 g/L;
   4. Prothrombin time > 1.5 x ULN;
   5. Activated partial thromboplastin time > 1.5 x ULN;
   6. Alanine aminotransferase and/or aspartate aminotransferase > 2 x ULN;
   7. Total bilirubin > 1.5 x ULN;
   8. Blood creatinine > 1.5 x ULN;
   9. Fasting blood glucose ≥ 11.1 mmol/L;
6. Without oxygen supplement during the screening period, the pulse oxygen saturation is < 92%;
7. 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;
8. 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);
9. Donated or lost ≥ 400 mL of blood within 3 months before screening;
10. Participated in any drug clinical trials within 3 months before screening (defined as the administration of the investigational product or placebo);
11. 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);
12. Subjects determined by the investigator to be unsuitable for participating in this clinical study for any other reason.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

7

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Haisco Pharmaceutical Group Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2020
• Primary Completion (Actual): January 5, 2021
• Study Completion (Actual): April 28, 2021

Study Registration Dates

• First Submitted: June 3, 2020
• First Submitted That Met QC Criteria: June 7, 2020
• First Posted (Actual): June 9, 2020

Study Record Updates

• Last Update Posted (Estimate): February 20, 2023
• Last Update Submitted That Met QC Criteria: February 17, 2023
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Perceptual Disorders; Agnosia
• Other Study ID Numbers: HSK21542-201

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No