Clinical trial NCT05478174: Efficacy and Safety of HSK3486 Compared to Propofol for Adults Undergoing Elective Surgery With General Anesthesia
Official title: A Multicenter, Randomized, Double-blinded, Propofol-controlled, Phase 3 Clinical Study to Evaluate the Efficacy and Safety of HSK3486 Injectable Emulsion for Induction of General Anesthesia in Adults Undergoing Elective Surgery
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: General Anesthesia
Lead sponsor: Haisco-USA Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2022-07-28
Enrollment: 400
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Surgical pre-induction analgesia
Primary purpose: TREATMENT

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 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 preinduction and induction periods, a timing device must be used to allow accuracy and sequencing of necessary assessments.

Eligibility criteria: 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/mental disorders must be considered stable on treatment (e.g., SSRIs, SNRIs, TCAs, MAOIs, psychotherapy) 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.
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.

Primary outcomes:
measure: Success Rate of General Anesthesia Induction
timeFrame: From the time of study drug administration to desired depth of anesthesia to MOAA/S≤1 ( up to 5 minutes)
Secondary outcomes:
measure: Percentage of Subjects With Successful Induction Who Maintain the Desired Depth of Anesthesia for General Elective Surgery, AND Without Significant Cardiac and Respiratory Depression
timeFrame: 15 minutes from end of drug administration
measure: Percentage of Subjects With Any Injection-site Pain on Numeric Rating Scale ≥1
timeFrame: From start of drug administration to MOAA/S ≤1 (up to 3 minutes)
Other outcomes:
Locations:
city: Sheffield
country: United States
facility: Shoals Medical Trials, Inc.
state: Alabama
city: Phoenix
country: United States
facility: Arizona Research Center
state: Arizona
city: Davis
country: United States
facility: UC Davis Health
state: California
city: Jacksonville
country: United States
facility: Coastal Clinical Research Specialists
state: Florida
city: Miami
country: United States
facility: University of Miami Hospital
state: Florida
city: Sarasota
country: United States
facility: Gulfcoast Research Institute, Llc
state: Florida
city: Tamarac
country: United States
facility: Phoenix Clinical Research
state: Florida
city: Tampa
country: United States
facility: ForCare Clinical Research
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Wichita
country: United States
facility: NextStage Clinical Research - Abay Neuroscience Center
state: Kansas
city: Pasadena
country: United States
facility: Chesapeake Research Group, Llc
state: Maryland
city: Boston
country: United States
facility: Brigham & Women'S Hospital
state: Massachusetts
city: Durham
country: United States
facility: Duke University Health
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Dayton
country: United States
facility: Midwest Clinical Research Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Bellaire
country: United States
facility: HD Research
state: Texas
city: Carrollton
country: United States
facility: Hd Research Llc.
state: Texas
city: Houston
country: United States
facility: The University of Texas - MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Urology San Antonio Research
state: Texas
city: San Antonio
country: United States
facility: Endeavor Clinical Trials
state: Texas
city: Salt Lake City
country: United States
facility: Jbr Clinical Research
state: Utah
Study officials:
References: