General Anesthesia
Conditions
Brief summary
To demonstrate HSK3486 0.4/0.2 mg/kg (0.4 mg/kg intravenous \[IV\] slow injection over 30 \[±5\] seconds for the first dose, an additional 0.2 mg/kg if needed) is non-inferior to Propofol 2.0/1.0 mg/kg (2.0 mg/kg IV slow injection over 30 \[±5\] seconds for first dose, an additional 1.0 mg/kg if needed) in success of induction of general anesthesia in adults undergoing elective surgery.
Detailed description
This is a global multicenter, randomized, double-blinded, propofol-controlled, phase 3 clinical study to evaluate the efficacy and safety of HSK3486 for induction of general anesthesia in adults undergoing elective surgery with endotracheal intubation. After screening, eligible subjects will be randomized in a 2:1 ratio to receive either HSK3486 0.4/0.2 mg/kg (i.e., 0.4 mg/kg IV slow injection over 30 \[±5\] seconds followed by an additional 0.2 mg/kg dose over 10 \[±2\] seconds if needed) or propofol 2.0/1.0 mg/kg (i.e., 2.0 mg/kg IV slow injection over 30 \[±5\] seconds followed by an additional 1.0 mg/kg dose over 10 \[±2\]seconds if needed) in a blinded manner. Enrolled subjects will be stratified by American Society of Anesthesiologists Physical Status (ASA-PS; I-II and III-IV), age (\<65 and ≥65 years), and Body Mass Index (BMI \<35 and ≥35 kg/m2). Endotracheal intubation will be performed after adequate anesthetic induction (Modified Observer's Assessment of Awareness/Sedation \[MOAA/S\] ≤1) (Appendix 1) has been achieved and administration of neuromuscular blocking agent. Before surgery, premedication is allowed except for sedative-hypnotic or analgesic drugs. Premedication should be recorded if used. Prior to administration of the study drug in the operating room, the preoperative readiness of each subject will be confirmed. Oxygen will be supplied through a facemask (oxygen flow rate: ≥4 L/min) at least 2 minutes before study drug administration. Subsequently, the investigator can adjust the oxygen flow according to the specific situation of the subject and maintenance IV solution (normal saline \[NS\], lactated ringer's \[LR\], or 5% dextrose) will be administrated through IV infusion. Throughout the pre-induction and induction periods, a timing device must be used to allow accuracy and sequencing of necessary assessments.
Interventions
DRUGHSK3486
HSK3486 for induction of general anesthesia
DRUGPropofol
Propofol for induction of general anesthesia
Sponsors
Haisco-USA Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
Double blinded, 2:1 ratio of HSK3489 and Propofol respectively
Intervention model description
Surgical pre-induction analgesia
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
Yes
Inclusion criteria
* Subjects must satisfy all of the following criteria at the screening visit: 1. Subjects undergoing elective surgery (non-emergency, non-cardiothoracic, and non-intracranial surgery anticipated to last at least 1 hour) requiring endotracheal intubation and inhalation general anesthesia during the maintenance period. Duration of surgery is defined as time from study drug administration to time of transfer from operating room to recovery room or PACU. 2. Males or females, aged ≥18 years old, with ASA PS I to IV (Appendix 6). For ASA-PS IV subjects, clinical status must be optimized at time of preoperative anesthesia evaluation per judgement of the anesthesiologist. 3. BMI ≥18 kg/m2. 4. Vital signs at screening: RR ≥10 and ≤24 breaths/min; SpO2 ≥92% in ambient air; SBP ≥90 and ≤160 mmHg; DBP ≥55 and ≤ 100 mmHg; HR ≥55 (or ≥50 if subjects are on beta blockers) and ≤100 beats/min. 5. For all women of childbearing potential, negative serum pregnancy test within the screening period and negative urine pregnancy test at baseline (Day 1). Additionally, women of childbearing potential\* and male subjects with female partners of childbearing potential must agree to use contraception as defined in 7.3.4 from the time of consent until 30 days post study drug administration. 6. For subjects with known hypothyroidism and/or on thyroid-hormone replacement treatment (i.e., thyroxine), or subjects suspected to have thyroid dysfunction based on clinical laboratory and physical exam, a TSH must drawn and be within normal levels. 7. Capable of understanding the procedures and methods of this study, willing to sign an Informed Consent Form (ICF), and able to complete this study in strict compliance with the study protocol. 8. Willing to comply with the site's COVID guidelines and testing requirements as applicable. 9. Patients with psychiatric/mental disorders must be considered stable on treatment (e.g., SSRIs, SNRIs, TCAs, MAOIs, psychotherapy) per investigator judgement, and no hospitalizations and urgent care due to the underlying psychiatric pathology for at least 12 months. * Women are considered of childbearing potential until becoming post-menopausal, unless she had a documented hysterectomy or bilateral oophorectomy / salpingo-oophorectomy. A woman is considered to be post-menopausal if she had no menses for at least 12 consecutive months (without an alternative medical cause).
Exclusion criteria
1. Contraindications to deep sedation/general anesthesia or a history of adverse reaction to sedation/general anesthesia. 2. Known to be allergic to eggs, soy products, opioids and their antidotes, or propofol; subjects having contraindications to propofol, opioids, and their antidotes. In cases where the only previous reaction to opioids was itching or nausea, subjects need not be excluded if the investigator believes the subject is not truly allergic to opioids. 3. Medical condition or evidence of increased sedation/general anesthesia risk as follows: 1. Cardiovascular disorder: uncontrolled hypertension (SBP \>160 mmHg and/or DBP \>100 mmHg) with or without antihypertensive therapy (antihypertensive therapy should be stable for 1 month prior to screening), serious arrhythmia (including the subjects with implanted pace makers), unstable heart failure, Adams-Stokes syndrome (i.e., syncope or near-syncope due to cardiac arrythmia), unstable angina, myocardial infarction occurring within 6 months prior to screening, history of tachycardia/bradycardia requiring medications, third degree atrioventricular block or QT interval corrected for HR using Fridericia's formula (QTcF) ≥450 ms for males and ≥470 ms for females. 2. History of severe obstructive lung disease (i.e., forced expiratory volume in 1 second \[FEV1\] \<50% predicted), history of bronchospasm requiring treatment in a hospital emergency room or hospitalization occurring within 3 months prior to screening, developing acute respiratory tract infection within 2 weeks prior to baseline (such as symptoms of fever, shortness of breath, wheezing, nasal congestion, and cough). 3. Cerebrovascular disease: subject with a history of serious craniocerebral injury, convulsion, seizure disorder, intracranial hypertension, cerebral aneurysm, or stroke. 4. Patients with psychiatric/mental disorders who have not been on a stable treatment regimen (e.g., SSRIs, SNRIs, TCAs, MAOIs, psychotherapy) per investigator judgement, for at least 12 months or who have been hospitalized or had emergent/urgent care due to the underlying psychiatric pathology within the last 12 months. 5. Uncontrolled clinically significant conditions of liver (e.g., severe hepatic insufficiency defined as Childs-Pugh class C), kidney, gastrointestinal tract, blood system, nervous system, or metabolic system diseases, judged by the investigator to be unsuitable for involvement in the study. 6. History of uncontrolled diabetes in the opinion of the investigator. 7. History of alcohol abuse within 3 months prior to screening, where alcohol abuse refers to daily alcohol drinking \>2 units of alcohol (1 unit = 360 mL of beer or 45 mL of spirit with a strength of 40% or 150 mL of wine). 8. History of drug abuse that, in the opinion of the investigator, may confound the interpretation of safety or efficacy in a study subject. 9. For subjects with known hypothyroidism and/or on thyroid-hormone replacement treatment (i.e., thyroxine), or subjects suspected to have thyroid dysfunction based on clinical laboratory and physical exam who has a TSH value outside the normal range. 4. Management risks of respiratory tract and judged by the investigator to be unsuitable for inclusion in the study as follows: 1. Asthma must be stable: stable doses of asthma medications for the past 6 months, no requirement for rescue inhalers or oral steroids within past 6 months, not evaluated in emergency department, urgent care, or hospitalized for an asthma attack within past 1 year. 2. History (or family history) of malignant hyperthermia. 3. Any previous failure of tracheal intubation. 4. Judged to have a difficult airway for endotracheal intubation in the opinion of the Investigator based on parameters such as modified Mallampati score (Grade III or IV \[Appendix 7\]), neck mobility, short thyromental distance, and/or history of difficult intubation). 5. Any medication that has the potential to interact synergistically with propofol or HSK3486, including but not limited to all sedatives and hypnotics (e.g., benzodiazepines and opioids), taken within 5 half-lives prior to Day 1. 6. Laboratory parameters measured at screening with the following levels: 1. Neutrophil count ≤1.5 x 109/L 2. Platelet count \<80 x 109/L 3. Hemoglobin \<90 g/L (without blood transfusion within 14 days) 4. Alanine transaminase and/or aspartate transaminase ≥2.0 x upper limit of normal (ULN) 5. Total bilirubin ≥2.0 x ULN 6. Severe renal impairment defined by creatinine clearance (CrCl) ≤30 mL/min 7. Female subjects with a positive pregnancy test at screening (serum) or baseline (urine); lactating subjects; any subject planning to get pregnant within 1 month after the study (including the male subject's partner). 8. Judged by the investigator to have any other factors that make the subject unsuitable for participation in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Success Rate of General Anesthesia Induction | From the time of study drug administration to desired depth of anesthesia to MOAA/S≤1( up to 5 minutes) | 1. Induction success (MOAA/S ≤1) after administration of the study drug, and 2. One or less top-up doses required without using any rescue drugs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Successful Induction Who Maintain the Desired Depth of Anesthesia for General Elective Surgery, AND Without Significant Cardiac and Respiratory Depression | 15 minutes from end of drug administration | The outcome is defined by all the following conditions: a) Desired depth of anesthesia for general elective surgery is defined if all following criteria are met: i) No clinical signs of inadequate depth of anesthesia, such as lacrimation, movement, vomiting, coughing, laryngospasm, bucking, swallowing reflex or bronchospasm etc. ii) No blood pressure (SBP, DBP, or MAP) increases more than 20% from baseline in response to any major operational procedures or noxious stimulus in defined period. iii) Subjects maintain desired depth of anesthesia for general elective surgery with BIS as an objective assessment (after reaching initial lowest value, BIS remains sustainable level at not more than 60). b) No significant respiratory depression, such as apnea, prior to the administration of rocuronium bromide. c) No significant cardiac depression indicated by blood pressure decrease that requires intervention, i.e., vasopressors and/or IV fluid resuscitation. |
| Proportion of Subjects With Any Injection-site Pain on Numeric Rating Scale ≥1 | From start of the drug administration to MOAA/S ≤1 (up to 3 minutes) | 0 = No Pain 1-3 = Mild Pain 4-6 = Moderate Pain 7-9 = Severe Pain 10 = Worst pain imaginable |
Countries
Poland, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| HSK3486 for General Anesthesia Induction HSK3486 for induction of general anesthesia
HSK3486: HSK3486 for induction of general anesthesia | 300 |
| Propofol for General Anesthesia Induction Propofol for induction of general anesthesia
Propofol: Propofol for induction of general anesthesia | 145 |
| Total | 445 |
Baseline characteristics
| Characteristic | HSK3486 for General Anesthesia Induction | Propofol for General Anesthesia Induction | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 71 Participants | 35 Participants | 106 Participants |
| Age, Categorical Between 18 and 65 years | 229 Participants | 110 Participants | 339 Participants |
| ASA-PS ASA-PS I | 47 Participants | 24 Participants | 71 Participants |
| ASA-PS ASA-PS II | 183 Participants | 90 Participants | 273 Participants |
| ASA-PS ASA-PS III | 70 Participants | 31 Participants | 101 Participants |
| BMI <35kg/m^2 | 237 Participants | 113 Participants | 350 Participants |
| BMI ≥35kg/m^2 | 63 Participants | 32 Participants | 95 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 91 Participants | 38 Participants | 129 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 204 Participants | 107 Participants | 311 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 38 Participants | 23 Participants | 61 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) White | 254 Participants | 114 Participants | 368 Participants |
| Region of Enrollment Poland | 27 participants | 15 participants | 42 participants |
| Region of Enrollment Spain | 39 participants | 11 participants | 50 participants |
| Region of Enrollment United States | 234 participants | 119 participants | 353 participants |
| Sex: Female, Male Female | 173 Participants | 74 Participants | 247 Participants |
| Sex: Female, Male Male | 127 Participants | 71 Participants | 198 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 300 | 0 / 145 |
| other Total, other adverse events | 185 / 300 | 96 / 145 |
| serious Total, serious adverse events | 5 / 300 | 1 / 145 |
Outcome results
Primary
Success Rate of General Anesthesia Induction
1. Induction success (MOAA/S ≤1) after administration of the study drug, and 2. One or less top-up doses required without using any rescue drugs.
Time frame: From the time of study drug administration to desired depth of anesthesia to MOAA/S≤1( up to 5 minutes)
Population: Completed primary efficacy measurement
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HSK3486 | Success Rate of General Anesthesia Induction | 298 Participants |
| Propofol | Success Rate of General Anesthesia Induction | 143 Participants |
Secondary
Percentage of Subjects With Successful Induction Who Maintain the Desired Depth of Anesthesia for General Elective Surgery, AND Without Significant Cardiac and Respiratory Depression
The outcome is defined by all the following conditions: a) Desired depth of anesthesia for general elective surgery is defined if all following criteria are met: i) No clinical signs of inadequate depth of anesthesia, such as lacrimation, movement, vomiting, coughing, laryngospasm, bucking, swallowing reflex or bronchospasm etc. ii) No blood pressure (SBP, DBP, or MAP) increases more than 20% from baseline in response to any major operational procedures or noxious stimulus in defined period. iii) Subjects maintain desired depth of anesthesia for general elective surgery with BIS as an objective assessment (after reaching initial lowest value, BIS remains sustainable level at not more than 60). b) No significant respiratory depression, such as apnea, prior to the administration of rocuronium bromide. c) No significant cardiac depression indicated by blood pressure decrease that requires intervention, i.e., vasopressors and/or IV fluid resuscitation.
Time frame: 15 minutes from end of drug administration
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HSK3486 | Percentage of Subjects With Successful Induction Who Maintain the Desired Depth of Anesthesia for General Elective Surgery, AND Without Significant Cardiac and Respiratory Depression | 81 Participants |
| Propofol | Percentage of Subjects With Successful Induction Who Maintain the Desired Depth of Anesthesia for General Elective Surgery, AND Without Significant Cardiac and Respiratory Depression | 45 Participants |
Secondary
Proportion of Subjects With Any Injection-site Pain on Numeric Rating Scale ≥1
0 = No Pain 1-3 = Mild Pain 4-6 = Moderate Pain 7-9 = Severe Pain 10 = Worst pain imaginable
Time frame: From start of the drug administration to MOAA/S ≤1 (up to 3 minutes)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HSK3486 | Proportion of Subjects With Any Injection-site Pain on Numeric Rating Scale ≥1 | 56 Participants |
| Propofol | Proportion of Subjects With Any Injection-site Pain on Numeric Rating Scale ≥1 | 86 Participants |