Clinical trial NCT05486416: Safety and Efficacy of HSK3486 Compared to Propofol for Induction of General Anesthesia in Adults With Elective Surgery
Official title: A Global 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: 2022-08-03
Enrollment: 466
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 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.

Eligibility criteria: 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.

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: Proportion 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: Proportion of subjects with any injection-site pain on Numeric Rating Scale
timeFrame: From start of the drug administration to MOAA/S ≤1 (up to 3 minutes)
Other outcomes:
Locations:
city: Florence
country: United States
facility: North Alabama Medical Center
state: Alabama
city: Sheffield
country: United States
facility: Shoals Medical Trials, Inc
state: Alabama
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Sarasota
country: United States
facility: Gulfcoast Research Institute
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: Atlanta
country: United States
facility: Atlanta Center for Medical Research
state: Georgia
city: Snellville
country: United States
facility: EBGS Clinical Research Center
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa Healthcare
state: Iowa
city: Louisville
country: United States
facility: University of Louisville Hospital
state: Kentucky
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Durham
country: United States
facility: M3 Emerging Medical Research
state: North Carolina
city: Durham
country: United States
facility: Duke University Hospital
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Bellaire
country: United States
facility: HD Research
state: Texas
city: Carrollton
country: United States
facility: HD Research
state: Texas
city: Houston
country: United States
facility: The University of Texas - MD Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: HD Research
state: Texas
city: San Antonio
country: United States
facility: Clinical Trials of Texas
state: Texas
city: San Antonio
country: United States
facility: Endeavor Clinical Trials
state: Texas
city: Opole
country: Poland
facility: Uniwersytecki Szpital Kliniczny W Opolu
city: Warsaw
country: Poland
facility: Państwowy Instytut Medyczny Mswia - Klinika Anestezjologii I Intensywnej Terapii
city: Zabrze
country: Poland
facility: Spsk Nr 1 Im. Prof. S. Szyszko
city: Barcelona
country: Spain
facility: Hospital Clinic De Barcelona
city: Ciudad Real
country: Spain
facility: Hospital General Universitario De Ciudad Real
city: Pamplona
country: Spain
facility: Universidad de Navarra - Clinica Universidad de Navarra en Pamplona
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia (CHUV)
Study officials:
References: