Efficacy and Safety of HSK3486 Compared to Propofol for Adults Undergoing Elective Surgery With General Anesthesia

This is an interventional treatment trial for General Anesthesia Read More

Inclusion Criteria:

• 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 at screening and must have negative urine pregnancy test at baseline (Day 1). Additionally, women of childbearing potential* must agree to use effective contraception as defined in 7.3.4 from the time of consent until 30 days post study drug administration.

  6. Capable of understanding the procedures and methods of this study, willing to sign an Informed Consent Form, and able to complete this study in strict compliance with the study protocol.

  7. Willing to comply with the site's COVID guidelines and testing requirements as applicable.

  8. Patients with psychiatric diseases (schizophrenia, mania) must be considered stable on treatment (with SSRIs, SNRIs, TCAs, and MAOIs) and no hospitalizations and urgent care for at least 1 year.

Women NOT of childbearing potential are defined as those who have been surgically sterilized (hysterectomy, bilateral salpingo-oophorectomy) or who are postmenopausal (defined 12 months since last regular menses).

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; subject having contraindications to propofol, opioids, and their antidotes.

  3. Medical condition or evidence of increased sedation/general anesthesia risk as follows:

  1. Cardiovascular disorders: 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)≥450ms for males and ≥470ms 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 diseases (schizophrenia, mania) who have not been on a stable treatment regimen (with SSRIs, SNRIs, TCAs, MAOIs) for at least 1 year or who have been hospitalized or had emergent/urgent care within the past year.
  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. Known glycosylated hemoglobin (HbA1c) greater than or equal to 10%.
  7. Known thyroid-stimulating hormone (TSH) value 10% outside the normal range or on thyroid replacement therapy with a known free T-4 level outside the normal range.
  8. History of alcohol abuse within 3 months prior to screening, where alcohol abuse refers to daily alcohol drinking >2 units (1 unit = 360 mL of beer or 45 mL of spirit with a strength of 40% or 150 mL of wine).
  9. History of drug abuse that, in the opinion of the investigator, may confound the interpretation of safety or efficacy in a study subject.

Diagnosis and main criteria for inclusion and exclusion:

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 at screening and must have negative urine pregnancy test at baseline (Day 1). Additionally, women of childbearing potential* must agree to use effective contraception as defined in 7.3.4 from the time of consent until 30 days post study drug administration.
6. Capable of understanding the procedures and methods of this study, willing to sign an Informed Consent Form, and able to complete this study in strict compliance with the study protocol.
7. Willing to comply with the site's COVID guidelines and testing requirements as applicable.

8. Patients with psychiatric diseases (schizophrenia, mania) must be considered stable on treatment (with SSRIs, SNRIs, TCAs, and MAOIs) and no hospitalizations and urgent care for at least 1 year.

   • Women NOT of childbearing potential are defined as those who have been surgically sterilized (hysterectomy, bilateral salpingo-oophorectomy) or who are postmenopausal (defined 12 months since last regular menses).

Exclusion criteria:

Subjects will be excluded from the study if they satisfy any of the following criteria at the screening visit:

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; subject having contraindications to propofol, opioids, and their antidotes.

3. Medical condition or evidence of increased sedation/general anesthesia risk as follows:

   1. Cardiovascular disorders: 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)≥450ms for males and ≥470ms 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 diseases (schizophrenia, mania) who have not been on a stable treatment regimen (with SSRIs, SNRIs, TCAs, MAOIs) for at least 1 year or who have been hospitalized or had emergent/urgent care within the past year.
   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. Known glycosylated hemoglobin (HbA1c) greater than or equal to 10%.
   7. Known thyroid-stimulating hormone (TSH) value 10% outside the normal range or on thyroid replacement therapy with a known free T-4 level outside the normal range.
   8. History of alcohol abuse within 3 months prior to screening, where alcohol abuse refers to daily alcohol drinking >2 units (1 unit = 360 mL of beer or 45 mL of spirit with a strength of 40% or 150 mL of wine).
   9. History of drug abuse that, in the opinion of the investigator, may confound the interpretation of safety or efficacy in a study subject.

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. Taking valproic acid (Depakote) within 1 week prior to Day 1; taking UGT1A9 inhibitors (Appendix 8), including but not limited to phenytoin, fosphenytoin, mefenamic acid, sorafenib, deferasirox, rifampicin, within 1 week prior to Day 1.

7. 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
8. Female subjects with a positive pregnancy test (serum or urine) at screening or baseline; lactating subjects; any subject planning to get pregnant within 1 month after the study (including the male subject's partner).
9. Judged by the investigator to have any other factors that make the subject unsuitable for participation in the study.