Clinical trial NCT05478174
Conditions: General Anesthesia
Sponsor: Haisco-USA Pharmaceuticals, Inc.
Start date: 2022-07-26; Completion date: 2023-11-14
Enrollment: 400 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: HSK3486 for general anesthesia induction arm 2: Propofol for general anesthesia induction
Interventions: intervention 1: HSK3486 intervention 2: Propofol
Intervention descriptions: intervention 1: HSK3486 for induction of general anesthesia intervention 2: Propofol for induction of general anesthesia.

Protocol documents:
Prot_000.pdf: 
Cover Page 
PROTOCOL V6.0 HSK3486-305 
 
TITLE OF STUDY: 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 
 
NCT NUMBER: NCT05478174 
 
DOCUMENT DATE: 25 FEBRUARY 2023 


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Protocol 
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 
Protocol Date: 25 Feb 2023 
Protocol Version: 6.0 
Investigational Product: HSK3486 
Protocol Reference Number: HSK3486-305 
Sponsor: 
Haisco-USA Pharmaceuticals, Inc 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 


 
 
 
 
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SUMMARY OF CHANGES –V.5.0, 05 Jan 2023 to V.6.0 25 Feb 2023 
The following is a high-level summary of changes made in protocol Version 6.0. The detailed 
changes (existing text and updated text) are provided in Appendix 13. 
• Screening and Day 1 can be conducted on the same day. Screening period has 
been updated to Day -13 to Day 1. 
• Local labs may be drawn within the screening period to confirm eligibility in cases 
where a separate screening visit is not feasible or the central laboratory results 
are not available prior to surgery. Required screening laboratory samples must 
also be sent to the central laboratory in these cases. 
• Clarification added to all applicable sections that preinduction fentanyl and 
midazolam can be reduced according to patient’s age and comorbitities as per the 
anesthesist’s discretion. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SPONSOR APPROVAL 
I have read the following and approve it: 
Version 6.0, 25 Feb 2023 
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INVESTIGATOR AGREEMENT 
I have read the following protocol and agree to conduct the study as described herein. 
 
 
 
 
 
 
 
[Name, Qualification(s)] 
 
Date 
Principal Investigator 


 
 
 
 
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SYNOPSIS 
 
Title of study: 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 
Indication: Induction of general anesthesia in adult subjects undergoing elective surgery with endotracheal 
intubation 
Number of study centers: Up to approximately 20 sites in the US will be included in this study.  
Development phase: Phase 3 
Objectives: 
Primary objective: 
• 
To demonstrate HSK3486 0.4/0.2 mg/kg (0.4 mg/kg intravenous [IV] slow injection 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 for first 
dose, an additional 1.0 mg/kg if needed) in success of induction of general anesthesia in adults undergoing 
elective surgery. 
Secondary objectives: 
Key secondary objectives: 
• 
To confirm that HSK3486 0.4/0.2 mg/kg leads to statistically significant less injection-site pain in all 
compared to propofol 2.0/1.0 mg/kg during the induction of general anesthesia in adults undergoing elective 
surgery. 
• 
To demonstrate HSK3486 0.4/0.2 mg/kg provides better anesthetic effects compared to propofol 2.0/1.0 
mg/kg without significant cardiac and respiratory depression in conjunction with other routinely used 
preinduction and maintenance anesthetic agents in the induction of general anesthesia in adults undergoing 
elective surgery.  
Additional Efficacy Objective: 
• 
To evaluate HSK3486 0.4/0.2 mg/kg induction time in general anesthesia compared to propofol. 
• 
To evaluate HSK3486 0.4/0.2 mg/kg time to the disappearance of eyelash reflex compared to propofol. 
• 
To confirm that HSK3486 0.4/0.2 mg/kg leads to statistically significant less moderate injection-site pain 
compared to propofol 2.0/1.0 mg/kg during the induction of general anesthesia in adults undergoing elective 
surgery. 
• 
To better characterize that HSK3486 0.4/0.2 mg/kg leads to statistically significant less average NRS scales in 
injection-site pain compared to propofol 2.0/1.0 mg/kg during the induction of general anesthesia in adults 
undergoing elective surgery. 
Safety: 
• 
To evaluate the overall safety profile of HSK3486 compared to propofol. 
Pharmacokinetic:  
• 
To characterize the HSK3486 population pharmacokinetic (PK) profile. 


 
 
 
 
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Methodology/study design: 
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.  
On Day 1, premedication is allowed prior to induction except for sedative-hypnotics, analgesics (eg., opioids, 
NSAIDs, APAP), or any medications that relieve pain (eg., Gabapentin), unless otherwise specified in the 
protocol. 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.  
Figure 1：Study design 
 


 
 
 
 
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Preinduction period: 
• 
Obtain vital signs (heart rate [HR], respiratory rate [RR], oxygen saturation [SpO2], systolic blood pressure 
[SBP], diastolic blood pressure [DBP], mean arterial pressure [MAP]), Temperature [Temp]; baseline 
value will be the measurement immediately prior to initiation of study drug administration. Attach 3-lead 
or 5-lead electrocardiogram (ECG) to subject and monitor continuously. In the event an abnormality is 
noted with 3-lead or 5-lead ECG, clinical significance of an abnormality should be documented, and the 
investigators will decide whether to add a 12-lead ECG.  
• 
Attach bispectral index (BIS [Appendix 2]) monitor to subject. Record the three most recent BIS values 
preceding midazolam administration. 
• 
Subjects will receive IV midazolam at dose 0.04 mg/kg, up to 3 mg maximum over 15 [±2] seconds at 5 
minutes [±30 seconds] prior to initiation of induction agents as premedication. The midazolam dose can be 
reduced according to patient’s age and comorbidities as per the anesthetist’s discretion. The start and end 
time of midazolam administration should be recorded. The end time of midazolam administration will 
begin the window to start of IP.  
• 
Subjects will receive preinduction IV fentanyl at a dose of 1 mcg/kg rounded up to the nearest 25 mcg, up 
to 100 mcg maximum over 15 [±2] seconds at 2 minutes [±10 seconds] prior to initiation of induction 
agents. The fentanyl dose can be reduced according to patient’s age and comorbidities as per the 
anesthetist’s discretion. The start and end time of fentanyl administration should be recorded. The end time 
of fentanyl administration will begin the window to start of IP. 
Note: Throughout the preinduction and induction periods, a timing device must be used to allow accuracy and 
sequencing of necessary assessments. 
• 
Information about any adverse events (AEs) and concomitant medications will be recorded. 
Induction period of general anesthesia: 
The induction of general anesthesia will be performed as follows:  


 
 
 
 
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• 
Monitor vital signs (HR, RR, SpO2, SBP, DBP, MAP, Temp) continuously. HR, RR, SBP, DBP, MAP, 
Temp should be recorded once every 2 minutes [±30 seconds], SpO2 value should be recorded once every 1 
minute [± 15 seconds] from the start of study drug administration (for every time point) for 30 minutes post 
start of study drug administration, for the judgment of key secondary endpoint.  
Note: Vital signs (HR, RR, SBP, DBP, MAP, Temp) monitor should be set to cycle every 1 minute to obtain 
vitals at least every 2 minutes (in case cycle requires longer than 1 minute).  
• 
Administer IV study drug (HSK3486 0.4 mg/kg or propofol 2.0 mg/kg) into vein located on the back of 
right or left hand (this IV location is strongly preferred rather than mandatory) at a port closest to the IV 
cannula (IV injection time: 30 [±5] seconds).  
• 
The MOAA/S will be evaluated every 30 [±10] seconds after end of study drug administration until 
MOAA/S ≤1 is reached.  
• 
If MOAA/S is still >1 at 1 minute [±10 seconds] post end of study drug administration, a top-up dose 
of 50% of the initial dose of study drug (either HSK3486 0.2 mg/kg or propofol 1 mg/kg depending 
on treatment group) will be given to the subject (IV injection time: 10 [±2] seconds). Start and end 
times of top-up dose administration will be recorded. The MOAA/S will be evaluated every 30 [±10] 
seconds post end of the top-up dose administration. 
• 
If MOAA/S is still >1 at 2 minutes [±10 seconds] post end of the top-up dose administration, then the 
rescue drug, propofol, will be given (in both treatment groups). The rescue dose is prepared as the 
initial calculated propofol dose (100%) and administered per propofol guidelines. The MOAA/S will 
be evaluated every 30 [±10] seconds post end of rescue drug administration until MOAA/S ≤1 is 
reached. 
• 
Administration of study drug must be initiated 5 minutes [±30 seconds] post midazolam preinduction 
medication administration stop time and at 2 minutes [±10 seconds] after preinduction fentanyl 
administration stop time. Top-up dose should be administered within 10 seconds once MOAA/S is 
evaluated >1. 
• 
Injection-site pain is evaluated verbally by Numeric Rating Scale (NRS; Appendix 3). Upon initiation of 
study drug administration, the investigator should immediately ask the subject to rate his or her pain at 
injection-site. As a general guidance, the evaluation should be done multiple times with the first evaluation 
occurring typically within 15 seconds after initiation of study drug injection and monitored until successful 
induction (MOAA/S ≤1). Related information, such as the occurrence and severity of injection pain (NRS 0-
10), shall be recorded. The maximum (highest value) injection-site pain will be recorded in EDC as NRS.  
• 
Post the end of initial study drug administration, the eyelash reflex will be evaluated every 30 [±10] 
seconds until loss of eyelash reflex. If there is a top-up dose, eyelash reflex will be evaluated every 30 
[±10] seconds post end of the top-up dose administration until loss of eyelash reflex. If there is rescue drug 
given, eyelash reflex will be evaluated every 30 [±10] seconds post end of the rescue drug until loss of 
eyelash reflex. The time of loss of eyelash reflex should be recorded. 
• 
BIS will be monitored continuously; record baseline BIS value prior to administering study drug. BIS 
values will be collected at the following timepoints from start of initial study drug administration: every 30 


 
 
 
 
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[±10] seconds for 5 minutes, then every 2 minutes [±30 seconds] for 30 minutes and then every 30 [±2] 
minutes for the duration of the surgery. 
• 
Monitor 3-lead or 5-lead electrocardiogram (ECG) continuously. Abnormalities that are clinically 
significant or not clinically significant should be recorded. The investigators will decide whether to add a 
12-lead ECG.  
• 
When MOAA/S ≤1 is reached, then IV rocuronium bromide (0.6 mg/kg) is to be administered for 
neuromuscular blockade to perform endotracheal intubation. The start and end times of rocuronium 
bromide administration should be recorded. RR should be collected until initiation of administration of 
rocuronium. 
   Note: For subjects with BMI >40 kg/m2, the rocuronium dose may be modified per investigator discretion. 
Note: Additional IV rocuronium is allowed per investigator’s discretion only in response to clinical symptoms 
during tracheal intubation, such as gag reflex and movement et al, or during surgical procedures. The start and 
end times of additional rocuronium bromide administration should be recorded.   
• 
Intubate subject once neuromuscular blockade has taken effect; if using twitch monitor, intubate once no 
twitches are noted. The start and end times of first and subsequent intubation attempts should be recorded. 
• 
During endotracheal intubation, evaluate and record clinical symptoms and/or signs for inadequate depth of 
anesthesia, such as lacrimation, movement, vomiting, coughing, laryngospasm, bucking, swallowing reflex 
and/or bronchospasm, etc. for at least 15 minutes from start of study drug administration. 
• 
Between the start of study drug administration and prior to the administration of rocuronium bromide, 
evaluate and record respiratory depression.    
Note: Respiratory depression includes apnea, defined as absence of thoracic movement lasting >30 seconds, 
prior to the administration of rocuronium bromide, or hypoxia, defined as SpO2 <90% lasting >30 seconds, or 
life-threatening apnea or hypoxia requiring immediate intervention. 
• 
Evaluate and record cardiac depression from start of study drug administration until the subject leaves the 
operating room. 
Note: Cardiac depression is defined as SBP <90 mmHg lasting >2 minutes plus requiring medical intervention 
such as inotropes, vasopressors, or IV fluid resuscitation, or life-threatening hypotension requiring immediate 
intervention. 
• 
Sevoflurane (an inhalation anesthetic agent) will be used for maintenance of general anesthesia. Initiate 
sevoflurane within 60 seconds after successful endotracheal intubation. The end-tidal concentration of 
sevoflurane should be 1.5-2.0% (The initial concentration that is set and start time of administration should 
be recorded).  
• 
Information about any adverse events (AEs) and concomitant medications will be recorded.  
Maintenance period of general anesthesia: 
• 
During the maintenance period of general anesthesia, the inhalational anesthetic agent sevoflurane will be 
used according to routine clinical practice, and the end-tidal concentration of sevoflurane should be 1.5-
2.0% within 15 minutes after initiation of study drug administration and can be adjusted to the desired 
effect after that. Propofol should not be used at any time all throughout the maintenance period.  
• 
During the maintenance period, end-tidal sevoflurane concentration will be monitored per standard of care.  


 
 
 
 
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• 
The BIS will be monitored continuously per standard of care and BIS values will be collected at the 
following timepoints from start of initial study drug administration: every 30 [±10] seconds until 5 minutes, 
then every 2 minutes [±30 seconds] from 5 minutes until 30 minutes and then every 30 [±2] minutes for the 
duration of the surgery.  
• 
Information about any adverse events (AEs) and concomitant medications will be recorded. 
• 
Additional IV fentanyl or other analgesic drug may be administered for intraoperative analgesia only after 
initiation of sevoflurane, preferably after 15 minutes following the initiation of study drug administration, 
start time and end time of initial study drug administration should be recorded; if additional drug used, the 
start and end time of administration should be recorded. 
• 
Patient management during surgery needs to follow routine best practice which includes Antiemetics 
Ondansetron, or other 5 HT-3 antagonists and/or Dexamethasone. Antiemetics should be given during 
surgery and before subjects wake up unless otherwise contraindicated. The use of antiemetics should be 
recorded in concomitant medications. 
Follow-up period (6 hours Post Study Drug; 24 hours Post Study Drug Administration (Day 2); Day 8 
Phone Contact): 
For the first 6 hours post study drug evaluation, study assessments and procedures will be assessed as indicated in 
the Schedule of Assessments: 
• 
After the surgery, vital signs (HR, RR, SpO2, SBP, DBP, MAP, Temp) will be assessed at 6 [±2] hours post 
start study drug administration.  
Note: If surgery lasts >4 hours, vital signs, clinical laboratory tests and 12-ECG should be obtained 1[+1] hour 
after completion of surgery. Duration of surgery is defined as time from study drug administration to time of 
transfer from operating room to recovery room or PACU. 
• 
Clinical laboratory tests (including hematology, blood chemistry, and urinalysis) will be obtained at 6 [±2] 
hours post start study drug administration for shipment to central laboratory. 
• 
Obtain 12-lead ECG at 6 [±2] hours post start study drug administration. 
• 
In the post-anesthesia care unit (PACU), once the subject is alert and oriented, repeat NRS for recall of 
pain at time of study drug administration and assess surgical awareness with recall using the Brice 
Awareness Questionnaire (Appendix 4). The assessment time and result should be recorded.  
• 
Information about any AEs and concomitant mediations will be collected and recorded.  
• 
After the surgery, subjects may remain in the hospital or observation unit if required based on standard of 
care and the clinical situation; however, if the subject is clinically stable after the Day 1 follow-up 
assessments and appropriate to be discharged home per the judgement of the investigator and surgeon, the 
subject may be released with supervision by a family member or friend, and must return to the clinic for the 
24-hour follow-up visit (Day 2). 
For the 24-hour follow-up (Day 2) visit, study assessments and procedures will be assessed as indicated in the 
Schedule of Assessments: 


 
 
 
 
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• 
24 [±6] hours post study drug administration (Day 2), obtain vital signs (HR, RR, SpO2, SBP, DBP, MAP, 
Temp).  
• 
Information about any AEs and concomitant mediations will be collected and recorded. 
Day 8: Phone Contact 
• 
Subjects will be evaluated by a follow-up telephone call 7 [±2] days after surgery. 
• 
Surgical awareness with recall will be re-assessed using the Brice Awareness Questionnaire.  
• 
Information about any AEs and associated medications will be collected and recorded. 
Population PK study: 
• 
All eligible subjects in this clinical study will be required to provide venous blood samples for population 
PK study per time schedule planned (Appendix 5).  
Data monitoring committee: 
An independent data monitoring committee (DMC) will be involved in the conduct of the study to ensure the 
safety of all subjects who have been administered study drug. The DMC will consist of 3 unblinded members: 2 
anesthesiologists with appropriate clinical expertise and 1 statistician. The DMC will review all available 
unblinded safety information at approximately 30% enrollment. Additionally, enrollment will be immediately 
stopped after one death during the study where a clear alternative cause is not readily apparent (i.e., deemed 
definitely or likely related to study drug); after 4 (4/399 [1%] ) non-fatal serious adverse events (SAEs) where a 
clear alternative cause is not readily apparent (i.e., deemed definitely or likely related to study drug); or after 8 
(8/399 [2%]) severe AEs of special interest (AESIs; Common Terminology Criteria for Adverse Events [CTCAE] 
Grade 3 or 4) of severe hypotension, bradycardia, hypoxia due to respiratory depression, or QTc prolongation 
occurring within 15 minutes of study drug administration, where a clear alternative cause is not readily apparent 
(i.e., deemed definitely or likely related to study drug), and lasting ≥10 minute duration despite routine 
interventions. AESIs of allergy/anaphylaxis or cardiac arrhythmia occurring from the initial dose of study drug 
until Day 2 where a clear alternative cause is not readily apparent will be evaluated as part of the stopping criteria. 
If these criteria are met, enrollment will be temporarily suspended while the DMC convenes to review all 
available unblinded data. Based on recommendations from the DMC, the Sponsor can terminate the study or 
resume enrollment if measures can be taken to effectively address (i.e., mitigate) the risk to safely continue the 
study, such as revising inclusion/exclusion criteria or study procedures. The final decision to suspend enrollment 
or proceed will be made by the Sponsor after consultation with the DMC members and taking into consideration 
their recommendations. Conduct of the DMC is described in the DMC Charter.    
Number of subjects: A total of 399 subjects; 266 subjects in HSK3486 group and 133 subjects in propofol group. 
Diagnosis and main criteria for inclusion and exclusion: 
Inclusion criteria: 
Subjects must satisfy all the following criteria at the screening and Day 1 visits: 
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. 


 
 
 
 
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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
* and male subjects 
with female partners 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: 
Subjects will be excluded from the study if they satisfy any of the following criteria at the screening or Day 1 
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; 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: 
a) 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.  
b) 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). 


 
 
 
 
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c) Cerebrovascular disease: subject with a history of serious craniocerebral injury, convulsion, seizure 
disorder, intracranial hypertension, cerebral aneurysm, or stroke.  
d) Patients with psychiatric/mental disorders who have not been on a stable treatment regimen (e.g., SSRIs, 
SNRIs, TCAs, MAOIs, psychotherapy) for at least 1 year or who have been hospitalized or had 
emergent/urgent care within the past year. 
e) 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. 
f) Known glycosylated hemoglobin (HbA1c) greater than or equal to 10%. 
g) 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. 
h) 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).  
i) 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: 
a) 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.  
b) History (or family history) of malignant hyperthermia. 
c) Any previous failure of tracheal intubation. 
d) 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: 
a) Neutrophil count ≤1.5 x 109/L 
b) Platelet count <80 x 109/L 
c) Hemoglobin <90 g/L (without blood transfusion within 14 days) 
d) Alanine transaminase and/or aspartate transaminase ≥2.0 x upper limit of normal (ULN) 
e) Total bilirubin ≥2.0 x ULN 
f) 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). 


 
 
 
 
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8. Judged by the investigator to have any other factors that make the subject unsuitable for participation in the 
study. 
Test products, dose, and mode of administration: 
Name: HSK3486 injectable emulsion  
Dose, route, frequency: 0.4 mg/kg, IV slow injection over 30 [±5] seconds, preoperatively; 1 top up dose (0.2 
mg/kg), IV injection over 10 [±2] seconds permitted if needed.  
For elderly subjects ≥65 years of age, the dose will be automatically adjusted to a 25% dose reduction. According 
to the judgment of the investigator, the dose can be further reduced by up to 50% of the calculated dose. The 
administration time should be extended to 1 minute for this population. 
For ASA grade 3-4 subjects, the dose can be reduced by 25-50% per investigator discretion. The administration 
time should be extended to 1 minute for these populations.  
For subjects with BMI ≤40 kg/m2, total body weight (TBW) will be used to determine HSK3486 dose; for subjects 
with BMI >40 kg/m2, lean body weight (LBW) will be used to determine HSK3486 dose, and rescue dose. LBW 
should be calculated using the Janmahasatian formula included below. 
The Janmahasatian Formula:  
• 
For males: LBW = (9270 x TBW (kg))/(6680 + (216 x BMI)) 
 
• 
For females: LBW = (9270 x TBW (kg))/(8780 + (244 x BMI)) 
 
HSK3486 injectable emulsion will be stored at ≤ 25 °C (77°F) away from light and should not be frozen. It should 
be shaken well before use. 
Reference therapy, dose, dose form, and mode of administration:   
Name: Propofol injection 
Dose, route, frequency: 2.0 mg/kg, IV slow injection over 30 [±5] seconds, preoperatively; 1 top up dose (1 
mg/kg), IV injection over 10 [±2] seconds is permitted if needed.  
For elderly subjects ≥65 years of age, the dose will be automatically adjusted to a 25% dose reduction. According 
to the judgment of the investigator, the dose can be further reduced by up to 50% of the calculated dose. The 
administration time should be extended to 1 minute for this population. 
For ASA grade 3-4 subjects, the dose can be reduced by 25-50% per investigator discretion. The administration 
time should be extended to 1 minute for these populations. 
For subjects with BMI ≤40 kg/m2, TBW will be used to determine propofol dose; for subjects with BMI >40 
kg/m2, LBW will be used to determine propofol dose, and Rescue dose. LBW should be calculated using the 
Janmahasatian formula included below. 


 
 
 
 
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The Janmahasatian Formula:  
• 
For males: LBW = (9270 x TBW (kg))/(6680 + (216 x BMI)) 
• 
For females: LBW = (9270 x TBW (kg))/(8780 + (244 x BMI)) 
 
Propofol will be stored between 4°C and 25°C (40°F to 77°F) away from light and should not be frozen. It should 
be shaken well before use.  
The rescue dose is prepared as 100% of the initial calculated dose and administered per propofol guidelines above.  
Duration of subject participation in study: 
The sequence and maximum duration of the study periods per subject will be as follows: 
• 
Screening: up to 14 days prior to the surgery and including the day of surgery (if needed) 
• 
Treatment: on the day of surgery 
• 
Follow-up: 24 hours post study drug administration 
• 
Phone contact: 1 week [±2 days] post-surgery 
Total duration for each subject is expected to be 22 [±2] days (including screening and 1 week follow up 
telephone call). 
Efficacy endpoints:  
Primary efficacy endpoint: 
• 
Success rate of general anesthesia induction: A successful general anesthesia induction will meet both of the 
following conditions: 
a) Induction success (MOAA/S ≤1) after administration of the study drug, and 
b) One or less top-up doses required without using any rescue drugs. 
Secondary efficacy endpoints: 
Key secondary endpoints: 
• 
The proportion of subjects with any injection-site pain at time of drug administration on the Numeric Rating 
Scale (NRS ≥1). 
• 
The proportion of subjects with successful induction who maintain the desired depth of anesthesia for general 
elective surgery, and without significant cardiac and respiratory depression within 15 minutes post initiation 
start of study drug administration, or up to the start of second tracheal intubation attempt if it is a difficult 
condition and not beyond 15 minutes post initiation start study drug administration, 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. 


 
 
 
 
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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). 
Note: Target BIS 40 to 60 for general anesthesia (Appendix 2).  
The BIS sustainable level at not more than 60 is defined as not more than 1 episode with BIS value 
observed >60 after reaching initial lowest value, in defined period. 
Note: It is strongly recommended that each site have available video laryngoscopy, or an acceptable 
alternative, for unanticipated difficult tracheal intubation. If more than one tracheal intubation attempt is 
made, the start and end times of first and subsequent intubation attempts should be recorded. 
b) No significant respiratory depression, such as apnea, prior to the administration of rocuronium bromide. 
Note: For the composite endpoint, respiratory depression includes apnea, defined as absence of thoracic 
movement lasting >30 seconds, or hypoxia, defined as SpO2 <90% lasting >30 seconds, or life-threatening 
apnea or hypoxia requiring immediate intervention. 
c) No significant cardiac depression indicated by blood pressure decrease that requires intervention, i.e., 
vasopressors and/or IV fluid resuscitation. 
Note: For the composite endpoint, cardiac depression is defined as SBP <90 mmHg lasting >2 minutes 
plus requiring medical intervention such as inotropes, vasopressors, or IV fluid resuscitation, or life-
threatening hypotension requiring immediate intervention. 
Other secondary endpoints: 
• 
Time to successful induction of general anesthesia: Time from the end of the first administration of the study 
drug to MOAA/S ≤1. 
• 
Time to the disappearance of eyelash reflex: Time from the end of the first administration of the study drug to 
the disappearance of eyelash reflex. 
• 
The proportion of the subjects with any moderate injection-site pain at time of drug administration on the 
Numeric Rating Scale (NRS ≥4). 
• 
The average injection site pain at time of drug administration of HSK3486 compared to propofol on NRS. 
 
Safety endpoints: 
• 
Safety assessments include Adverse events (AE), adverse events of special interest (AESI), and serious 
adverse events (SAE)clinical laboratory test results, vital signs (supine HR, SBP and DBP, MAP, RR, and 
SpO2), ECG findings, physical examination findings, and administration of additional medications, or any 
interventions including medical interventions, e.g., administration of vasoactive drugs to treat clinically 
relevant changes in blood pressure. 
 


 
 
 
 
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Pharmacokinetic endpoints: 
Plasma HSK3486 concentration at scheduled timepoints (Appendix 5). 
Sample size evaluation: 
A total of 399 subjects (266 in HSK3486 0.4/0.2 mg/kg group and 133 in propofol 2.0/1.0 mg/kg group) need to 
be enrolled 2:1 into this study based on the following assumptions: 
• 
For the primary endpoint, a sample size of 215 patients will give at least 90% power (providing the primary 
endpoint is statistically significant) assuming that type I error is 0.025 (1-sided), the success rate of general 
anesthesia induction of HSK3486 and propofol are both 97%, and non-inferiority margin (NIM) is -8%. 
• 
For the key secondary endpoint of incidence of injection-site pain, a sample size of 365 patients will give 90% 
power (providing the primary endpoint is statistically significant) assuming α= 0.015 (2-sided) and the 
proportion of subjects who meet the endpoint criteria of any injection-site pain are 6.8% and 20.5% for 
HSK3486 and propofol, respectively. 
• 
For the key secondary composite endpoint, a sample size of 338 patients will give 90% power (providing the 
primary endpoint is statistically significant) to the superior testing, assuming α= 0.035 (2-sided), the 
proportion of subjects with successful induction, maintained desired depth of anesthesia for general elective 
surgery, without significant cardiac depression within the 15-minute post initiation start of study drug 
administration observation period and no significant respiratory depression (prior to administration of 
rocuronium bromide) of HSK3486 and propofol are 82% and 65%, respectively (i.e., 17% treatment effect). 
 
To power statistical testing for all three endpoints at 90% and provide sufficient safety data, it is decided that 399 
patients will be randomized and treated in this study (266 in HSK3486 0.4/0.2 mg/kg group and 133 in propofol 
2.0/1.0 mg/kg group).  
Statistical methods: 
Statistical analysis sets: 
Full Analysis Set (FAS): All randomized subjects who have received any dose of the study drug (HSK3486 or 
propofol). 
Per Protocol Set (PPS): All subjects from FAS who have completed primary efficacy endpoint measurement will 
be considered for PPS. Subjects with any important protocol deviations will be reviewed after database lock and 
prior to study unblinding and may be excluded from PPS if these important deviations will impact the efficacy 
evaluations. 
Safety Set (SS): Includes all randomized subjects who have received any dose of the study drug and have post-
dose safety assessment data. 


 
 
 
 
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General principles: 
Continuous variables will be summarized by the standard descriptive statistics: number of subjects (n), mean, 
standard deviation (SD), median, minimum, and maximum. Frequency of subjects or events and percentages will 
be summarized in categorical variables. 
Efficacy analysis: 
(a) Primary efficacy analysis 
• 
Success rate of general anesthesia induction in both groups and rate difference between groups and its 
95% confidence interval (CI) are estimated by Farrington-Manning method in the FAS. The lower limit of 
95% CI of rate difference will be compared with the non-inferiority margin of -8% to confirm the 
establishment of non-inferiority. FAS subjects who are non-evaluable for anesthesia induction will be 
counted as treatment failures. 
(b) Secondary efficacy analysis 
• 
The 2 key secondary endpoints will be analyzed in parallel. The proportion of subjects with successful 
induction, who maintain desired depth of anesthesia for general elective surgery, and without significant 
respiratory depression (prior to administration of rocuronium bromide) and cardiac depression between 
the time of successful induction and 15 minutes post study drug administration in both groups and the 
difference between groups and 95% CI will be calculated. The p-value for comparison between groups 
will be obtained based on Chi-square test. 
• 
The proportion of the subjects with any injection-site pain (NRS ≥1) and moderate injection-site pain 
(NRS ≥4) will be analyzed, as well as the mean NRS score for each treatment group, using the same 
method as stated above for the secondary composite endpoint.   
• 
The median and its 95% CI of time to successful induction of general anesthesia will be provided by 
groups using the Kaplan-Meier (KM) method. 
• 
Time to the disappearance of eyelash reflex will be analyzed using similar statistical methods as time to 
successful induction of general anesthesia. 
• 
The change of BIS during the period of anesthesia post study drug administration up to 15 minutes will be 
summarized descriptively by treatment group. 
• 
Recall of awareness during surgery, assessed postoperatively, will be evaluated using the Brice Awareness 
Questionnaire. 
• 
The use of study drugs and rescue drugs will be summarized descriptively by treatment group. 
• 
The proportion of subjects with successful induction without non-optimal anesthetic effects within 15 
minutes post initiation of administration of study drugs will be analyzed using the similar statistical 
methods as for the secondary composite efficacy endpoint. 
Safety analysis: 
 
All AEs will be coded according to the MedDRA version 24.0 or later and graded for severity according to 
CTCAE version 5.0. The number and percentage of subjects with treatment-emergent adverse events (TEAEs), 
SAEs, AEs of Special Interest (AESI), TEAEs related to study drug, SAEs related to study drug, TEAEs of Grade 


 
 
 
 
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2 or higher, TEAEs leading to treatment discontinuation, TEAEs leading to study discontinuation, and TEAEs 
leading to death will be summarized by system organ class (SOC), preferred term (PT), and groups. In addition, 
the severity of TEAEs and relationship to study drug will be summarized by SOC, PT, and groups.  
Laboratory test variables will be summarized by treatment group and visit using descriptive statistics. Shift tables 
between baseline and post-baseline time points will be presented by laboratory test and treatment group. 
Laboratory tests with categorical results that cannot be analyzed by change from baseline or shift table analysis 
will not be included in these summaries but will be listed.  
Descriptive statistics of vital signs, pulse oximetry measurements, and ECG results at each visit will be presented. 
Note: Since injection-site pain has been recorded and analyzed in the efficacy endpoints, it is no longer recorded 
in the Safety endpoints. 
Population PK analysis: 
The plasma concentration data from this study will be pooled with data from other clinical trials of HSK3486 to 
establish a population PK model. This model will be used to evaluate the effects of internal and external covariates 
on the PK of HSK3486. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
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SCHEDULE OF ASSESSMENTS 
 
Screening 
Study 
treatment 
Follow-up visits 
Phone 
contact 
 
Day -13 to 
Day 1 p 
(prior to 
surgery) 
Day 1  
(day of 
surgery) 
6-hour and 
24 hour (Day 2) i follow-up after 
study drug administration  
Day 8 
1 week (±2 
days) post 
day of 
surgery 
 
 
 
PACU 
6 (±2) hours 24 (±6) hours 
(Day 2) 
 
Written informed 
consent 
X 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
Verify 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Modified Mallampati 
score assessment 
X 
 
 
 
 
 
Physical exam a 
X  
 
 
 
 
 
Vital signs  
X 
X j 
 
X k 
X k 
 
Height, weight, and 
BMI 
X 
X 
 
 
 
 
12-lead ECG 
 
X 
X f 
 
X f 
 
 
Clinical laboratory 
tests  
X lp 
 
 
X k 
 
 
Serum pregnancy test 
(females)  
X lp 
 
 
 
 
 
Urine pregnancy test 
(females)  
 
X l 
 
 
 
 
Instruct subject to fast 
minimum of 6 hours 
before surgery o 
X 
 
 
 
 
 
Confirm preoperative 
readiness b 
 
X 
 
 
 
 


 
 
 
 
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Screening 
Study 
treatment 
Follow-up visits 
Phone 
contact 
 
Day -13 to 
Day 1 p 
(prior to 
surgery) 
Day 1  
(day of 
surgery) 
6-hour and 
24 hour (Day 2) i follow-up after 
study drug administration  
Day 8 
1 week (±2 
days) post 
day of 
surgery 
 
 
 
PACU 
6 (±2) hours 24 (±6) hours 
(Day 2) 
 
Randomization  
 
X 
 
 
 
 
Start maintenance IV 
infusion (NS, LR, or 
5% dextrose) 
 
X 
 
 
 
 
Administration of 
preinduction IV 
midazolam 
 
X 
 
 
 
 
Administration of 
preinduction IV 
fentanyl 
 
X 
 
 
 
 
Administer oxygen via 
face mask (≥4 L/min)  
 
X 
 
 
 
 
Administration of 
study drug c 
 
X 
 
 
 
 
Pain NRS d 
 
X 
X 
 
 
 
Monitor BIS e 
 
X 
 
 
 
 
Monitor eyelash reflex 
 
X 
 
 
 
 
Monitor MOAA/S 
 
X 
 
 
 
 
Monitor 3-lead or 5-
lead ECG 
continuously f 
 
X 
 
 
 
 
Administration of IV 
rocuronium g 
 
X 
 
 
 
 
Endotracheal 
intubation g 
 
X 
 
 
 
 


 
 
 
 
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Screening 
Study 
treatment 
Follow-up visits 
Phone 
contact 
 
Day -13 to 
Day 1 p 
(prior to 
surgery) 
Day 1  
(day of 
surgery) 
6-hour and 
24 hour (Day 2) i follow-up after 
study drug administration  
Day 8 
1 week (±2 
days) post 
day of 
surgery 
 
 
 
PACU 
6 (±2) hours 24 (±6) hours 
(Day 2) 
 
General anesthesia 
maintenance per 
routine practice 
(sevoflurane must be 
used as inhalational 
agent; record use of 
any alternative drugs) h 
 
X 
 
 
 
 
Blood sample 
collection for 
population PK study 
 
X m 
 
 
 
 
Brice Awareness 
Questionnaire 
 
 
X n 
 
 
X n 
Adverse events and 
prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
Abbreviations: ASA-PS = American Society of Anesthesiologists Physical Status; BIS = bispectral index; BMI = 
body mass index; DBP = diastolic blood pressure; ECG = electrocardiogram; HR = heart rate; IV = intravenous; 
LR = lactated ringer’s; MAP = mean arterial pressure; MOAA/S = Modified Observer’s Assessment of 
Awareness/Sedation; NRS = Numeric Rating Scale; NS = normal saline; OR = operating room; PACU = post-
anesthesia care unit; PK = pharmacokinetic; RR = respiratory rate; SBP = systolic blood pressure; SpO2 = 
peripheral capillary oxygen saturation. 
a. 
Physical examination will include ASA-PS score (Appendix 6). 
b. Subject is hemodynamically stable and has followed preoperative instructions, and there is no evidence of acute 
illness such as fever. 
c. 
Administer IV study drug (HSK3486 0.4 mg/kg or propofol 2.0 mg/kg) on the back of right or left hand vein 
(this IV location is strongly preferred rather than mandatory) at a port closest to the IV cannula (IV injection 
time: 30 [±5] seconds). The MOAA/S will be evaluated every 30 [±10] seconds after end of injection until 
MOAA/S ≤1 is reached. If MOAA/S is still >1 at 1 minute [±10 seconds] post end of study drug administration, 
a top-up dose of 50% of the initial dose of study drug (either HSK3486 0.2 mg/kg or propofol 1 mg/kg 
depending on treatment group) will be given to the subject (IV injection time: 10 [±2] seconds) and start and 


 
 
 
 
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end time of administration will be recorded. The MOAA/S will be evaluated every 30 [±10] seconds post end of 
the top-up dose. If MOAA/S is still >1 at 2 minutes [±10 seconds] post end of the top-up dose, then the rescue 
drug, propofol (100% of the initial calculated dose), will be given (in both treatment groups). The MOAA/S will 
be evaluated every 30 [±10] seconds post end of rescue drug administration until MOAA/S ≤1 is reached. 
Administration of study drug must be initiated 5 minutes [±30 seconds] post midazolam preinduction 
medication administration stop time. Top-up doses should be administered within 10 seconds once MOAA/S is 
evaluated >1. 
d. Prior to entering the OR, orient the subject to the use of the NRS assessment. Upon initiation of study drug 
administration, the investigator should immediately ask the subject to rate his or her pain. As a general 
guidance, the evaluation should be done multiple times with the first evaluation occurring typically within 15 
seconds after initiation of study drug injection and monitored until successful induction (MOAA/S ≤1). Related 
information such as the occurrence and severity of injection pain (NRS 0-10) shall be recorded. The maximum 
(highest value) injection-site pain should be recorded. Pain during the injection of study drug in the hand/arm 
should be distinguished from unrelated puncture pain from the IV site or due to adhesive tape at the IV site.  
When injection pain occurs, the subject’s pain should be graded verbally using the NRS (0-10) and should be 
recorded. The subject should be asked to rate the pain on a scale from 0, which is no pain, to 10, which is the 
worst pain imaginable. Ask the subject to point to the number on the scale that best represents the intensity of 
the pain now. In the PACU, once the subject is alert and oriented, repeat NRS for recall of pain at time of study 
drug administration. 
e. 
At preinduction, attach BIS monitor to subject. Record the three most recent BIS values before midazolam 
administration. Also, record baseline BIS value prior to administering study drug. The BIS values will be 
collected at the following timepoints at start of initial study drug administration: every 30 [±10] seconds until 5 
minutes, then every 2 minutes [± 30 seconds] until 30 minutes and then every 30 [±2] minutes for the duration 
of the surgery. 
f. 
Obtain 12-lead ECG at Day 1 visit only if the screening ECG is more than 1 week from the Day 1 visit. During 
the surgery, 3-lead or 5-lead ECG will be monitored continuously and the investigators will decide whether to 
add a 12-lead ECG. A 12-lead ECG will be obtained at 6 [±2] hours post study drug administration and as 
clinically indicated. 
g. When MOAA/S ≤1 is reached, IV rocuronium bromide (0.6 mg/kg) is to be administered for neuromuscular 
blockade to perform endotracheal intubation. RR collected until initiation of administration of rocuronium. 
Intubate subject once neuromuscular blockade (rocuronium) has taken effect; if using twitch monitor, intubate 
once no twitches are noted. The start and end of first and subsequent intubation attempt time should be 
recorded. 
h. An inhalational anesthetic agent, Sevoflurane (an inhalation anesthetic agent) will be used for maintenance of 
general anesthesia. Initiate sevoflurane within 60 seconds after successful endotracheal intubation. The end-tidal 
concentration of sevoflurane should be 1.5-2.0% (The initial concentration that is set and start time of 
administration should be recorded). 
i. 
After the surgery, subjects may remain in the hospital or observation unit if required based on standard of care 
and the clinical situation; however, if the subject is clinically stable after the Day 1 follow-up assessments and 
appropriate to be discharged home per the judgement of the investigator and surgeon, the subject may be 
released with supervision by a family member or friend, and must return to the clinic for the 24-hour follow-up 
visit (Day 2). 


 
 
 
 
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j. 
On the day of surgery prior to entering the operating room (after the subject has been resting supine for ≥5 
minutes), vital signs (HR, RR, SpO2, SBP, DBP, MAP, Temp) will be collected. During preinduction, obtain 
baseline vital signs (baseline value will be the measurement immediately prior to initiation of study drug 
administration). During the induction of general anesthesia, monitor vital signs (HR, RR, SpO2, SBP, DBP, 
MAP, Temp) continuously. HR, RR, SBP, DBP, MAP, Temp should be recorded once every 2 minutes [±30] 
seconds, SpO2 value should be recorded once every 1 minute [± 15 seconds] from the start of study drug 
administration (for every time point) for 30 minutes post start of study drug administration, for the judgment of 
key secondary endpoint. After the surgery, vital signs (HR, RR, SpO2, SBP, DBP, MAP, Temp) will be 
assessed at 6 [±2] hours post study drug administration. 
k. At 6 [±2] hours post study drug administration, obtain vital signs (HR, RR, SpO2, SBP, DBP, MAP, Temp) and 
clinical laboratory tests (including hematology, blood chemistry, and urinalysis). At 24 [±6] hours post study 
drug administration (Day 2), obtain vital signs (HR, RR, SpO2, SBP, DBP, MAP, Temp). 
l. 
Clinical laboratory tests (Appendix 10) include hematology, blood chemistry, and urinalysis; pregnancy tests 
for all women of childbearing potential (serum sample at screening and urine sample at baseline. If screening 
and baseline are both conducted on Day 1, a urine sample for pregnancy testing is not required if serum 
pregnancy eligibility is confirmed with an approved local lab as per footnote p). HbA1c and TSH test (with free 
T-4 if TSH abnormal) will only be done during the screening period.  
m. The blood collection time points for population PK analysis are listed in Appendix 5. Approximately 2 mL of 
venous blood is collected at each time point. 
n. The Brice Awareness Questionnaire is administered in the PACU once the subject is alert and oriented. The 
questionnaire is repeated at Day 8. 
o. Per investigator discretion, in otherwise healthy patients, clear liquids may be ingested for up to 2 hours prior to 
surgery. These liquids should not include alcohol. Examples of clear liquids include, but are not limited to, 
water and fruit juices without pulp, carbonated beverages, carbohydrate-rich nutritional drinks, clear tea, and 
black coffee. 
p. In cases where a separate screening visit is not feasible, or the central laboratory results are not available on Day 
1, screening activities may be conducted on Day 1 prior to surgery. A study approved local laboratory may be 
used to confirm eligibility. In these cases, required screening laboratory samples must be drawn in parallel and 
sent to the central laboratory.     


 
 
 
 
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TABLE OF CONTENTS 
SPONSOR APPROVAL .....................................................................................................3 
INVESTIGATOR AGREEMENT.......................................................................................4 
SYNOPSIS ..........................................................................................................................5 
SCHEDULE OF ASSESSMENTS ....................................................................................20 
TABLE OF CONTENTS ...................................................................................................25 
LIST OF FIGURES ...........................................................................................................28 
LIST OF ABBREVIATIONS ............................................................................................29 
1. 
INTRODUCTION ...............................................................................................31 
1.1. 
Study Rationale .................................................................................................31 
1.2. 
Background .......................................................................................................32 
1.3. 
Benefit-risk Assessment ....................................................................................33 
2. 
OBJECTIVES AND ENDPOINTS .....................................................................35 
2.1. 
Objectives ..........................................................................................................35 
2.2. 
Endpoints ..........................................................................................................36 
3. 
INVESTIGATION PLAN ...................................................................................38 
3.1. 
Overall Study Design and Plan Description......................................................38 
3.2. 
Discussion of Study Design, Including the Choice of Control Groups ............38 
3.3. 
End of Study Definition ....................................................................................39 
3.4. 
Selection of Doses in the Study ........................................................................39 
3.4.1. 
Selection of Dose for HSK3486 ........................................................................ 39 
3.4.2. 
Selection of Dose for Propofol .......................................................................... 40 
3.5. 
Data Monitoring Committee .............................................................................41 
4. 
SELECTION OF STUDY POPULATION .........................................................42 
4.1. 
Inclusion Criteria ...............................................................................................42 
4.2. 
Exclusion Criteria..............................................................................................43 
4.3. 
Subject Discontinuation from the Study ...........................................................45 
4.3.1. 
Screen Failures .................................................................................................. 45 
4.3.2. 
Subject Discontinuation from Study Treatment ................................................ 45 
4.3.3. 
Lost to Follow-up .............................................................................................. 46 
4.3.4. 
Replacement Procedures ................................................................................... 46 
4.3.5. 
Follow-up of Subjects Prematurely Discontinued from the Study Treatment 
Regimen or Withdrawn from Study ................................................................ 47 
4.4. 
Study Stopping Criteria .....................................................................................47 
5. 
STUDY TREATMENTS ....................................................................................49 
5.1. 
Treatments Administered ..................................................................................49 
5.2. 
Preparation, Storage, Handling, and Accountability .........................................49 
5.3. 
Method of Treatment Assignment ....................................................................51 
5.3.1. 
Dose Modification ............................................................................................. 52 
5.4. 
Blinding .............................................................................................................52 
5.5. 
Treatment Compliance ......................................................................................53 
5.6. 
Preinduction Drugs ...........................................................................................53 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ....................54 
6.1. 
Concomitant Therapies .....................................................................................54 


 
 
 
 
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6.2. 
Prohibited Therapies .........................................................................................55 
7. 
STUDY ASSESSMENTS AND PROCEDURES ..............................................56 
7.1. 
Study Procedures ...............................................................................................56 
7.1.1. 
Screening Period (Day -13 to Day 0) ................................................................ 56 
7.1.2. 
Day of Surgery (Day 1) ..................................................................................... 57 
7.1.3. 
Follow-up Period 6 (±2) hour Post Study Drug and 24-hour Post Study Drug Visit 
[Day 2] ............................................................................................................ 61 
7.1.4. 
Phone Contact (Day 8) ...................................................................................... 62 
7.2. 
Efficacy Assessments ........................................................................................63 
7.2.1. 
Success Rate of Anesthesia Induction............................................................... 63 
7.2.2. 
Composite Endpoint to Evaluate Desired Depth of Anesthesia........................ 63 
7.2.3. 
Injection-site Pain.............................................................................................. 64 
7.2.4. 
Time to Successful Anesthesia Induction ......................................................... 64 
7.2.5. 
Time to Loss of Eyelash Reflex ........................................................................ 65 
7.2.6. 
Successful induction without non-optimal anesthetic effects ........................... 65 
7.2.7. 
Changes in the Bispectral Index ........................................................................ 65 
7.2.8. 
Brice Awareness Questionnaire ........................................................................ 65 
7.2.9. 
Use of Study Drugs and Alternative Drugs....................................................... 65 
7.3. 
Safety and Tolerability Assessments ................................................................65 
7.3.1. 
Adverse Events.................................................................................................. 65 
7.3.2. 
Reporting Serious Adverse Events.................................................................... 66 
7.3.3. 
Adverse Events of Special Interest ................................................................... 67 
7.3.4. 
Contraception and Pregnancy ........................................................................... 69 
7.3.5. 
Clinical Laboratory Evaluations ....................................................................... 69 
7.3.6. 
Vital Signs, Physical Examination, and Other Safety Evaluations ................... 70 
7.3.7. 
Use of Additional Medication or Any Interventions......................................... 71 
7.4. 
Pharmacokinetic Analysis .................................................................................71 
8. 
SAMPLE SIZE AND DATA ANALYSES ........................................................73 
8.1. 
Determination of Sample Size ..........................................................................73 
8.2. 
Analysis Populations .........................................................................................73 
8.3. 
General Considerations .....................................................................................74 
8.4. 
Efficacy Analysis ..............................................................................................74 
8.4.1. 
Primary Efficacy Outcome Measure ................................................................. 74 
8.4.2. 
Justification of the Non-inferiority Margin ....................................................... 74 
8.4.3. 
Secondary Efficacy Outcome Measures ........................................................... 75 
8.4.4. 
Methods for the Control of Type I Error ........................................................... 75 
8.5. 
Safety Analysis .................................................................................................76 
8.6. 
Pharmacokinetic Analysis .................................................................................77 
8.7. 
Interim Analysis ................................................................................................77 
9. 
REFERENCES ....................................................................................................78 
10. 
APPENDICES .....................................................................................................80 
Appendix 1 
Modified Observer’s Assessment of Awareness/Sedation (MOAA/S) 
Scale ..................................................................................................................80 
Appendix 2 Bispectral Index (BIS)....................................................................................81 
Appendix 3 Numerical Rating Scale (NRS) for Grading of Injection-site Pain ................82 


 
 
 
 
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Appendix 4 Brice Awareness Questionnaire .....................................................................83 
Appendix 5 
Pharmacokinetic (PK) Blood Samples Collection Timetable ....................85 
Appendix 6 
American Society of Anesthesiologists (ASA) Physical Status Grade .....86 
Appendix 7 
Mallampati Classification ..........................................................................87 
Appendix 8 
Drugs that May Prolong the QT Interval ...................................................88 
Appendix 9 
Adverse Event Definitions .........................................................................90 
Appendix 10 Clinical Laboratory Evaluations ..................................................................94 
Appendix 11 Regulatory, Ethical, and Study Oversight Considerations ...........................96 
Appendix 12 Study design (a larger version) ..................................................................100 
Appendix 13 Detailed Summary of Changes...................................................................101 
 


 
 
 
 
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LIST OF FIGURES 
Figure 1     Study design ............................................................................................................ 6 
Figure 2  The BIS Index is scaled to correlate with important clinical endpoints during 
administration of anesthetic agent. ............................................................................................... 81 
Figure 3  BIS Index Range: A Continuum of Clinical State and EEG Changes ....................... 82 


 
 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
Adverse Event of Special Interest 
ASA-PS 
American Society of Anesthesiologists Physical Status 
BIS 
bispectral index 
BMI 
body mass index 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CRA 
clinical research associate 
CRO 
Contract Research Organization 
CSA 
clinical study agreement 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
diastolic blood pressure 
DMC 
data monitoring committee 
DSS 
Drug Safety Services 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EEG 
electroencephalogram 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
HR 
heart rate 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
IV 
intravenous 
IXRS 
Interactive Voice/Web Response Technology 
IMP 
Investigational Medicinal Products 
kg 
kilogram 
L 
Liter  
LBW 
lean body weight 
LR 
Lactated ringer’s 
ISD 
Initiation of study drug 
MAP 
mean arterial pressure 
mcg 
microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 


 
 
 
 
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Abbreviation 
Definition 
min 
minute 
mL 
milliliter 
MOAA/S 
Modified Observer’s Assessment of Awareness/Sedation 
NIM 
non-inferiority Margin 
NRS 
Numeric Rating Scale 
NS 
normal saline 
NMPA 
National Medical Products Administration 
NDA 
New Drug Application 
PACU 
post-anesthesia care unit 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPS 
Per Protocol Set 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RBC 
red blood cell 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SpO2 
oxygen saturation 
SS 
Safety Set 
SUSAR 
suspected unexpected serious adverse reaction 
TBW 
total body weight 
TEAE 
treatment-emergent adverse event 
Temp 
temperature 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
WBC 
white blood cell 
 
 


 
 
 
 
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1. INTRODUCTION 
Propofol is one of the most widely used intravenous (IV) anesthetics in clinical procedures. It 
induces anesthesia effectively, produces a short duration of anesthesia that allows subjects to 
recover quickly, and is widely used in the induction and maintenance of general anesthesia for 
surgery and out subject surgical procedures. However, propofol also comes with pronounced 
shortcomings, in particular, pain on injection [1], propofol-induced decrease in diastolic blood 
pressure (DBP) and mean arterial pressure (MAP), respiratory depression [2], and excessive lipid 
intake causing subjects to suffer from disorders of lipid metabolism, etc. 
HSK3486 injectable emulsion (hereinafter referred to as HSK3486) is a new IV anesthetic drug 
developed by Sichuan Haisco Pharmaceutical Co., Ltd. HSK3486 is intended to be used in the 
induction of adult sedation/general anesthesia. HSK3486 has a novel structural design that 
provides higher potency compared to propofol, and potentially results in less site pain and 
cardiopulmonary instability. Clinical data to date demonstrated HSK3486 significantly reduces 
pain on injection and reduces hypotensive effects while still providing anesthesia induction rates 
equivalent to propofol. 
1.1. Study Rationale 
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. The objective of this study is to 
demonstrate that HSK3486 is non-inferior to propofol in the induction of general anesthesia and, 
furthermore, to demonstrate better anesthetic effects (i.e., desired depth of anesthesia) compared 
to propofol with potential for less cardiac and respiratory depression. Clinical signs of inadequate 
depth of sedation during endotracheal intubation include tachycardia, hypertensive response, 
preserved reflexes (e.g., coughing), bronchospasm, movement on painful stimuli, and a 
bispectral index (BIS) score >60 (Appendix 2). Cardiovascular responses have been found to be 
sensitive indicators of noxious stimuli (e.g., endotracheal intubation) during general anesthesia 
[3,4]. The primary endpoint is successful induction of anesthesia defined by Modified Observer’s 
Assessment of Awareness/Sedation (MOAA/S) ≤1 without >1 top-up doses. A key secondary 
endpoint requires inducing a desired depth of anesthesia without cardiac and respiratory 
depression for 15 minutes post initiation of the study drug administration, which is defined by 
meeting all of the following: no lacrimation, movement, vomiting, coughing, laryngospasm, 
bucking, swallowing reflex and/or bronchospasm, etc.; no blood pressure (BP) increase >20% 
from baseline; and a BIS score <60. Furthermore, subjects must not exhibit a decrease in BP 
requiring intervention, or significant respiratory depression or apnea requiring intervention prior 
to pharmacologic paralysis for intubation. Incorporating these criteria into a composite endpoint 


 
 
 
 
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provides a multidimensional approach to assessing an ideal depth of anesthesia which is 
clinically meaningful and relevant.   
Results from the Phase 3 HSK3486-302 study showed that fewer subjects treated with HSK3486 
compared to propofol demonstrated inadequate depth of anesthesia for 15 minutes post-dose as 
indicated by an increase in BP >20% or heart rate (HR) >30% from baseline, or BIS score >60 
(HSK3486 24% compared to propofol 46%, p=0.0026). These data support using the composite 
secondary endpoint and thus has the ability to show a statistically significant difference between 
HSK3486 versus propofol in achieving the desired depth of anesthesia for induction of general 
anesthesia. 
1.2. Background 
Induction of general anesthesia refers to the transition in a patient's status from an awake state to 
an anesthesia state in which the patient can then be operated.  
Propofol is widely used clinically and has become the most commonly used IV anesthetic for the 
induction of general anesthesia in clinical practice due to its fast onset, rapid recovery, high 
clearance, and convenient target-controlled IV slow injection. However, when propofol is given 
at its traditional induction dose (2.0-2.5 mg/kg), a single loading dose can cause severe 
hemodynamic fluctuations, resulting in a significant drop in the patient’s blood pressure, i.e., 
15% to 40% [6,7], especially in elderly patients [8]. At the same time, the incidence of 
respiratory depression is also high when propofol is used; in addition, as the most common 
adverse reaction of propofol [5], injection-site pain increases the stress and anxiety of the patient, 
directly or indirectly affecting the smoothness of anesthesia induction. Due to these 
shortcomings, a new and more advantageous sedative/anesthetic is needed in the market. 
Pain on injection is one of the key indicators in clinical trials. Methods employed in many 
clinical practices to alleviate pain on propofol injection have demonstrated negligible effects [1]. 
Pain on propofol injection is widely believed to be related to the aqueous phase concentration of 
the drug in the lipid emulsion formulation [9].  
The active ingredient HSK3486 is a chemical entity similar to propofol. It is a single 
diastereomer with 2 R-type chiral centers; the strategy in the medicinal design of HSK3486 is to 
realize systematic improvement in the pharmacological and physicochemical properties of the 
drug-receptor binding, thereby resulting in a compound that is expected to be clinically superior 
to propofol. HSK3486 has the pharmacodynamic (PD) characteristics of fast onset and quick 
stable recovery. HSK3486 has better target selectivity and higher in vitro and in vivo activities 
than propofol, and its potency is approximately 4 to 5 times that of propofol; the free HSK3486 
concentration in water phase measured by "ultrafiltration" is lower than that of propofol (MCT 


 
 
 
 
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Fresenius), suggesting that the injection pain of HSK3486 may be reduced or eliminated versus 
propofol. 
The primary mechanism of action for HSK3486 is to enable chloride ion influx by enhancing the 
GABAA-mediated ion channel, so as to inhibit the central nervous system. This channel is also a 
major target of propofol action. 
As of Sept 2022, 26 Phase I to III clinical studies evaluating HSK3486 have been completed and 
4 are ongoing or planned. Among the 26 completed studies, a total of 1202 were enrolled in the 
HSK3486 group for observation (94 in Australia + 1108 in China), including 286 healthy 
subjects (including 24 elderly), 16 subjects with mild to moderate liver damage, 20 subjects with 
mild to moderate renal damage, 236 patients who underwent colonoscopy, 15 subjects who 
underwent gastroscopy, 278 subjects who underwent elective surgery, 135 subjects who 
underwent bronchoscopy, 126 subjects with mechanical ventilation in ICU, and 90 subjects 
undergoing gynecology outpatient surgery. Results showed that HSK3486 is generally safe and 
well tolerated. HSK3486 featured quick onset, rapid pace of regaining consciousness, and 
approximately 4 to 5 times the potency of propofol. At the same time, compared with propofol 
the incidence of injection pain is extremely low, less respiratory depression, lower incidence of 
hypotension, and less impact on the circulatory system.  
HSK3486 was approved by the NMPA for "Sedation in Gastrointestinal Endoscopy" and 
"Induction of General Anesthesia" on December 11, 2020 and February 2, 2021, respectively. 
The NDA registration applications for the indications of "sedation for bronchoscopy diagnosis 
and treatment" and "general anesthesia induction and maintenance" were accepted by the NMPA 
on February, 2021 and June, 2021, respectively. 
For more details of clinical studies of HSK3486 conducted, please refer to the Investigator’s 
Brochure [10]. 
1.3. Benefit-risk Assessment 
To date, 26 completed Phase I to III clinical studies of HSK3486 have been carried out and a 
total of 1202 subjects have been exposed to HSK3486. Analysis of data from 1202 subjects has 
been completed. HSK3486 was generally safe and well tolerated. HSK3486 had better 
performance than propofol, as manifested by the following: the types of adverse reactions were 
generally comparable with those of propofol but with a slightly lower incidence; however, the 
incidence of injection-site pain was significantly lower than propofol, the incidence of dizziness 
and respiratory-related AEs as well as the proportion of subjects in need of airway management 
were lower than propofol, the incidence and extent of AEs of cardiovascular depression were 
comparable to those of propofol. 


 
 
 
 
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HSK3486 showed rapid onset of general anesthesia, less airway reactivity during endotracheal 
intubation (e.g., coughing), relatively stable vital signs, time to successful induction comparable 
to or slightly better than that of propofol (refer to Propofol US PI 2017), and potency 
approximately 4 to 5 times than that of propofol in 156 enrolled subjects undergoing an elective 
surgery; it meets the needs of general anesthesia induction during surgery well.  
To date, HSK3486 has been shown to be a safe and effective sedative/anesthetic in prior clinical 
trials that is suitable for induction of general anesthesia.  
Phase III studies in the US will be conducted to further evaluate the efficacy and safety of 
HSK3486. In these Phase 3 studies, study drug will be administered preoperatively in a 
controlled clinical setting by healthcare providers who have experience in general anesthesia. 
Changes in vital signs will be closely monitored during anesthesia, and corresponding risk 
preventions and control measures will be implemented for known drug reactions such as 
hypotension and sinus bradycardia, so as to ensure the safety of subjects in clinical studies. An 
independent data monitoring committee (DMC) will be involved in the conduct of this study to 
maintain the safety of all subjects dosed with the study drug. 
In summary, the safety profile of propofol has been well described based on its clinical use over 
the past several decades. In 24 clinical studies thus far, HSK3486 has demonstrated a safety 
profile comparable to propofol, with potentially less cardiopulmonary instability, coupled with 
the additional benefit of less injection-site pain. The favorable benefit-risk assessment supports 
the continued evaluation of HSK3486 for induction of general anesthesia. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of HSK3486 may be found in the Investigator’s Brochure [10].  


 
 
 
 
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2. OBJECTIVES AND ENDPOINTS 
2.1. Objectives 
The primary objective of this study is: 
 To demonstrate HSK3486 0.4/0.2 mg/kg (0.4 mg/kg IV slow injection for the first dose, an 
additional 0.2 mg/kg dose if needed) is non-inferior to propofol 2.0/1.0 mg/kg (2.0 mg/kg IV 
slow injection for first dose, an additional 1.0 mg/kg dose if needed) in success of induction 
of general anesthesia in adults undergoing elective surgery. 
The secondary objectives of this study are: 
Key secondary objectives: 
 To confirm that HSK3486 0.4/0.2 mg/kg leads to statistically significant less injection-site 
pain in all compared to propofol 2.0/1.0 mg/kg during the induction of general anesthesia in 
adults undergoing elective surgery. 
 To demonstrate HSK3486 0.4/0.2 mg/kg provides better anesthetic effects compared to 
propofol 2.0/1.0 mg/kg without significant cardiac and respiratory depression in conjunction 
with other routinely used preinduction and maintenance anesthetic agents in the induction of 
general anesthesia in adults undergoing elective surgery. 
Additional Efficacy Objective: 
 To evaluate HSK3486 0.4/0.2 mg/kg induction time in general anesthesia compared to 
propofol. 
 To evaluate HSK3486 0.4/0.2 mg/kg time to the disappearance of eyelash reflex compared to 
propofol. 
 To confirm that HSK3486 0.4/0.2 mg/kg leads to statistically significant less moderate 
injection-site pain compared to propofol 2.0/1.0 mg/kg during the induction of general 
anesthesia in adults undergoing elective surgery. 
 To better characterize that HSK3486 0.4/0.2 mg/kg leads to statistically significant less 
average NRS scales in injection-site pain compared to propofol 2.0/1.0 mg/kg during the 
induction of general anesthesia in adults undergoing elective surgery. 
Safety: 
 To evaluate the overall safety profile of HSK3486 compared to propofol. 
Pharmacokinetic:  
 To characterize the HSK3486 population pharmacokinetic (PK) profile. 


 
 
 
 
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2.2. Endpoints 
The primary efficacy endpoint is: 
 Success rate of general anesthesia induction: A successful general anesthesia induction will 
meet both of the following conditions: 
a) Induction success (MOAA/S ≤1) after administration of the study drug, and 
b) One or less top-up dose required without using any rescue drugs. 
 
The secondary efficacy endpoints are: 
Key secondary endpoints: 
 The proportion of subjects with any injection-site pain at time of drug administration on the 
Numeric Rating Scale (NRS ≥1). 
 
 The proportion of subjects with successful induction who maintain the desired depth of 
anesthesia for general elective surgery, and without significant cardiac and respiratory 
depression within 15 minutes post initiation start of study drug administration, or up to the 
start of second tracheal intubation attempt if it is a difficult condition and not beyond 15 
minutes post initiation study drug administration, 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). 
Note: Target BIS 40-60 for general anesthesia (Appendix 2). 
The BIS sustainable level at not more than 60 is defined as not more than 1 episode 
with BIS value observed >60 after reaching initial lowest value, in defined period. 
Note: It is strongly recommended that each site have available video laryngoscopy, or an 
acceptable alternative, for unanticipated difficult tracheal intubation. If more than one 
tracheal intubation attempt is made, the start and end times of first and subsequent 
intubation attempts should be recorded. 


 
 
 
 
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b) No significant respiratory depression, such as apnea, prior to the administration of 
rocuronium bromide.  
Note: For the composite endpoint, respiratory depression includes apnea, defined as 
absence of thoracic movement lasting >30 seconds, or hypoxia, defined as oxygen 
saturation (SpO2) <90% lasting >30 seconds, or life-threatening respiratory 
depression requiring immediate intervention. 
c) No significant cardiac depression indicated by BP decrease that requires intervention, 
i.e., vasopressors and/or IV fluid resuscitation. 
Note: For the composite endpoint, cardiac depression is defined as SBP <90 mmHg 
lasting >2 minutes plus requiring medical intervention such as inotropes, 
vasopressors, or IV fluid resuscitation, or life-threatening hypotension requiring 
immediate intervention. 
Other secondary endpoints: 
 Time to successful induction of general anesthesia: Time from the end of the first 
administration of the study drug to MOAA/S ≤1. 
 Time to the disappearance of eyelash reflex: Time from the end of the first administration of 
the study drug to the disappearance of eyelash reflex. 
 The proportion of the subjects with any moderate injection-site pain at time of drug 
administration on the Numeric Rating Scale (NRS ≥4). 
 The average injection site pain at time of drug administration of HSK3486 compared to 
propofol on NRS.     
The safety endpoints are: 
 Safety assessments include AEs, adverse events of special interest (AESI), clinical laboratory 
test results, vital signs (supine HR, SBP and DBP, MAP, RR, and SpO2), electrocardiogram 
(ECG) findings, physical examination findings, and administration of additional medications, 
or any interventions including medical interventions, e.g., administration of vasoactive drugs 
to treat clinically relevant changes in BP. 
The PK endpoint is: 
 Plasma HSK3486 concentration at scheduled time points (Appendix 5). 


 
 
 
 
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3. INVESTIGATION PLAN 
3.1. Overall Study Design and Plan 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 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 if needed) in a blinded manner. Enrolled 
subjects will be stratified by American Society of Anesthesiologist 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. 
On Day 1, premedication is allowed prior to induction except for sedative hypnotics, analgesics 
(eg., opioids, NSAIDs, APAP), or any medications that relieve pain (eg., Gabapentin), unless 
otherwise specified in the protocol. Premedication should be recorded if used. 
Assessments and procedures completed prior to the administration of the study drug in the 
operating room, the preinduction period, induction period, maintenance period and the follow-up 
period can be found in Section 7 – Study Assessments and Procedures. 
Population PK Study 
All eligible subjects in this clinical study will be required to provide venous blood samples for 
population PK study per time schedule planned (Appendix 5). 
3.2. Discussion of Study Design, Including the Choice of Control Groups 
Propofol is selected as the rescue/alternative drug (trade name: Diprivan). Given that propofol is 
the most common IV drug for anesthesia, should induction fail, the investigator, based on the 
status of the subject, should give propofol as the first choice of rescue medication; however, 
based on the discretion of the investigator, an alternative drug may be administered at the 
appropriate dose and timing as determined by the investigator. 
The population in this study includes subjects undergoing elective surgeries that require 
endotracheal intubation under general anesthesia. For safety considerations, subjects undergoing 
emergency, cardiothoracic, and intracranial surgeries are excluded. 


 
 
 
 
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3.3. End of Study Definition 
The end of the study is defined as the date of the last visit of the last subject in the study. 
3.4. Selection of Doses in the Study 
3.4.1. 
Selection of Dose for HSK3486 
By analyzing the results of the dose-ascending group and the extension stage (primary) in the 
Phase II study of HSK3486 for induction of general anesthesia, the following can be seen that: 
 Dose selection: Although the efficacy of the 0.5mg/kg HSK3486 group was comparable to 
that of the 2.0mg/kg propofol group, the efficacy of the 0.5mg/kg HSK3486 group was 
slightly better than that of the 0.3mg/kg and 0.4mg/kg HSK3486 groups, as manifested by a 
faster rate of successful induction and a shorter intubation time. In addition, the 0.5mg/kg 
HSK3486 group did not need top-up doses. However, the safety of the 0.5mg/kg HSK3486 
group was slightly worse, as manifested by a larger decrease in BP, higher incidence of 
injection pain than 0.3 mg/kg HSK3486, and more cases of transient and prolonged QT 
interval. The 0.3mg/kg HSK3486 group showed better safety and a relatively small 
proportion of adverse drug reactions (ADRs). However, compared with the propofol group, 
the 0.3mg/kg group had longer time to successful induction, more obvious intubation 
reactions, and larger fluctuations in BP and HR, suggesting that the inhibitory effect of 
0.3 mg/kg HSK3486 on intubation reactions is not strong enough. At a suitable dose, 
HSK3486 can be used to induce general anesthesia with a reliable efficacy and safety profile. 
Based on above considerations, it is reasonable to choose the dose of 0.4 mg/kg (initial 
dose)/0.2 mg/kg (top-up dose) as the recommended HSK3486 dose for Phase III clinical 
studies. 
 Number of top-up doses and dosing interval: Based on the results of Phase II study for 
induction of general anesthesia, during induction, 1 (1/8) subject in the dose-escalation group 
(HSK3486 0.4/0.2mg/kg group) received 1 top-up dose of study drug, and 1 (1/22) subject in 
the dose-extension stage (0.3/0.15mg/kg group) received 1 top-up dose of study drug. The 
time to successful induction was about 0.71 to 1 minute. Therefore, in the design of Phase III 
study on induction of general anesthesia, the top-up dose is set at 1 minute ±10 seconds after 
the initial dose of the study drug. If the number of top-up doses is more than 1, the induction 
is considered to have failed. 
 Criteria for the selection of top-up dose: The criteria for a top-up dose in the Phase III study 
of induction of general anesthesia are based on the results of the previous Phase II and III 
studies in China and are determined according to the MOAA/S score, i.e., if MOAA/S ≤1 is 
not reached, a top-up dose is required. 
 A 25% dose reduction is required for elderly subjects ≥65 years of age for both HSK3486 


 
 
 
 
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and propofol. For elderly subjects ≥65 years of age, the dose will be automatically adjusted 
to a 25% dose reduction. According to the judgment of the investigator, the dose can be 
further reduced by up to 50%. For ASA grade 3-4 subjects, the dose can be reduced by 25-
50% per investigator discretion. The administration time should be extended to 1 minute for 
these populations. 
 Data from a PK study in elderly subjects (Study HSK3486-108) suggests that there are no 
significant differences in the PK exposures at 0.4 mg/kg between elderly (≥65 years old) and 
non-elderly (<65 years old), consistent with physiologically based PK modeling results. A 
similar efficacy and safety profile was also demonstrated between 0.3 mg/kg elderly and 0.4 
mg/kg non-elderly. Of note, both propofol US and UK labels currently recommend a 25% 
dose reduction in subjects 65 or older. 
  The HSK3486 dose will be modified for obese subjects: for subjects with BMI ≤40 kg/m2, 
total body weight (TBW) will be used to determine dose; for subjects with BMI >40 kg/m2, 
lean body weight (LBW) will be used to determine dose. 
 Based on population PK (PopPK) modeling, subjects with BMI >45 kg/m2 can be expected to 
have higher simulated maximum concentration (Cmax) and area-under-the-curve (AUC[0-24 h]) 
than the PK exposure identified in the Phase 1 single-ascending-dose studies. 
 In obese subjects, fat mass and LBW do not increase proportionately. Obese subjects have 
both an increased amount of fat and LBW; however, LBW accounts for as much as 20% to 
40% of the excess TBW. The LBW has been shown to correlate with cardiac output, which is 
an important determinant in the early distribution kinetics of drugs. Based on published 
literature, LBW is the ideal weight scalar for drug administration in subjects with BMI >40 
[11, 12]. 
 The anesthetic PD response in subjects with BMI >40 kg/m2 is likely to be different. It has 
been reported that morbidly obese subjects have significantly decreased half-maximal 
effective concentration (EC50) values compared to control subjects, which suggests increased 
brain sensitivity to propofol in the morbidly obese population [13, 14]. 
3.4.2. 
Selection of Dose for Propofol 
Propofol has the characteristics of fast onset, rapid recovery, high clearance, and convenient 
target-controlled slow injection. It has become the most commonly used IV anesthetic in clinical 
practice. Among various propofol products, Diprivan is the most widely used both domestically 
and overseas; therefore, propofol is selected as the positive control drug.  
Rationale for the selection of the initial and top-up doses of propofol:  
In the packaging insert of propofol [9], the dose for inducing general anesthesia is 2.0 to 2.5 
mg/kg. The results of the dose-ascending and extension stages of Phase II trials on induction of 
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rate in induction of general anesthesia with good safety and tolerability. Among them, 2.5 mg/kg 
was found to have a higher incidence of ADRs during dose escalation, so 2.0 mg/kg was selected 
as the control dose in the extension stage; in summary, to better compare the differences in the 
efficacy and safety of HSK3486 and propofol, 2.0 mg/kg of propofol has been selected as the 
initial dose, and the top up- dose is the same as that in the design of the Phase II study on 
induction of general anesthesia, i.e., 1.0 mg/kg. 
The propofol dose will be modified for obese subjects to match HSK3486 dosing regimens due 
to similar rationales as HSK3486 noted above: for subjects with BMI ≤40 kg/m2, TBW will be 
used to determine dose; for subjects with BMI >40 kg/m2, LBW will be used to determine dose. 
3.5. Data Monitoring Committee 
An independent DMC will be involved in the conduct of the study to ensure the safety and well-
being of all subjects who have been administered study drug is maintained. The DMC will 
consist of 3 unblinded members: 2 anesthesiologists with appropriate clinical expertise and 1 
statistician. The DMC will review all available unblinded safety information at approximately 
30% enrollment. Additionally, enrollment will be immediately stopped after one death during the 
study where a clear alternative cause is not readily apparent (i.e., deemed definitely or likely 
related to study drug); after 4 (4/399 [1%]) non-fatal serious adverse events (SAEs) where a clear 
alternative cause is not readily apparent (i.e., deemed definitely or likely related to study drug); 
or after 8 (8/399 [2%]) severe AEs of special interest (AESIs; Common Terminology Criteria 
[CTCAE] Grade 3 and 4) of severe hypotension, bradycardia, hypoxia due to respiratory 
depression, or QTc prolongation occurring within 15 minutes of study drug administration, 
where a clear alternative cause is not readily apparent (i.e., deemed definitely or likely related to 
study drug), and lasting ≥10 minute duration despite routine interventions. AESIs of 
allergy/anaphylaxis or cardiac arrhythmia occurring from the initial dose of study drug until Day 
2 where a clear alternative cause is not readily apparent will be evaluated as part of the stopping 
criteria. If these criteria are met, enrollment will be temporarily suspended while the DMC 
convenes to review all available unblinded data. Based on recommendations from the DMC, the 
Sponsor can terminate the study or resume enrollment if measures can be taken to effectively 
address (i.e., mitigate) the risk to safely continue the study, such as revising inclusion/exclusion 
criteria or study procedures. The final decision to suspend enrollment or proceed will be made by 
the Sponsor after consultation with the DMC members and taking into consideration their 
recommendations. Conduct of the DMC is described in the DMC Charter.  
 


 
 
 
 
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4. SELECTION OF STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
4.1. Inclusion Criteria 
Subjects must satisfy all of the following criteria at the screening and Day 1 visits: 
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 a 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. 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. 
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 hospitalization 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). 
 


 
 
 
 
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4.2. Exclusion Criteria 
Subjects will be excluded from the study if they satisfy any of the following criteria at the 
screening or Day 1 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; 
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: 
a) 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 
b) 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). 
c) Cerebrovascular disease: subject with a history of serious craniocerebral injury, 
convulsion, seizure disorder, intracranial hypertension, cerebral aneurysm, or stroke.  
d) Patients with psychiatric/mental disorders who have not been on a stable treatment 
regimen (e.g., SSRIs, SNRIs, TCAs, MAOIs, psychotherapy) for at least 1 year or 
who have been hospitalized or had emergent/urgent care within the past year. 
e) 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. 
f) Known glycosylated hemoglobin (HbA1c) greater than or equal to 10%. 


 
 
 
 
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g) 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. 
h) 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).  
i) 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: 
a) 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. 
b) History (or family history) of malignant hyperthermia. 
c) Any previous failure of tracheal intubation. 
d) 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: 
a) Neutrophil count ≤1.5 x 109/L 
b) Platelet count <80 x 109/L 
c) Hemoglobin <90 g/L (without blood transfusion within 14 days) 
d) Alanine transaminase and/or aspartate transaminase ≥2.0 x upper limit of normal 
(ULN) 
e) Total bilirubin ≥2.0 x ULN 
f) 
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. 


 
 
 
 
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4.3. Subject Discontinuation from the Study 
Subject discontinuation from the study criteria will include but is not limited to the following: 
1. Withdrawal of informed consent; 
2. If it is believed that continued participation in the study will be detrimental to the 
subject’s health as determined by the investigators and Sponsor's medical personnel; or 
3. Other. 
Subjects may withdraw from the study at any time at his/her own request or may be withdrawn at 
any time at the discretion of the investigator for safety, behavioral, or administrative reasons. 
Subjects should complete pre-withdrawal examinations as much as possible (same as the 
follow-up examinations) prior to withdrawal. For subjects who prematurely withdraw from the 
study, the investigator should ask for the reasons for withdrawal and record in the original 
documents and electronic Case Report Form (eCRF) and complete the test items for the end of 
study visit. During the study, if it is found that a female subject or the sexual partner of a male 
subject is pregnant, the investigator must immediately report it to the Sponsor and the Ethics 
Committee (EC). All relevant information must be recorded in the source file and the eCRF. 
4.3.1. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure subjects to meet the Consolidated Standards of Reporting 
Trials publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAEs. 
Subjects who do not meet the criteria for participation in this study may be rescreened once 
within 60 days. Re-screening must be approved by the medical monitor if the screen fail reason 
is anything other than the screening window has elapsed. Rescreened subjects should be assigned 
the same subject number as the initial screening. 
4.3.2. 
Subject Discontinuation from Study Treatment 
If a subject experiences an AESI of severe hypotension, bradycardia, hypoxia due to respiratory 
depression, QTc prolongation, cardiac arrythmia, or allergy/anaphylaxis which persists despite 
routine interventions and does not achieve MOAA/S ≤1 after the initial dose of study drug thus 
requiring a top-up dose, the subject should stop study treatment and not receive the top-up dose. 
It is up to the discretion of the Investigator and surgeon whether to proceed with the surgery 
using alternative standard-of-care medications to induce general anesthesia. Subjects who stop 


 
 
 
 
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study treatment will remain in the study and continue to be followed for safety assessments 
according to the Schedule of Assessments.   
If the subject withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. Additionally, subjects 
may request destruction of any samples taken and not tested, and the investigator must document 
this in the site study records. Refer to the Schedule of Assessments for data to be collected at the 
time of study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
Additional reasons for study treatment discontinuation can include, but are not limited to: 
 Death 
 Adverse event 
 Sponsor determination 
 Investigator discretion 
 
4.3.3. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit or declines a phone contact (phone visit) by study site: 
 The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible, counsel the subject on the importance of maintaining the assigned visit schedule 
and ascertain whether or not the subject wishes to and/or should continue in the study. 
 In cases in which the subject is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject’s medical record. 
 Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up. 
 
4.3.4. 
Replacement Procedures 
Subjects who discontinue or withdraw from the study will not be replaced. 


 
 
 
 
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4.3.5. 
Follow-up of Subjects Prematurely Discontinued from the Study Treatment 
Regimen or Withdrawn from Study 
Subjects who discontinue from the study will be asked to complete final study procedures and 
will be contacted for the Follow-up Telephone Call as described in the Schedule of Assessments. 
All SAEs that are ongoing at the time of discontinuation, or that develop prior to the final 
Follow-up Telephone Call, will be followed for 30 days, or until resolution or stabilization. 
4.4. Study Stopping Criteria 
Enrollment will be immediately stopped after one death where a clear alternative cause is not 
readily apparent (i.e., deemed definitely or likely related to study drug); after 4 (4/399 [1%]) 
non-fatal serious adverse events (SAEs) where a clear alternative cause is not readily apparent 
(i.e., deemed definitely or likely related to study drug); or after 8(8/399 [2%]) severe AEs of 
special interest (AESIs; Common Terminology Criteria for Adverse Events [CTCAE] Grade 3, 4 
or 5) of severe hypotension, bradycardia, hypoxia due to respiratory depression, or QTc 
prolongation occurring within 15 minutes of study drug administration, where a clear alternative 
cause is not readily apparent (i.e., deemed definitely or likely related to study drug), and lasting 
≥10 minute duration despite routine interventions. AESIs of allergy/anaphylaxis or cardiac 
arrhythmia occurring from the initial dose of study drug until Day 2 where a clear alternative 
cause is not readily apparent will be evaluated as part of the stopping criteria. If these criteria are 
met, enrollment will be temporarily suspended while the DMC convenes to review all available 
unblinded data. Based on recommendations from the DMC, the Sponsor can terminate the study 
or resume enrollment if measures can be taken to effectively address (i.e., mitigate) the risk to 
safely continue the study, such as revising inclusion/exclusion criteria or study procedures. The 
final decision to suspend enrollment or proceed will be made by the Sponsor after consultation 
with the DMC members and taking into consideration their recommendations. Conduct of the 
DMC is described in the DMC Charter. 
The determination of thresholds to suspend enrollment incorporates safety data from the prior 
Phase 3 study in China (Study HSK3486-302) evaluating HSK3486 compared to propofol for 
induction of general anesthesia in subjects undergoing elective surgery. In that study, 1 (1/176 
[0.6%]) propofol-treated subject experienced an SAE of bronchospasm (deemed unlikely related 
to study drug), and 2 (2/176 [1%]) subjects experienced severe AESIs of hypotension (deemed 
related to study drug; 1 HSK3486-treated subject and 1 propofol-treated subject). However, the 
prior Phase 3 study in China enrolled a healthier subject population, in that only ASA-PS class I 
to II subjects, no elderly subjects (age >65), and no obese subjects (BMI>30) were included.  
Inclusion criteria for the current study includes ASA-PS class III to IV subjects, elderly subjects 
(age >65 years with no upper limit), and obese subjects (BMI >30 with no upper limit). It is 
anticipated this study will enroll a less healthy subject population with more comorbidities, 
therefore, thresholds to suspend enrollment of 4 (4/399 [1%]) non-fatal SAEs related to study 


 
 
 
 
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drug and 8 (8/399 [2%]) severe AEs of special interest (CTCAE grade 3 and 4) of severe 
hypotension, bradycardia, hypoxia due to respiratory depression or QTc prolongation occurring 
within 15 minutes of study drug administration or allergy/anaphylaxis or cardiac arrhythmia 
occurring within 2 days of study drug administration have been selected using clinical 
judgement. 
The Sponsor reserves the right to close a study site or terminate the study at any time for any 
reason at the sole discretion of the Sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study site closure visit has been performed.  
Reasons for study termination may include, but are not limited to: 
 Adverse events unknown to date (i.e., not previously reported in any similar investigational 
study drug trial with respect to their nature, severity, and/or duration); 
 Increased frequency and/or severity and/or duration of known, anticipated, or previously 
reported AEs (this may also apply to AEs defined at check-in as baseline signs and 
symptoms); 
 Medical or ethical reasons affecting the continued performance of the study; 
 Difficulties in the recruitment of subjects; 
 Cancellation of drug development. 
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.  
Reasons for the early closure of a study site by the Sponsor or investigator may include, but are 
not limited to: 
 Failure of the investigator to comply with the protocol, the requirements of the Institutional 
Review Board (IRB)/EC or local health authorities, the Sponsor's procedures, or GCP 
guidelines 
 Inadequate recruitment of participants by the investigator. 


 
 
 
 
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5. STUDY TREATMENTS 
5.1. Treatments Administered 
Investigational drug: HSK3486 injectable emulsion  
Specification: 20 mL: 0.05 g  
Supplier: Sichuan Haisco Pharmaceutical Co., Ltd. 
Control drug: Propofol injection  
Trade name: Diprivan 
Strength: 20 mL: 0.2 g 
Supplier: Sichuan Haisco Pharmaceutical Co., Ltd. 
Before the study drugs are delivered to the study site, the drug packaging unit (non-blinded) and 
other non-blinded personnel are responsible for packaging and labeling the study drugs based on 
the maximum quantity of study drug that each site might require during the induction of general 
anesthesia to avoid the need to request more drugs during the course of the study. The study 
drugs for each subject shall be packaged individually. 
5.2. Preparation, Storage, Handling, and Accountability 
HSK3486 should be stored at ≤ 25 °C (77°F) away from light and should not be frozen. Propofol 
should be stored between 4°C and 25°C (40°F-77°F) and should not be frozen. Both HSK3486 
and propofol should be shaken well before use. The investigator or designee must confirm 
appropriate temperature conditions have been maintained during transit for all study treatment 
received and any discrepancies are reported and resolved before use of the study treatment. All 
study treatments must be stored in a secure, environmentally controlled, and monitored (manual 
or automated) area in accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff. 
The Sponsor will provide sufficient amounts of the study drugs during the study. After the 
Sponsor provides the study drug to the study site, the principal investigator or authorized 
representative will sign for receipt upon verification and record information of the study drugs. 
Once receiving the study drugs, the study site should store it under the storage conditions 
specified in the drug label. The study drugs should be kept by designated personnel 
(non-blinded) authorized by the investigator for regular accounting and record of the drug 
quantity. Non-blinded clinical research associates (CRAs) will supervise the drug management. 


 
 
 
 
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Only subjects enrolled in the study may receive study treatment and only trained and authorized 
site staff may supply or administer study treatment. The investigator, institution, or the head of 
the medical institution (where applicable) is responsible for study treatment accountability, 
reconciliation, and record maintenance (i.e., receipt, reconciliation, and final disposition 
records). The study drugs cannot be used for any purpose other than this clinical study, and it 
may not be sold or transferred to anyone who is not involved in this clinical study. 
The use of each study drug should be recorded in a timely manner with a signature upon review. 
All remaining drug products, packaging, and labels are returned or destroyed at the sites after 
Sponsor authorization during and after the study. Remaining empty vials and packages are 
destroyed and recorded according to the standard operating procedures at local study sites. 
Further guidance and information for the final disposition of unused study treatment are provided 
in the pharmacy manual. 
Drug Preparation 
On the day of drug administration, the non-blinded preparation personnel will locate the 
corresponding study drug according to the drug number applied by the Interactive Web Response 
System (IXRS) and convert the drug volume according to formula below; the drug will then be 
drawn into a certain number of syringes (1 initial dose + 1 top-up dose). In addition, the required 
alternative (rescue) drug for the subjects is also prepared. 
The non-blinded administration personnel will check the drug information recorded by the 
preparation staff and transfer the study drug to the operating room. Both the drug volume 
calculation and drug preparation processes should be documented in the drug dispensing record 
form. 
Staff for drug preparation and administration are non-blinded and must not disclose subject 
administration information to investigators, subjects, or any other blind personnel. 
Doses and method of administration for HSK3486 are as below: 
Volume of initial/top-up dose = dose group (mg/kg) x baseline body weight (kg) ÷ 2.5 mg/mL. 
HSK3486 is administered by using 30 [±5] seconds of slow injection. If a top-up dose is 
required, 50% of the initial dose is given via slow injection over 10 [±2] seconds. 
For elderly subjects ≥65 years of age, the dose will be automatically adjusted to a 25% dose 
reduction. According to the judgment of the investigator, the dose can be further reduced by up 
to 50% of the calculated dose. The administration time should be extended to 1 minute for this 
population. 


 
 
 
 
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For ASA grade 3-4 subjects, the dose can be reduced by 25-50% per investigator discretion. The 
administration time should be extended to 1 minute for these populations.  
For subjects with BMI ≤40 kg/m2, TBW will be used to determine HSK3486 dose; for subjects 
with BMI >40 kg/m2, LBW will be used to determine HSK3486 dose, and Rescue dose. LBW 
should be calculated using the Janmahasatian formula included below. 
The Janmahasatian Formula:  
• 
For males: LBW = (9270 x TBW (kg))/(6680 + (216 x BMI))  
• 
For females: LBW = (9270 x TBW (kg))/(8780 + (244 x BMI)) 
Doses and method of administration for propofol are as below: 
Volume of initial/top-up dose of propofol = dose group (mg/kg) x baseline body weight (kg) ÷ 
10 mg/mL. The method of administration of propofol is the same as that of HSK3486. 
For elderly subjects ≥65 years of age, the dose will be automatically adjusted to a 25% dose 
reduction. According to the judgment of the investigator, the dose can be further reduced by up 
to 50% of the calculated dose. The administration time should be extended to 1 minute for this 
population. 
For ASA grade 3-4 subjects, the dose can be reduced by 25-50% per investigator discretion. The 
administration time should be extended to 1 minute for these populations.  
For subjects with BMI ≤40 kg/m2, TBW will be used to determine propofol dose; for subjects 
with BMI >40 kg/m2, LBW will be used to determine propofol dose, and Rescue dose. LBW 
should be calculated using the Janmahasatian formula included below. 
The Janmahasatian Formula:  
• 
For males: LBW = (9270 x TBW (kg))/(6680 + (216 x BMI))  
• 
For females: LBW = (9270 x TBW (kg))/(8780 + (244 x BMI)) 
 
The rescue dose is prepared as 100% of the initial calculated dose and administered per propofol 
guidelines above. 
5.3. Method of Treatment Assignment 
The randomization of the subjects in this study is completed using the IXRS. After the subjects 
pass the screening, the investigator(s) or designee shall log into the IXRS and enter the general 
information of each subject, such as the screening number, sex, age, height, and body weight, to 


 
 
 
 
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obtain the randomization number. Then, the randomization number and corresponding treatment 
group are assigned using the IXRS and submitted to the drug preparation personnel (non-
blinded) for drug preparation. The non-blinded site staff will have to log into the IXRS to obtain 
the kit numbers and dosages. 
Study treatment will be dispensed at baseline visit summarized in the Schedule of Assessments.  
5.3.1. 
Dose Modification 
Dosage adjustments are not allowed unless these conditions are stipulated in the protocol. For 
elderly subjects ≥65 years of age, the dose will be automatically adjusted to a 25% dose 
reduction. According to the judgment of the investigator, the dose can be further reduced by up 
to 50% of the calculated dose. For ASA grade 3-4 subjects, the dose can be reduced by 25-50% 
per investigator discretion. The administration time should be extended to 1 minute for these 
populations. 
Both the HSK3486 and the propofol doses will be modified for morbidly obese subjects: For 
subjects with BMI ≤40 kg/m2, TBW will be used to determine dose; for subjects with BMI >40 
kg/m2, LBW will be used to determine dose. 
5.4. Blinding 
This is a double-blind study. The IXRS will be programmed with blind-breaking instructions. 
The study blind may be broken if, in the opinion of the investigator, it is in the subject’s best 
interest to know the study treatment assignment. Sponsor must be notified before the blind is 
broken unless identification of the study treatment is required for a medical emergency in which 
the knowledge of the specific blinded study treatment will affect the immediate management of 
the subject’s condition (e.g., antidote is available). In this case, Sponsor must be notified within 
24 hours after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation and eCRF, as applicable. 
The study staff are divided into 2 groups: blinded and non-blinded. The study ensures that the 
investigators, subjects, and the entire operating process of the study are blinded. 
Blinded staff include the principal investigator, study nurse, clinical research coordinator, 
blinded CRA, and all the other personnel involved in the documentation, assessment, analysis, 
and review of efficacy/safety endpoint data. These staff are primarily responsible for all study 
procedures other than drug management (such as subject screening, documentation, assessment, 
analysis, and review of efficacy and safety endpoints). 
The non-blinded staff are responsible for the management, preparation, and administration of the 
study drug. Detailed descriptions of blinding procedures are described in the Blinding Plan. 


 
 
 
 
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Once the study is started, both the blinded and non-blinded study staff ensure that their 
respective responsibilities are performed in strict accordance with protocol requirements. The 
blinded and non-blinded staff ensure that no communication related to study drug groups takes 
place to avoid unintentional unblinding. 
5.5. Treatment Compliance 
All study drugs will be administered at the site by site personnel; therefore, subject compliance 
will not be measured. 
5.6.  Preinduction Drugs 
Fentanyl and Midazolam 
All subjects will receive preinduction IV midazolam at dose 0.04 mg/kg, up to 3 mg maximum 
per subject over 15 [±2] seconds at 5 minutes [±30 seconds] prior to initiating induction agents 
as premedication. And all subjects will receive preinduction IV fentanyl 1 mcg/kg rounded up to 
the nearest 25 mcg, up to 100 mcg maximum. Fentanyl and midazolam doses can be reduced 
according to patient’s age and comorbidities as per the anesthetist’s discretion. Note: 
Administration of study drug must be initiated at 2 minutes [±10 seconds] after preinduction 
fentanyl administration stop time. 
 


 
 
 
 
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6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. Concomitant Therapies 
The investigator will review all medications and therapies taken by the subject (or are intended 
to be taken during the study) during screening and will assess whether or not the medications or 
therapies will impact the study.  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the subject is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
 reason for use 
 dates of administration including start and end dates 
 dosage information including dose and frequency. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Any medications/supplements/vitamins used by the subjects during Day of Surgery and after 
surgery until the end of the study (Day 8) are classified as concomitant medication except for 
study drugs.  
Any medications/supplements/vitamins used before the Day of Surgery are classified as previous 
medications. All previous medications used by the subjects within 1 month before screening 
should be recorded in the source medical record and the eCRF. 
A record of concomitant medication should consist of drug name (generic name), dose and 
number of daily doses, method of administration, start and end time of administration, and 
reason for use. 
Before the end of the surgery, antiemetics and hemostatics can be used according to the clinical 
situation of the subjects, and postoperative use of antibiotics, hemostatics, antiemetics, and 
analgesics can be determined by the investigators when needed. 
During the study, drugs that may affect the QT interval should be used with caution (Appendix 
8); in case of an emergency where such drugs must be used, please record the use of the drugs 
and the reason. 


 
 
 
 
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6.2. Prohibited Therapies 
No sedative hypnotics, anesthetic drugs, analgesics, systemic neuromuscular blocking agents or 
any medications that relieve pain other than those prescribed in the protocol are allowed on Day 
1 until the completion of endotracheal intubation, including but not limited to the following: 
 Inhalation anesthetics: isoflurane, enflurane, desflurane, halothane, anesthetic ether, nitrous 
oxide 
Note: Sevoflurane will be used for maintenance of general anesthesia upon the completion 
of endotracheal intubation. 
 Intravenous anesthetics: thiopental sodium, ketamine, etomidate, sodium oxybate 
 Systemic neuromuscular blocking agents (other than protocol-prescribed rocuronium): 
atracurium, cisatracurium, mivacurium, succinylcholine, vecuronium, pancuronium 
Note: Regional and local neuromuscular blocking agents and anesthetics are permitted if not 
involving the upper extremity where study drug is administered.   
 Analgesics: morphine, methadone, codeine, pentazocine, tramadol, NSAIDs, APAP etc. 
Note: Additional IV fentanyl may be administered for intraoperative analgesia only after 
initiation of sevoflurane, preferably after 15 minutes following the end of study drug 
administration.  
 Other drugs that relieve pain: Gabapentin 
 Benzodiazepines: Valium, Ativan, etc. 
 


 
 
 
 
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7. STUDY ASSESSMENTS AND PROCEDURES 
7.1. Study Procedures  
7.1.1. 
Screening Period (Day -13 to Day 1) 
During the screening period and before the investigator conducts any study procedures, he/she 
will discuss with subjects their clinical condition, the commonly used anesthesia methods, the 
characteristics of the study drug, and the possible adverse reactions that can be caused by the 
study drug. The subjects will sign the ICF and receive a signed copy.  
After signing the ICF, the subject will be assigned a screening number, and the following 
procedures/evaluations will be conducted as indicated in the Schedule of Assessments: 
 Assess inclusion/exclusion criteria. 
 Demographics. 
 Collect medical history (disease history, allergy history, alcohol history and surgical 
anesthesia history, etc.). 
 Prior medications. 
 Modified Mallampati score assessment (Appendix 7). 
 Physical examination, including ASA-PS score (Appendix 6). 
 Vital signs (HR, RR, SpO2, SBP, DBP, MAP, Temp) after the subject has been resting supine 
for ≥5 minutes. 
 Height, weight, and calculated BMI. 
 12-lead ECG. 
 Clinical laboratory tests (hematology, blood chemistry, and urinalysis, etc.). 
 HbA1c and TSH test (with free T-4 if TSH abnormal) will only be done during the screening 
period.   
 Conduct serum human chorionic gonadotropin (HCG) test (for women of childbearing 
potential only). 
 Instruct subject to fast at least 6 hours before surgery. Per investigator discretion, in 
otherwise healthy patients, clear liquids may be ingested for up to 2 hours prior to surgery. 
These liquids should not include alcohol. Examples of clear liquids include, but are not 
limited to, water and fruit juices without pulp, carbonated beverages, carbohydrate-rich 
nutritional drinks, clear tea, and black coffee. 
 Document AEs (after signing informed consent).  
During screening, the preference is for laboratory tests to be processed centrally to confirm 
eligibility. However, in cases where a separate screening visit is not feasible or the central 


 
 
 
 
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laboratory results are not available on Day 1, a study approved local laboratory may be used to 
confirm eligibility. In these cases, required screening laboratory samples must be drawn in 
parallel and sent to the central laboratory.     
Note: This study only collects the subjects' disease history within 6 months before screening and 
all previous medications used within 1 month before screening, and the above information 
should be recorded in the source medical record and the eCRF. 
7.1.2. 
Day of Surgery (Day 1) 
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). 
Height, weight, and BMI will be obtained prior to dosing study drug. The most recent BMI will 
be used to calculate study drug dose. 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 IV top-up dose 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 top-up 
dose if needed) in a blinded manner. 
All throughout the preinduction and induction periods a timing device must be used to allow 
accuracy and sequencing of necessary assessments.  
On the day of surgery, the following procedures as indicated in the Schedule of Assessments will 
occur: 
Prior to entering the operating room: 
• Refer to 7.1.1 for certain cases where local labs may be drawn to confirm eligibility. 
 Measure vital signs (HR, RR, SpO2, SBP, DBP, MAP, Temp) to confirm consistent with 
eligibility criteria (after the subject has been resting supine for ≥5 minutes). 
 Conduct urine human chorionic gonadotropin (HCG) test (for women of childbearing 
potential only). 
 Obtain 12-lead ECG if the screening ECG is more than 1-week from the baseline visit, the 
12-lead ECG should be repeated to assess its compliance with the inclusion/exclusion 
criteria. 
 Verify inclusion/exclusion criteria. 
 Height, weight, and calculated BMI. 
 Premedication allowed except sedative-hypnotics, analgesic drugs or any medications that 


 
 
 
 
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relieve pain. 
 Orient subject to the use of the NRS pain assessment. 
Preinduction period: 
 Confirm preoperative readiness (subject is hemodynamically stable and has followed 
preoperative instructions, and there is no evidence of acute illness such as fever). 
 Obtain vital signs (heart rate [HR], respiratory rate [RR], oxygen saturation [SpO2], systolic 
blood pressure [SBP], diastolic blood pressure [DBP], mean arterial pressure [MAP]), 
Temperature [Temp]; baseline value will be the measurement immediately prior to initiation 
of study drug administration.  
 Start maintenance IV infusion (NS, LR, or 5% dextrose solution). 
 Attach 3-lead or 5-lead electrocardiogram (ECG) to subject and monitor continuously. In the 
event an abnormality is noted with 3-lead or 5-lead ECG, clinical significance of an 
abnormality should be documented, and the investigators will decide whether to add a 12-
lead ECG.  
 Administer oxygen via face mask (≥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.   
 Attach BIS monitor to subject (either in preoperative anesthesia unit or in operating room, 
depending on local practice). Record the three most recent BIS values preceding midazolam 
administration. 
 Subjects will receive IV midazolam at dose 0.04 mg/kg, up to 3 mg maximum per subject 
over 15 [±2] seconds at 5 minutes [±30 seconds] prior to initiation of induction agents as 
premedication. The midazolam dose can be reduced according to patient’s age and 
comorbidities as per the anesthetist’s discretion. The start and end time of midazolam 
administration should be recorded. The end time of midazolam administration will begin the 
window to start of IP. 
 Subjects will receive preinduction IV fentanyl at a dose of 1 mcg/kg rounded up to the 
nearest 25 mcg, up to 100 mcg maximum over 15 [±2] seconds at 2 minutes [±10 seconds] 
prior to initiation of induction agents. The fentanyl dose can be reduced according to 
patient’s age and comorbidities as per the anesthetist’s discretion. The start and end time of 
fentanyl administration should be recorded. The end time of fentanyl administration will 
begin the window to start of IP.     
 Information about any adverse events (AEs) and concomitant medications will be recorded. 
 Note: Throughout the preinduction and induction periods, a timing device must be used to 
allow accuracy and sequencing of necessary assessments.  
Induction period of general anesthesia: 


 
 
 
 
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 Monitor vital signs (HR, RR, SpO2, SBP, DBP, MAP, Temp) continuously. HR, RR, SBP, 
DBP, MAP, Temp should be recorded once every 2 minutes [±30 seconds], SpO2 value 
should be recorded once every 1 minute [±15 seconds] from the start of study drug 
administration (for every time point) for 30 minutes post start of study drug administration 
for the judgment of key secondary endpoint. 
Note: Vital signs (HR, RR, SBP, DBP, MAP, Temp) monitor should be set to cycle every 1 
minute to obtain vitals at least every 2 minutes (in case cycle requires longer than 1 minute).  
 Administer IV study drug (HSK3486 0.4 mg/kg or propofol 2.0 mg/kg) into vein located on 
the back of right or left hand (this IV location is strongly preferred rather than mandatory) at 
a port closest to the IV cannula (IV injection time: 30 [±5] seconds). 
 The MOAA/S will be evaluated every 30 [±10] seconds after end of study drug 
administration until MOAA/S ≤1 is reached. 
 If MOAA/S is still >1 at 1 minute [±10 seconds] post end of study drug administration, a top-
up dose of 50% of the initial dose of study drug (either HSK3486 0.2 mg/kg or propofol 1 
mg/kg depending on treatment group) will be given to the subject (IV injection time: 10 
[±2] seconds). Start and end times of top-up dose administration will be recorded. The 
MOAA/S will be evaluated every 30 [±10] seconds post end of the top-up dose 
administration. 
 If MOAA/S is still >1 at 2 minutes [±10 seconds] post end of the top-up dose administration, 
then the rescue drug, propofol, will be given (in both treatment groups). The rescue dose is 
prepared as the initial calculated dose (100%) and administered per propofol guidelines. The 
MOAA/S will be evaluated every 30 [±10] seconds post end of rescue drug administration 
until MOAA/S ≤1 is reached. 
 Administration of study drug must be initiated 5 minutes [±30 seconds] post midazolam 
preinduction medication administration stop time. Top-up doses should be administered 
within 10 seconds once MOAA/S is evaluated >1. 
 Injection-site pain is evaluated verbally by Numeric Rating Scale (NRS; Appendix 3). Upon 
administration of study drug injection, the investigator should immediately ask the subject to 
rate his or her pain at injection-site. As a general guidance, the evaluation should be done 
multiple times with the first evaluation occurring typically within 15 seconds after initiation 
of study drug injection and monitored until successful induction (MOAA/S ≤1). Related 
information such as the occurrence and severity of injection pain (NRS 0-10) shall be 
recorded. The maximum (highest value) injection-site pain will be recorded in EDC as NRS. 
Pain during the injection of study drug in the hand/arm should be distinguished from 
unrelated puncture pain from the IV site or due to adhesive tape at the IV site.   
 Post the end of initial study drug administration, the eyelash reflex will be evaluated every 30 
[±10] seconds until loss of eyelash reflex. If there is a top-up dose, eyelash reflex will be 
evaluated every 30 [±10] seconds post end of the top-up dose administration until loss of 
eyelash reflex. If there is rescue drug given, eyelash reflex will be evaluated every 30 [±10] 


 
 
 
 
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seconds post end of the rescue drug until loss of eyelash reflex. The time of loss of eyelash 
reflex should be recorded. 
 BIS will be monitored continuously; record baseline BIS value prior to administering study 
drug. BIS values will be collected at the following timepoints from start of initial study drug 
administration: every 30 [±10] seconds until 5 minutes, then every 2 minutes [±30 seconds] 
until 30 minutes and then every 30 [±2] minutes for the duration of the surgery. 
 Monitor 3-lead or 5-lead electrocardiogram (ECG) continuously. Abnormalities of clinical 
significance and non clinical significance should be recorded. The investigators decide 
whether to add a 12-lead ECG based on the subject's condition.  
 When MOAA/S ≤1 is reached, then IV rocuronium bromide (0.6 mg/kg) is to be 
administered for neuromuscular blockade to perform endotracheal intubation. The start and 
end times of rocuronium bromide administration should be recorded. RR collected until 
initiation of administration of rocuronium. 
Note: For subjects with BMI > 40 kg/m2, the rocuronium dose may be modified per        
investigator discretion. 
Note: Additional IV rocuronium is allowed per investigator’s discretion only in response to 
clinical symptoms during tracheal intubation, such as gag reflex and movement et al, or 
during surgical procedures. The start and end times of additional rocuronium bromide 
administration should be recorded.   
 Intubate subject once neuromuscular blockade has taken effect; if using twitch monitor, 
intubate once no twitches are noted. The start and end times of first and subsequent 
intubation attempts should be recorded. 
 During endotracheal intubation, evaluate and record clinical symptoms and/or signs for 
inadequate depth of anesthesia, such as lacrimation, movement, vomiting, coughing, 
laryngospasm, bucking, swallowing reflex, and/or bronchospasm, etc. for at least 15 minutes 
from start of study drug administration. 
 Between start of study drug administration and prior to the administration of rocuronium 
bromide, evaluate and record respiratory depression. 
Note: Respiratory depression includes apnea, defined as absence of thoracic movement 
lasting >30 seconds, prior to the administration of rocuronium bromide, or hypoxia, defined 
as SpO2 <90% lasting >30 seconds; or life-threatening apnea or hypoxia requiring immediate 
intervention. 
  Evaluate and record cardiac depression from start of study drug administration until the 
subject leaves the operating room. 
Note: Cardiac depression is defined as SBP <90 mmHg lasting >2 minutes plus requiring 
medical intervention such as inotropes, vasopressors, or IV fluid resuscitation, or life-
threatening hypotension requiring immediate intervention. 
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anesthesia. Initiate sevoflurane within 60 seconds after successful endotracheal intubation. 
The end-tidal concentration of sevoflurane should be 1.5-2.0 % (The initial concentration 
that is set and start time of administration should be recorded).  
 Information about any adverse events (AEs) and concomitant medications will be recorded. 
Maintenance period of general anesthesia: 
 During the maintenance period of general anesthesia, the inhalational anesthetic agent 
sevoflurane will be used according to routine clinical practice, and the end-tidal of 
sevoflurane should be 1.5-2.0 % within 15 minutes after initiation of study drug 
administration and can be adjusted to the desired effect after that.  
 Propofol should not be used at any time all throughout the maintenance period.  
 During the maintenance period, end-tidal sevoflurane concentration will be monitored per 
standard of care.  
 The BIS will be monitored continuously per standard of care, and BIS values will be 
collected at the following timepoints from start of initial study drug administration: every 30 
[±10] seconds until 5 minutes, then every 2 minutes [± 30 seconds] until 30 minutes and then 
every 30 [±2] minutes for the duration of the surgery.     
 Additional IV fentanyl or other analgesic drug may be administered for intraoperative 
analgesia only after initiation of sevoflurane, preferably after 15 minutes following the 
initiation of study drug administration, start time and end time of initial study drug 
administration should be recorded; if additional drug used, the start and end time of 
administration should be recorded. 
 Subject management during surgery needs to follow routine best practice which includes 
Antiemetics Ondansetron, or other 5 HT-3 antagonists and/or Dexamethasone. Antiemetics 
should be given during surgery and before subjects wake up unless otherwise 
contraindicated. The use of antiemetics should be recorded in concomitant medications.   
 Monitor 3-lead or 5-lead ECG continuously. Abnormalities of clinical significance and non 
clinical significance should be recorded. The investigators decide whether to add a 12-lead 
ECG based on the Subject's condition. Information about any adverse events (AEs) and 
concomitant medications will be recorded. 
 Blood sample for population PK study will be collected at the time points as indicated in 
(Appendix 5).  
 Information about any adverse events (AEs) and concomitant medications will be recorded. 
7.1.3. 
Follow-up Period 6 (±2) hour Post Study Drug and 24-hour Post Study Drug Visit 
[Day 2] 
For the first 6 (±2) hour post study drug evaluation, study assessments and procedures will be 
assessed as indicated in Schedule of Assessments: 


 
 
 
 
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 Postoperatively, the subject will be monitored per facility/institution standard of care in the 
PACU until the 6 (±2) hour Follow-up assessments. However, when deemed discharge ready 
per institution/facility policy, inpatients may be transferred to their rooms where the 6 hour 
follow up assessments can be performed. For subjects undergoing outpatient surgery, upon 
discharge readiness they may be released from the PACU but must remain in the 
facility/institution as well as be accompanied by a responsible individual. The responsible 
party can be either a personal acquaintance or personnel from the institution. 
 In the PACU, once the subject is alert and oriented, repeat NRS for recall of pain at time of 
study drug administration and assess surgical awareness with recall using the Brice 
Awareness Questionnaire (Appendix 4). 
 After the surgery, vital signs (HR, RR, SpO2, SBP, DBP, MAP, Temp) will be assessed at 6 
(±2) hours post study drug administration.  
 Clinical laboratory tests (hematology, blood chemistry, and urinalysis) will be obtained at 6 
(±2) hours post administration of study drug for shipment to central laboratory. 
 Obtain 12-lead ECG at 6 (±2) hours post study drug administration, and as clinically 
indicated. 
Note: If surgery lasts >4 hours, vital signs, clinical laboratory tests, and ECG should be 
obtained 1 (+1) hour after completion of surgery. Duration of surgery is defined as time from 
study drug administration to time of transfer from operating room to recovery room or PACU. 
 Document AEs and concomitant medications. 
 After the surgery, subjects may remain in the hospital or observation unit if required based on 
standard of care and the clinical situation; however, if the subject is clinically stable after the 
Day 1 follow-up assessments and appropriate to be discharged home per the judgement of 
the investigator and surgeon, the subject may be released with supervision by a family 
member or friend, and must return to the clinic for the 24-hour follow-up visit (Day 2).  
For the 24-hour follow-up visit, study assessments and procedures will be assessed as indicated 
in Schedule of Assessments: 
 24 (±6) hours post study drug administration (Day 2), obtain vital signs (HR, RR, SpO2, SBP, 
DBP, MAP, Temp). 
 Information about any AEs and concomitant mediations will be collected and recorded. 
7.1.4. 
Phone Contact (Day 8) 
Subjects will be evaluated by a follow-up telephone call 7 (±2) days after surgery:  
 Surgical awareness with recall will be re-assessed using the Brice Awareness Questionnaire. 
 Information about any AEs and associated medications will be collected and recorded.  


 
 
 
 
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7.2. Efficacy Assessments 
7.2.1. 
Success Rate of Anesthesia Induction  
Success rate of anesthesia induction: The proportion of subjects with successful anesthesia 
induction in all subjects of the group. 
A successful anesthetic induction should meet both of following conditions: 
1.  Successful induction of anesthesia (MOAA/S ≤ 1) after the dosing of the study drug, 
and 
2.  One or less top-up dose required without using any rescue drugs. 
Scoring criteria: According to the MOAA/S scale (Appendix 1), observation and evaluation 
are carried out stepwise, and the cross-level evaluation should not be carried out.  
MOAA/S scoring: The subject's name is called during induction to observe the subject's response 
to name calling with a normal tone. Lightly stimulate or shake the subject after the subject falls 
asleep and observe the subject's response to painful stimulation. If the subject does not respond 
to the light stimulus or shaking but responds to painful stimulation (by squeezing the trapezius 
muscle), the MOAA/S score is 1 and the time from the end of the dosing of the study drug to 
when MOAA/S is ≤1 should be recorded. 
7.2.2. 
Composite Endpoint to Evaluate Desired Depth of Anesthesia 
Composite endpoint of desired depth of anesthesia for general elective surgery is defined if all 
following criteria are met:  
 Proportion of successfully induced subjects treated with HSK3486 compared to propofol 
with no any clinical symptoms in response to tracheal intubation, such as lacrimation, 
movement, vomiting, coughing, laryngospasm, bucking, swallowing reflex or bronchospasm, 
or an event where no SBP, DBP, or MAP increases more than 20% from baseline in response 
to any major operational procedures or noxious stimulus in defined period, within 15 minutes 
post initiation start of study drug administration or up to the start of second tracheal 
intubation attempt. 
 Subjects maintain desired depth of anesthesia for general elective surgery within 15 minutes 
post initiation of study drug administration with BIS as an objective assessment (after 
reaching the initial lowest value, BIS remains sustainable level at not more than 60 during 15 
minutes after study drug administration). 
Note: Target BIS 40 to 60 for general anesthesia (see Appendix 2 for BIS guidance). 
The BIS sustainable level at not more than 60 is defined as not more than 1 episode with BIS 
value observed >60 after reaching initial lowest value, in defined period. 


 
 
 
 
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 No significant respiratory depression, such as apnea, prior to the administration of 
rocuronium bromide. 
Note: For the composite endpoint, respiratory depression includes apnea, defined as absence 
of thoracic movement lasting >30 seconds, or hypoxia, defined as SpO2 <90% lasting >30 
seconds, or life-threatening apnea or hypoxia requiring immediate intervention. 
 No significant cardiac depression indicated by blood pressure decrease that requires 
intervention, i.e., vasopressors and/or IV fluid resuscitation. 
Note: For the composite endpoint, cardiac depression is defined as SBP <90 mmHg lasting 
>2 minutes plus requiring medical intervention such as inotropes, vasopressors, or IV fluid 
resuscitation, or life-threatening hypotension requiring immediate intervention. 
7.2.3. 
Injection-site Pain  
Injection-site pain is evaluated verbally during study drug administration using the NRS, ranging 
from 0 (no pain) to 10 (worse imaginable pain) (see Appendix 3). Recollection of pain during 
study drug administration will be assessed in the PACU once the subject is awake and oriented. 
During the baseline visit, the subject should be oriented to the NRS for the evaluation of 
injection-site pain. Upon initiation of study drug administration, the investigator should 
immediately ask the subject to rate his or her pain. As a general guidance, the evaluation should 
be done multiple times with the first evaluation occurring typically within 15 seconds after 
initiation of study drug administration and monitored until successful induction (MOAA/S ≤1). 
Related information such as the occurrence and severity of injection pain (NRS 0-10) shall be 
recorded. The maximum (highest value) injection-site pain should be recorded. Pain during the 
injection of study drug in the hand/arm should be distinguished from unrelated puncture 
pain from the IV site or due to adhesive tape at the IV site.  When injection pain occurs, the 
subject’s pain should be graded verbally using the NRS (0-10) and should be recorded. The 
subject should be asked to rate the pain on a scale from 0, which is no pain, to 10, which is the 
worst pain imaginable. Ask the subject to point to the number on the scale that best represents 
the intensity of the pain now. In the PACU, once the subject is alert and oriented, repeat NRS for 
recall of pain at time of study drug administration. 
7.2.4. 
 Time to Successful Anesthesia Induction 
The time to successful anesthesia induction is evaluated during the induction period and is 
defined as the time from the end of the first administration of the study drug to the time when 
MOAA/S ≤1. 


 
 
 
 
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7.2.5. 
 Time to Loss of Eyelash Reflex 
The time to loss of eyelash reflex is evaluated during the induction period and defined as the 
time from the end of the first administration of the study drug to the time when eyelash reflex is 
lost. 
7.2.6. 
Successful induction without non-optimal anesthetic effects  
The proportion of subjects with successful induction without non-optimal anesthetic effects 
within 15 minutes post initiation of administration of study drugs will be analyzed using the 
similar statistical methods as for the secondary composite efficacy endpoint. 
 
7.2.7. 
Changes in the Bispectral Index  
From the start of study drug administration to the end of the surgery, the subjects are 
continuously monitored for their BIS, which is recorded at specified time points to understand 
the changes in the BIS of the subjects throughout the entire anesthesia period (see Appendix 2) 
for BIS guidance). 
7.2.8. 
Brice Awareness Questionnaire 
Recall of awareness during surgery, assessed postoperatively, will be evaluated using the Brice 
Awareness Questionnaire (see Appendix 4). 
7.2.9. 
Use of Study Drugs and Alternative Drugs 
The use of HSK3486 and propofol (including the time and use of top-up dose, the amount of 
top-up dose, and the total dose) is evaluated from the end of study drug administration to the 
time of successful induction. The use of alternative drug (propofol) (including the time and use 
of top-up dose, the amount of top-up dose, and the total dose), as well as the proportion of 
subjects using the rescue/remedial drug (propofol), is evaluated from the beginning of the dosing 
of the study drug to the time of successful induction. The proportion of subjects using the 
alternative drug (propofol) will also be calculated for each dose group. 
7.3. Safety and Tolerability Assessments 
7.3.1. 
Adverse Events 
Adverse event definitions and assignment of severity and causality are detailed in (Appendix 9). 
Adverse events will be elicited from the subject (or, when appropriate, from a caregiver, 
surrogate, or the subject’s legally authorized representative) by the study site staff using a 


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non-leading question such as “How are you feeling today?” or “Have you had any health 
concerns since your last visit?”  
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or the study, or that caused the subject 
to discontinue the HSK3486 (see Section 4.3.2). 
When possible, AEs should be reported as the unifying diagnosis rather than individual signs and 
symptoms of an underlying condition (e.g., fever, cough, and elevated white blood cells [WBC] 
associated with pneumonia should be reported as pneumonia). Laboratory values themselves are 
usually not AEs, especially when a component of the underlying AE (e.g., an elevated WBC 
associated with pneumonia should not be reported as a separate AE). 
AEs Do Not Include the Following: 
 Anesthetic effect-related sleepiness, somnolence, or even loss of consciousness occurring
during administration (i.e., the intended therapeutic effect of the drug under study)
 Chronic diseases that are present before participating in the clinical study
 Elective medical examination or surgery scheduled prior to enrollment into the study
 Overdose of the study drug or concomitant medication not resulting in any signs or
symptoms
 Lack of efficacy should be captured as a treatment failure for clinical efficacy, not as an AE.
7.3.2. 
Reporting Serious Adverse Events 
For the definition of an SAE please see Appendix 9. All SAEs, occurring after the signing of the 
ICF until the end of study and regardless of study drug relationship, must be reported by SAE 
Electronic Case Report Form (eCRF) form within the clinical database (Medidata RAVE) within 
24 hours of obtaining knowledge of the event. The Investigator will be responsible for reporting 
serious adverse events to the IRB/EC. 
In the case of clinical database outage or the site is unable to access the system, the investigators 
will be requested to complete a Safety Event Report Form in English and report it by facsimile or 
email to     . The facsimile report should include all available information requested on the SAE 
Form. Initial reports of SAEs should never be left on telephone voicemails. Always email or fax 
SAE reports and follow with a telephone call if needed. 
Serious Adverse Event Reporting Contact Information: 


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The SAE Form will collect data surrounding the event (e.g., the nature of the symptom[s], time 
of onset in relation to initiation of therapy, duration, intensity, and whether or not therapy was 
interrupted or discontinued). The investigator’s assessment of the probable cause of the event 
will also be included. In addition, relevant medical history, concomitant medications, laboratory 
and diagnostic tests reports, and procedures as well as all pertinent medical information related 
to the event will also be collected. 
Rho will forward SAE queries requesting incomplete or missing information directly to the 
investigator. It is the investigator’s responsibility to be diligent in providing this information 
back to Rho as soon as it is available.   
If an Investigator becomes aware of a serious adverse event within 30 days after the last dose of 
study drug and it is considered by him/her to be caused by the study drug with a reasonable 
possibility, the event must be documented and reported through completion of the adverse event 
eCRF. 
7.3.3. 
Adverse Events of Special Interest 
The AESIs due to pharmacological effect of an anesthetic agent include hypoxemia, 
bradycardia, severe hypotension, allergy/anaphylaxis, cardiac arrhythmia and QTc prolongation 
which are defined as follows: 
• Hypoxemia due to respiratory depression is defined as SpO2 <90% with duration of >30
seconds. Hypoxemia is evaluated from the initial dose of study drug until the subject leaves
the operating room. Those occurring within 15 minutes from the end of the last dose of
study drug will be categorized as drug related unless an obvious cause is ascertained.
• Bradycardia is defined as a heart rate of <45 beats/minute that lasts >30 seconds and
requires intervention (treatment). Bradycardia is evaluated from the initial dose of study
drug until the subject leaves the operating room. Those occurring within 15 minutes from
the end of the last dose of study drug will be categorized as drug related unless an obvious
cause is ascertained.


 
 
 
 
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• Severe hypotension is defined as an SBP <90 mmHg that lasts >2 minutes requiring 
treatment. Severe hypotension is evaluated from the initial dose of study drug until the 
subject leaves the operating room. Those occurring within 15 minutes from the end of the 
last dose of study drug will be categorized as drug related unless an obvious cause is 
ascertained.  
• Allergy/anaphylaxis may include angioedema, bronchospasm, erythema, and hypotension.  
Allergy/anaphylaxis is evaluated from the initial dose of study drug until visit Day 2.  
• Cardiac arrhythmia is any rhythm not arising from the sinus node (atrial fibrillation, atrial 
flutter, Torsade de pointes). Cardiac arrythmia is evaluated from the initial dose of study 
drug until visit Day 2.  
• QTc prolongation: QTc intervals of > 450 ms in males and > 470 ms in females occurring 
within 15 minutes from the end of the last dose of study drug are considered QTc 
prolongation. Patients who reach an absolute QT interval of more than 500 ms upon QTc 
correction for rate should be reassessed, and immediate action should be taken to correct 
any possible concomitant risk factors [15, 16]. 
AESI start time, end time (both should be accurate to the second and the duration should be 
calculated) and treatment measures should be recorded (if any).  
Note: Vital sign values out of range (or suspected as being erroneous) should be confirmed 
with a second measurement before recording as the confirmed value. 
Note: Since injection-site pain has been recorded and analyzed in the efficacy endpoints, it 
is no longer recorded in the Safety endpoints (see section 7.2.3) for injection-site pain 
evaluation. 
Note: The list and definitions of AESIs as modified in protocol version 5.0 will be 
implemented retroactively to include applicable events for all study subjects. The list 
and definitions were modified primarily based on the background rates of adverse 
events in previously completed studies and include those events that were uncommon, 
rare, or very rare (> 1/1,000; >1/10,000; <1/10,000 respectively) that are clinically 
significant. 
 
7.3.3.1. 
Abuse-related AEs of Interest 
Both HSK3486 and propofol cross the blood-brain barrier and have CNS effects, which are the 
intended pharmacological action of the drug (e.g., sedation, anesthesia/unconsciousness). Any 
untoward change from baseline that is not the intended or desired effect of the study drug should 
be reported as an AE. Investigators and site personnel should monitor for and report abuse-
related AEs of interest, which include euphoria, dissociative effects, hallucinations, psychosis, 
changes in mood, impaired cognition, attention and psychomotor effects, and inappropriate 
affect, overdoses, abuse, and misuse.   


 
 
 
 
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For all abuse-related AEs of interest, the time of onset and duration of the event, dose 
administered, severity and outcome should be recorded. 
While not AEs, any subject dropouts and lost or unaccounted for drug product (which could be 
indicative of abuse-related aberrant behavior) needs to be documented and recorded by site 
personnel. 
7.3.4. 
Contraception and Pregnancy 
Currently, the effects of HSK3486 on the fetus are still unknown. Therefore, female subjects of 
childbearing potential and male subjects with female partners of childbearing potential are 
required to adopt appropriate contraceptive measures before (from screening) and during the 
study (30 days post study drug administration). For male subjects who have not been sterilized 
(vasectomy), their female partners of childbearing potential must also use appropriate 
contraception. Effective contraceptive measures include female bilateral tubal ligation, male 
vasectomy, hormone contraceptives (oral, implanted, injected and transdermal), the combination 
of intrauterine contraceptive device and barrier contraceptive (condoms, cervical caps) or 
abstinence. Male subjects should refrain from donating sperm from Day 1 to 30 days post study 
drug administration. 
If a female subject or a female sexual partner of a male subject who has taken the study drug 
becomes pregnant during the study period (from signing ICF to 30 days post study drug 
administration), the investigators should immediately record the pregnancy information and fill 
out a pregnancy-specific report and notify the Contract Research Organization (CRO) designated 
by the Sponsor within 24 hours of being informed of the event. The investigators should also 
report the event to the IRB/EC in accordance with the ethical requirements of each study site. 
The pharmacovigilance personnel of the CRO should review the pregnancy report form in 
accordance with the standard operating procedures and report it to the Sponsor within 24 hours 
of being informed of the event. If the event occurs during the study period, the pregnant female 
subject should withdraw from the study for reasons of protocol deviation. 
A pregnancy event should be followed up to the end of pregnancy or 8 weeks after the fetus is 
born. The follow-up information of pregnancy events is recorded in the source file. 
If pregnancy results meet SAE criteria, i.e., spontaneous abortion, induced abortion, stillbirth, 
neonatal death, and congenital malformations (including deformities in aborted babies), the 
investigator shall report in accordance with the SAE reporting procedure.  
7.3.5. 
Clinical Laboratory Evaluations 
Laboratory tests include the following: 


 
 
 
 
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 Blood routine (Hematology) (about 2 mL of blood sample): WBC count with differential (% 
and absolute count) including neutrophils, lymphocytes, monocytes, basophils, eosinophils; 
red blood cell (RBC) count, Hb, hematocrit (HCT), MCH, MCHC, MCV and platelet count 
(PLT). 
 Blood biochemistry (about 5 mL of blood sample): liver function (aspartate aminotransferase 
[AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP], gamma-glutamyl 
transferase [GGT], total bilirubin [TBIL], total protein [TP], albumin [ALB], lactate 
dehydrogenase [LDH]), blood lipids (triglycerides [TG], cholesterol [TC], low-density 
lipoprotein [LDL], high-density lipoprotein [HDL]), electrolytes (sodium [Na], potassium 
[K]), chloride [Cl], calcium [Ca], phosphorus [P], bicarbonate [HCO3], renal function (uric 
acid [UA], blood urea nitrogen [BUN], creatinine [Cr]), blood glucose (Glu), thyroid 
stimulating hormone [TSH] (free T-4 if TSH is abnormal) and hemoglobin A1c [HbA1c]. 
 Urinalysis (about 7 mL of fresh urine sample): color and appearance, urinary protein (PRO), 
urinary glucose (GLU), microscopic exam including urinary WBCs and RBCs, urinary 
ketone bodies (KET), pH and specific gravity, leukocytes, bilirubin, nitrite, and occult blood. 
Laboratory tests are performed in the screening period and 6 (±2) hours post administration of 
study drug except for HbA1c and TSH (with free T-4 if TSH abnormal). HbA1c and TSH are 
only drawn at the screening visit. In cases where a separate screening visit is not feasible or the 
central laboratory results are not available on Day 1, a study approved local laboratory may be 
used to confirm eligibility. In these cases, required screening laboratory samples must be drawn 
in parallel and sent to the central laboratory. Local laboratory results will be maintained in the 
source documents but not be entered into the eCRF.     
For cases where central and local labs are drawn at the same time, blood volumes noted above in 
bullets 1 and 2 will be increased to approximately 15 mL total. Urine volume noted in bullet 3 
will be increased to approximately 15 mL.  
7.3.6. 
Vital Signs, Physical Examination, and Other Safety Evaluations 
7.3.6.1. 
Vital Signs 
Vital signs include RR, HR, SpO2, Temp, BP (SBP, DBP, and MAP).   
During screening, vital sign examination should be performed after resting for at least 5 minutes. 
If the results exceed the inclusion/exclusion criteria and are confirmed after repeated tests, the 
subject shall not be enrolled. 
For the pre-anesthetic preparation period, after the anesthetic monitor is mounted, baseline vital 
signs values will be the measurement immediately prior to initiation of study drug 
administration.  


 
 
 
 
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During anesthesia induction and maintenance period, vital signs are continuously monitored, and 
values are recorded once every 2 minutes [±30 seconds] (including vital signs monitored at the 
start of medication) for 30 minutes post study drug administration (SpO2 value should be 
recorded once every 1 minute [±15 seconds]), and then at 6 [±2] hours post study drug 
administration, and at the 24-hour (Day 2) visit.  
7.3.6.2. 
Physical Examinations  
Physical examinations include skin, head, and neck, cardiovascular system, respiratory system, 
gastrointestinal system, psychological and neurological system, and musculoskeletal system. 
ASA-PS and Mallampati (oropharyngeal exam) classifications will also be evaluated. These 
assessments will be completed at screening, and a focused physical exam will be repeated as 
needed to assess AEs. 
7.3.6.3. 
12-lead ECG and 3-lead/5-lead ECG 
In the 12-lead ECG examination, the values of QT interval, QTcF interval, PR interval, QRS 
interval, RR interval and their clinical significance determinations are recorded. 
The 12-lead ECG examination is done during the screening period. At baseline, if the screening 
ECG is more than 1-week from the baseline visit, the 12-lead ECG should be repeated to assess 
its compliance with the inclusion/exclusion criteria (the result is also used as the baseline value). 
During the surgery, a 3-lead or 5-lead ECG (i.e., rhythm strip) is monitored continuously. If the 
3-lead ECG shows clinically significant abnormalities, the investigators will decide whether to 
add a 12-lead ECG based per investigator’s discretion. 
7.3.7. 
Use of Additional Medication or Any Interventions 
Administration of additional medication or any interventions including medical interventions, 
e.g., administration of vasoactive drugs, necessary due to a clinically relevant change in BP, 
should be documented.  
7.4. Pharmacokinetic Analysis 
To maintain the blind, all subjects should undergo PK blood sampling regardless of their groups. 
However, only the blood samples in the HSK3486 group are tested and analyzed; unless 
requested by the Sponsor or its designated personnel, the propofol group may also be analyzed. 
To ensure the accuracy of the PK data, it is necessary to accurately record the actual start and 
end time of dosing, the dose, and the blood sampling time of each subject. 


 
 
 
 
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The blood collection time points are listed in Appendix 5. Approximately 2 mL of venous blood 
is collected at each time point. 
For the requirements of collection, processing, transportation, and analysis of blood samples, 
please see "Central Laboratory Manual". 


 
 
 
 
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8. SAMPLE SIZE AND DATA ANALYSES 
8.1. Determination of Sample Size  
A total of 399 subjects (266 in HSK3486 0.4/0.2 mg/kg group and 133 in propofol 2.0/1.0 mg/kg 
group) need to be enrolled 2:1 into this study based on the following assumptions: 
 For the primary endpoint, a sample size of 215 subjects will give at least 90% power 
assuming that type I error is 0.025 (1-sided), the success rate of general anesthesia induction 
of HSK3486 and propofol are both 97%, and non-inferiority margin (NIM) is -8%. 
 For the key secondary endpoint of incidence of injection-site pain, a sample size of 365 
subjects will give 90% power (providing the first primary endpoint is statistically significant) 
assuming α=0.015 (2-sided) and the proportion of subjects who meet the endpoint criteria of 
any injection-site pain are 6.8% and 20.5% for HSK3486 and propofol, respectively. 
 For the key secondary composite endpoint, a sample size of 338 subjects will give 90% 
power (providing the first primary endpoint is statistically significant) to the superior testing, 
assuming α=0.05 (2-sided), the proportion of subjects with successful induction, maintained 
desired depth of anesthesia for general elective surgery, without significant cardiac and 
respiratory depression within the 15 minute post initiation start of study drug administration 
observation period and no significant respiratory depression (prior to administration of 
rocuronium bromide) of HSK3486 and propofol are 82% and 65%, respectively (i.e., 17% 
treatment effect). 
To power statistical testing for all three endpoints at 90% and provide sufficient safety data, 399 
subjects will be randomized and treated in this study (266 in HSK3486 0.4/0.2 mg/kg group and 
133 in propofol 2.0/1.0 mg/kg group).  
Enrolled subjects will be stratified between the 2 treatment groups by ASA-PS grade I to II and 
III to IV; age <65 and ≥65 years; and BMI <35 and ≥35 kg/m2. The stratification schema will be 
described in the Statistical Analysis Plan. 
8.2. Analysis Populations 
Full Analysis Set (FAS): All randomized subjects who have received any dose of the study drug 
(HSK3486 or propofol).  
Per Protocol Set (PPS): All subjects from FAS who have completed primary efficacy endpoint 
measurement will be considered for PPS. Subjects with any important protocol deviations will be 
reviewed after database lock and prior to study unblinding and may be excluded from PPS if 
these important deviations will impact the efficacy evaluations.  
Safety Set (SS): Includes all randomized subjects who have received any dose of the study drug 
and have post-dose safety assessment data. 


 
 
 
 
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The FAS will be the primary analysis population for efficacy and PPS will be the supportive 
analysis population for efficacy analysis. Safety endpoints will be analyzed using the SS. 
8.3. General Considerations 
Continuous variables will be summarized by the standard descriptive statistics: number of 
subjects (n), mean, standard deviation (SD), median, minimum, and maximum. Frequency of 
subjects or events and percentages will be summarized in categorical variables. Details of the 
statistical analyses will be given in a separated Statistical Analysis Plan (SAP). 
8.4. Efficacy Analysis 
8.4.1. 
Primary Efficacy Outcome Measure 
The statistical null hypothesis to be tested is: 
𝐻𝐻0: 𝑝𝑝𝑡𝑡−𝑝𝑝𝑐𝑐≤𝛿𝛿 
With the alternative hypothesis: 
𝐻𝐻1: 𝑝𝑝𝑡𝑡−𝑝𝑝𝑐𝑐> 𝛿𝛿 
Where pt and pc are the anesthesia success rates for the HSK3486 and propofol arms, 
respectively, and δ is the NIM. This hypothesis will be tested at the 1-sided α=0.025 level. 
Success rate of general anesthesia induction in both groups and rate difference between groups 
and its 95% confidence interval (CI) are estimated by Farrington-Manning method in the FAS. 
The stratification factors will be included in the analysis. The lower limit of 95% CI of rate 
difference will be compared with the NIM of -8% to confirm the establishment of non-
inferiority. The FAS subjects who are non-evaluable for anesthesia success will be counted as 
treatment failures. 
8.4.2. 
Justification of the Non-inferiority Margin  
The NIM for this study is based on the expectation that the active control, propofol, and 
HSK3486 will both perform similarly to historical evidence, achieving ≥97% efficacy for 
induction of general anesthesia, defined as achieving MOAA/S ≤1 after 1 dose, with no more 
than 1 top-up dose if needed. Since the expected response rates are ≥97%, there is little concern 
for loss of assay sensitivity (i.e., loss of efficacy) from historical performance or loss of the 
“constancy assumption.” Furthermore, the exercise of attempting to identify the M1 based on 
historical literature would lead to an unacceptably large margin, then applying clinical judgement 
to establish the M2 (often 50% of the M1) (Food and Drug Administration [FDA] Guidance for 


 
 
 
 
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Industry: Non-Inferiority Clinical Trials to Establish Effectiveness, 2016) would lead to a NIM 
>10%, which permits too much uncertainty to be acceptable or useful. Using a NIM of 8% is 
clinically relevant and meaningful for this indication. 
8.4.3. 
Secondary Efficacy Outcome Measures 
The proportion of subjects with successful induction, who maintain desired depth of anesthesia 
for general elective surgery, and without significant cardiac and respiratory depression between 
the time of successful induction and 15 minutes post initiation of study drug administration (prior 
to administration of rocuronium bromide) in both groups and difference between groups and 
95% CI will be calculated. The p-value for comparison between groups will be obtained based 
on the Cochran-Mantel-Haenszel Chi-squared test using the stratification factors in the study 
randomization. 
The proportion of the subjects with any injection-site pain (NRS ≥1) and moderate pain (NRS 
≥4) will be analyzed, as well as the mean NRS pain score for each treatment group. 
The median and its 95% CI of time to successful induction of general anesthesia and time to the 
disappearance of eyelash reflex will be provided by groups using the Kaplan-Meier (KM) 
method. The KM estimates and 95% CIs at selected time points will also be reported.  
The proportion of subjects with successful induction without non-optimal anesthetic effects 
within 15 minutes post initiation of administration of study drugs will be analyzed using the 
similar statistical methods as for the secondary composite efficacy endpoint. 
The change of BIS during the period of anesthesia post study drug administration up to 15 
minutes will be summarized descriptively by treatment group. 
The Brice Awareness Questionnaire results will be summarized descriptively by treatment group. 
The use of study drugs and remediation drugs will be summarized descriptively by treatment 
group and between-group p-values. 
8.4.4. 
Methods for the Control of Type I Error 
The primary endpoint of non-inferiority to propofol for successful induction of general  
anesthesia will be tested first. If the null hypothesis fails to be rejected, the testing stops. If the 
primary endpoint is statistically significant, then the key secondary endpoints will be tested in 
parallel using a weighted Bonferroni-Holm step-down approach with weights w1=0.7 for the 
proportion of subjects who maintain the desired depth of anesthesia, and w2=0.3 for the incidence 
of injection-site pain. In this procedure, the p-values for the secondary endpoints are divided by 
their respective alpha levels, then the endpoint for which this calculation is smaller (i.e., test pj < 
αj for j=arg min (p1/0.035, p2/0.015)) is tested. If the first test is rejected, then the other endpoint 


 
 
 
 
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is tested at α=0.05; otherwise testing stops. This procedure controls the familywise Type I error 
rate at the overall α=0.05 level for the key secondary endpoints. The analyses for all other 
secondary endpoints will be descriptive, and any testing that may be done will not be adjusted to 
maintain Type I error. 
 
8.5. Safety Analysis 
Safety endpoints include AEs, clinical laboratory test results, vital signs (supine HR, SBP and 
DBP, RR, and SpO2, ECG findings, physical examination findings, and administration of 
additional medication or any interventions including medical interventions, e.g., administration 
of vasoactive drugs, necessary due to a clinically relevant change in BP. No formal statistical 
analysis of the safety data will be performed. 
All AEs will be coded according to the MedDRA version 24.0 or later and graded for severity 
according to CTCAE version 5.0. The number and percentage of subjects with treatment-
emergent adverse events (TEAEs), SAEs, AESIs (Section 7.3.3), TEAEs related to study drug, 
SAEs related to study drug, TEAEs of Grade 2 or higher, TEAEs leading to treatment 
discontinuation, TEAEs leading to study discontinuation, and TEAEs leading to death will be 
summarized by system organ class (SOC), preferred term (PT), and groups. In addition, the 
severity of TEAEs and relationship to study drug will be summarized by SOC, PT, and treatment 
groups.  
Laboratory test variables will be summarized by treatment group and visit using descriptive 
statistics. Shift tables between baseline and post-baseline time points will be presented by 
laboratory test and treatment group. Laboratory tests with categorical results that cannot be 
analyzed by change from baseline or shift table analysis will not be included in these summaries 
but will be listed.  
Descriptive statistics of vital signs, pulse oximetry measurements, site pain on study drug 
administration with intensity rating on a verbal score, and ECG results at each visit will be 
presented. 
Note: Since injection-site pain has been recorded and analyzed in the efficacy endpoints, it is no 
longer recorded in the Safety endpoints. 
An independent DMC will be involved in the review of all safety data at approximately 30% 
enrollment, and on an ad hoc (as needed) basis as described in Section 3.5, as well as described 
in the DMC Charter.   


 
 
 
 
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8.6. Pharmacokinetic Analysis 
The plasma concentration data from this study will be pooled with those from other clinical trials 
of HSK3486 to establish a population PK model. This model will be used to evaluate the effects 
of internal and external covariates on the PK of HSK3486.  
8.7. Interim Analysis 
No formal interim analyses will be conducted. 


 
 
 
 
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9. REFERENCES 
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3. Gao JD, Zhao YJ, Xu CS, et al. Evaluation of entropy for monitoring the depth of 
anesthesia compared with bispectral index: a multicenter clinical trial. Chin Med J. 
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4. Gélinas C, Arbour C. Behavioral and physiologic indicators during a nociceptive 
procedure in conscious and unconscious mechanically ventilated adults: similar or 
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5. Joo HS, Perks WJ. Sevoflurane versus propofol for anesthetic induction: a meta-analysis. 
Anesth Analg. 2000;91(1):213-9. 
6. Sebel PS, Lowdon JD. Propofol: a new intravenous anesthetic. Anesthesiology. 
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7. Chan VW, Chung FF. Propofol infusion for induction and maintenance of anesthesia in 
elderly patients: recovery and hemodynamic profiles. Journal of Clinical Anesthesia. 
1997;8(4):317-23. 
8. Dundee JW, Robinson FP, Mccollum JSC, et al. Sensitivity to propofol in the elderly. 
Anaesthesia, 1986;41(5):482-5. 
9. Doenicke AW, Roizen MF, Rau J, et al. Reducing pain during propofol injection: the role 
of the solvent. Anesth Analg. 1996;82(3):472-47. 
10. HSK3486 Injectable Emulsion Investigator's Brochure, V8.0, Oct 10, 2022. 
11. Jerry, et al. Lean body weight scalar for the anesthetic induction dose of propofol in 
morbidly obese subjects. Anesth Analg. 2011 Jul;113(1):57-62. 
12. Nightingal, et al. Peri-operative management of the obese surgical patient 2015: 
Association of Anaesthetists of Great Britain and Ireland Society for Obesity and 
Bariatric Anaesthesia. Anaesthesia. 2015 Jul;70(7):859-76. 
13. Dong D, et al. Morbid Obesity Alters Both Pharmacokinetics and Pharmacodynamics of 
Propofol: Dosing Recommendation for Anesthesia Induction. Drug Metab Dispos. 2016 
Oct;44(10):1579-83. 
14. Ingrande, et al.  Dose adjustment of anaesthetics in the morbidly obese. 2010 Dec;105 
Suppl 1:i16-23. 
15. Kishida H, Cole JS, Surawicz B. Negative U wave: a highly specific but poorly 
understood sign of heart disease. Am J Cardiol. 1982 Jun;49(8):2030-6. doi: 
10.1016/0002-9149(82)90225-9. PMID: 6211085. 


 
 
 
 
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16. Document E 14: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential of Non-Antiarrhythmic Drugs, Rockville, Md: US Department of Health and 
Human Services, Food and Drug Administration; October 2005. 
 


 
 
 
 
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10. APPENDICES 
Appendix 1 Modified Observer’s Assessment of Awareness/Sedation (MOAA/S) Scale  
The assessment for MOAA/S is performed stepwise and skipping of any grade is not allowed. 
The judgment of recovery can be based on a reverse order of scoring. 
Grade 
Description 
Grade 5 
Completely awake; responds readily to name spoken in normal 
tone 
Grade 4 
Lethargic response to name spoken in normal tone 
Grade 3 
Responds only after name is called loudly and repeatedly 
Grade 2 
Responds only after mild prodding or shaking 
Grade 1 
Responds only after painful trapezius squeeze (including 
active and reflex withdrawals) 
Grade 0 
No response after painful stimulus (trapezius squeeze) 
 
 
 


 
 
 
 
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Appendix 2 Bispectral Index (BIS) 
The BIS Index is a number between 0 and 100 scaled to correlate with important clinical 
endpoints and electroencephalogram (EEG) states during administration of anesthetic agents 
(Figure 2). The BIS values near 100 represent an “awake” clinical state while 0 denotes the 
maximal electroencephalogram (EEG) effect possible (i.e., an isoelectric EEG). 
Figure 2  
The BIS Index is scaled to correlate with important clinical endpoints during 
administration of anesthetic agent. 
 
It should be noted that the BIS Index range represents a continuum that correlates to the clinical 
state and expected responses (Figure 3). 
This chart below reflects a general association between clinical state and BIS values. Ranges are 
based on results from a multicenter study of the BIS involving the administration of specific 
anesthetic agents. The BIS values and ranges assume that the EEG is free of artifacts that can 
affect its performance. Titration of anesthetics to BIS ranges should be dependent upon the 
individual goals established for each subject. These goals and associated BIS ranges may vary 
over time and in the context of subject status and treatment plan. 
 


 
 
 
 
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Figure 3  
BIS Index Range: A Continuum of Clinical State and EEG Changes 
 
Appendix 3 Numerical Rating Scale (NRS) for Grading of Injection-site Pain 
 
 
 
 
 


 
 
 
 
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Appendix 4 Brice Awareness Questionnaire 
1) What is the last thing you remember before going to sleep? 
-Being in the pre-op area 
-Seeing the operating room 
-Being with family 
-Hearing voices 
-Feeling mask on face 
-Smell of gas 
-Burning or stinging in the IV line 
-Other [Free Text]: 
 
2) What is the first thing you remember after waking up? 
-Hearing voices 
-Feeling breathing tube 
-Feeling mask on face 
-Feeling pain 
-Seeing the operating room 
-Being in the recovery room 
-Being with family 
-Being in ICU 
-Nothing 
-Other [Free Text]: 
 
3) Do you remember anything between going to sleep and waking up? 
-No 
-Yes: 
-Hearing voices 
-Hearing events of the surgery 
-Unable to move or breathe 
-Anxiety/stress 
-Feeling pain 
-Sensation of breathing tube 
-Feeling surgery without pain 
-Other [Free Text]: 
 
4) Did you dream during your procedure? 
-No 
-Yes: 
-What about [Free Text]: 
 
5) Were your dreams disturbing to you? 
-No 
-Yes 
6) What was the worst thing about your operation? 


 
 
 
 
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-Anxiety 
-Pain 
-Recovery process 
-Functional limitations 
-Awareness 
-Other [Free Text]: 
 


 
 
 
 
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Appendix 5 Pharmacokinetic (PK) Blood Samples Collection Timetable 
Phase 
Time 
Allowed Time 
Window 
PK Blood Sample 
Collection2 
Before dosing study drug 
 
Before the 1st dose 
of study drug 
administration 
Within 10 minutes 
prior to study drug 
administration 
X 
After the end of last dose of study drug1 
 
2 minutes3 
±30 seconds 
X 
 
3 ~ 30 minutes 
Not applicable 
X 
 
60 ~ 120 minutes 
Not applicable 
X 
Note: 
1. Up to 1 top-up dose of study drug is allowed. “The end of last dose of study drug” refers 
to the last dose of study drug for induction of general anesthesia. This is calculated from 
post study drug administration. For example, if the subject only receives the initial dose 
of study drug and has achieved successful anesthesia induction, then “the end of last dose 
of study drug” means the initial dose of study drug. If the subject receives an additional 
top-up dose in the anesthesia induction, “the end of last dose of study drug” means the 
last top-up dose of study drug.  
2. All subjects are required to provide venous PK blood samples. The blood volume is 
approximately 2 mL per sample. The PK blood samples will be taken from a second IV. 
3. For subjects requiring rescue medication, the 2-minute PK sample must be taken prior to 
rescue medication being administered.  
 
 


 
 
 
 
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Appendix 6 American Society of Anesthesiologists (ASA) Physical Status Grade 
Before anesthesia, the ASA classifies subjects into 5 grades according to their physical 
conditions and the risk of surgery:  
 ASA I: Normal and healthy. No systemic diseases other than local lesions. 
 ASA II: A subject with mild systemic disease. 
 ASA III: A subject with severe systemic disease that results in functional limitations but not 
incapacity. 
 ASA IV: A subject with severe systemic disease that is a constant threat to life and results in 
incapacity. 
 ASA V: A moribund subject who is not expected to survive without the operation. If it is an 
emergency surgery, mark "Emergency" or "E" before the evaluated level shown above.  
Subjects assessed as ASA I or ASA II have good tolerability to anesthesia and surgery, and the 
process of anesthesia is smooth. Subjects assessed as ASA Ⅲ are under certain risks of 
anesthesia. The pre-anesthetic preparation should be adequate. Effective measures should be 
taken to prevent complications that may occur during anesthesia. Subjects assessed as ASA IV 
are under particularly high risks of anesthesia. Subjects assessed as ASA V are under extremely 
high risks of anesthesia and surgery for their extremely critical conditions, extremely poor 
tolerability to anesthesia, and death that may occur at any time. Thus, pre-anesthetic preparation 
is more important and shall be adequate, careful, and comprehensive.


 
 
 
 
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Appendix 7 Mallampati Classification 
 
The Modified Mallampati classification is a simple scoring system to help predict difficult 
intubation. It relates the amount of mouth opening to the size of the tongue and provides an 
estimate of space available for oral intubation by direct laryngoscopy. Class I is present when the 
soft palate, uvula, and pillars are visible; Class II when the soft palate and uvula are visible; 
Class III when only the soft palate and base of the uvula are visible; and Class IV when only the 
hard palate is visible. Mallampati Class I and II predict easy laryngoscopy, Class III predicts 
difficulty, and Class IV predicts extreme difficulty. 
 


 
 
 
 
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Appendix 8 Drugs that May Prolong the QT Interval 
Drugs that prolong QT interval (including but not limited to 
the following) 
Antibiotics 
Clarithromycin 
Azithromycin 
Erythromycin 
Roxithromycin 
Metronidazole 
Moxifloxacin 
Antiarrhythmics 
Quinidine 
Sotalol 
Amiodarone 
Disopyramide 
Procainamide 
Antipsychotics 
Fluphenazine 
Droperidol 
Haloperidol 
Thioridazine 
Pimozide 
Clozapine 
Olanzapine 
Chlorpromazine 
Quetiapine 
Antifungals 
Fluconazole 
Ketoconazole 
Itraconazole 
Antimalarial drugs 
Mefloquine 
Chloroquine 
Antidepressants 
Amitriptyline 
Imipramine 
Clomipramine 
Dosulepin 
Doxepin 
Fluoxeitine 
Paroxetine 
Sertraline 


 
 
 
 
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Citalopram 
Fluvoxamine 
Anti-tumor drugs 
Anthracyclines 
5-fluoropyrimidine 
Antihistamines 
Diphenhydramine 
Terfenadine 
Astemizole 
Other drugs 
Indapamide 
Cisapride 
 
 
 


 
 
 
 
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Appendix 9 Adverse Event Definitions 
Definitions 
An adverse event (AE) is:  
 Any untoward medical occurrence in a study subject, regardless of whether or not 
considered drug-related. The examples are as follows: 
 Any clinically significant recurrence or worsening of a pre-existing condition. 
 An AE occurring from overdose of a Sponsor study drug whether accidental or intentional 
(i.e., a dose higher than that prescribed by a healthcare professional for clinical reasons). 
 A treatment-emergent AE is defined as: an AE that occurs after the subject starts treatment 
with the IMP. 
A pre-existing condition is a clinical condition (including a condition being treated) that is 
diagnosed before the subject signs the Informed Consent Form and that is documented as part of 
the subject’s medical history. 
Note: A procedure is not an AE, but the reason for a procedure may be an AE. 
The diagnosis should be recorded, in preference to listing the individual signs and symptoms. For 
example, symptoms of fever, cough, and elevated white blood cells should be reported as 
pneumonia rather than the individual signs and symptoms. Abnormal laboratory values are 
typically not reported as AEs by themselves, but rather are included with the underlying 
diagnosis. For example, a low serum hemoglobin value associated with gastrointestinal bleeding 
should not be reported separately from the underlying diagnosis of gastrointestinal hemorrhage. 
Reporting of Adverse Events 
At each visit, the investigator, or delegate, will determine whether or not any AEs have occurred. 
Non-leading questions such as “How are you feeling today?” or “Have you had any health 
concerns since your last visit?” should be used to elicit the subject to report any possible AEs. If 
any AEs have occurred, they will be recorded in the AE section of the electronic Case Report 
Form (eCRF) and in the subject’s source documents.  
AEs will be collected from the time of informed consent until the final study visit. AEs that are 
related to the investigational drug and continue beyond the normal collection period (i.e., are 
ongoing at the time a subject exits the study) will be followed until resolution or stabilization. 
Assessment of Severity 
The investigator will be asked to provide an assessment of the AE severity using the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 classification. This study will 


 
 
 
 
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enroll subjects undergoing elective surgeries requiring general anesthesia using endotracheal 
intubation; however, not all subjects will be healthy volunteers. Elective surgery does not 
necessarily mean optional surgery. Elective means the surgery can be scheduled in advance, and 
it can still be associated with serious conditions. The intent is to exclude emergent surgeries for 
life-threatening conditions, while still including a diverse, heterogenous patient population such 
as ASA-PS III-IV, elderly, and morbidly obese subjects with comorbidities. The CTCAE 
Version 5 severity classification is as follows:  
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
 Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activity of daily living (preparing meals, shopping for groceries or 
clothes, using the telephone, managing money). 
 Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activity of daily living (bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden). 
 Grade 4: Life-threatening consequences; urgent intervention indicated. 
 Grade 5: Death related to AE. 
 
Relationship to Study Treatment 
The investigator will make a determination of the relationship of the AE to the study drug using 
a 4-category system according to the following guidelines: 
 Not related: When the AE is definitely caused by the subject’s clinical state, or the study 
procedure/conditions. There is no association between the study drug and the reported event; 
there is a clear alternative explanation; a causal relationship is non plausible. 
 Unlikely Related: Underlying or concurrent disease or other drugs/exposures provide 
plausible alternative explanations. Temporal relationship to study drug administration makes 
a causal relationship improbable. 
 Likely Related: There is a reasonable possibility that the drug caused the AE; the event is 
unlikely attributed to underlying or concurrent disease or other drugs/exposures (i.e., 
alternative explanation). There is a reasonable time sequence to administration of the study 
drug. 
 Definitely Related: A definite causal relationship exists between the drug administration and 
the AE; including a plausible time relationship to drug administration, and it cannot be 
explained by underlying or concurrent disease or other drugs/exposures; abates upon 


 
 
 
 
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discontinuation of the drug, follows a known or hypothesized cause-effect relationship, and 
(if appropriate) reappears when the drug is reintroduced. 
Action Taken for Adverse Events 
The investigator or designee will record the action taken for the AE in the eCRF. Actions taken 
will include: 
 Dose increased: The medication schedule was modified by addition, either by changing the 
frequency, strength, or amount. 
 Dose not changed: The medication schedule was not changed. 
 Dose reduced: The medication schedule was modified by subtraction, either by changing the 
frequency, strength, or amount. 
 Drug interrupted: The medication schedule was modified by temporarily terminating the 
prescribed regimen of medication. 
 Drug withdrawn: The medication schedule was modified through termination of the 
prescribed regimen of medication. 
 Not applicable 
 Unknown 
 
Follow-up of Adverse Events 
All serious AEs (SAEs) that are ongoing at the time of discontinuation, or that develop prior to 
the final Follow-up Telephone Call, will be followed for 30 days, or until resolution or 
stabilization. 
Serious Adverse Events 
An SAE is any AE occurring at any dose that meets 1 or more of the following criteria: 
 Results in death 
 Is life-threatening (see below) 
 Requires subject hospitalization or prolongation of an existing hospitalization (see below) 
 Results in a persistent or significant disability or incapacity (see below) 
 Results in a congenital anomaly or birth defect 
 Results in an important medical event (see below). 
Additionally, important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered SAEs when, based on appropriate medical judgment, 
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of the outcomes listed above. Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room, blood dyscrasias or convulsions that do not require 
hospitalization, or development of drug dependency or drug abuse. 
A life-threatening adverse event is any AE that places the subject at immediate risk of death 
from the event as it occurred. A life-threatening event does not include an event that might have 
caused death had it occurred in a more severe form but that did not create an immediate risk of 
death as it actually occurred. For example, drug-induced hepatitis that resolved without evidence 
of hepatic failure would not be considered life-threatening, even though drug-induced hepatitis 
of a more severe nature can be fatal. Hospitalization is to be considered only as an overnight 
admission.  
Hospitalization or prolongation of a hospitalization is a criterion for considering an AE to be 
serious.  
The following circumstances should not be considered an AE/SAE: 
 Planned hospitalization for the surgery required for study participation. 
 Hospitalization or prolongation of hospitalization is part of a routine procedure followed by 
the study center (e.g., stent removal after surgery). This should be recorded in the study file. 
 Hospitalization for surgical follow-up required as routine standard of care. 
In addition, a hospitalization planned before the start of the study for a pre-existing condition that 
has not worsened does not constitute an SAE (e.g., elective hospitalization for a total knee 
replacement due to a pre-existing condition of osteoarthritis of the knee that has not worsened 
during the study).   
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions (i.e., the AE resulted in a significant, persistent, or permanent change, impairment, 
damage, or disruption in the subject’s bodily function/structure, physical activities, or quality of 
life).   
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
those situations where important medical events may not be immediately life-threatening or 
result in death, hospitalization, disability, or incapacity. These include events that may jeopardize 
the subject or may require medical intervention to prevent one or more outcomes listed in the 
definition of serious. Such events should usually be considered as serious. 


 
 
 
 
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Appendix 10 Clinical Laboratory Evaluations 
The following clinical laboratory analytes will be assessed:  
Chemistry (Chem-20): 
Hematology (CBC): 
Albumin 
Hematocrit 
ALP 
Hemoglobin 
ALT 
MCH 
AST 
MCHC 
BUN 
MCV 
Calcium 
Platelet count  
Chloride 
RBC count 
Cholesterol (TC, LDL, HDL, TG) 
WBC count 
Creatinine 
WBC differential 
GGT 
(% & ABS count) 
Glucose 
Basophils 
LDH 
Eosinophils 
Phosphorus 
Lymphocytes 
Potassium 
Monocytes 
Sodium 
Neutrophils 
Bilirubin (Total and Indirect) 
 
Total CO2 (measured as bicarbonate) 
 Hormone: 
Total protein 
Urine pregnancy test  local laboratory 
only (For females only) 
Uric acid  
Serum pregnancy test (For females only) 
 
TSH* (free T-4 if TSH abnormal) 
 
 
Complete Urinalysis (UA): 
Glycosylated Hemoglobin 
Color and appearance  
HbA1c* 
pH and specific gravity 
 
Bilirubin 
 
Glucose 
 
Ketones  
 
Leukocytes  
 
Nitrite  
 
Occult blood  
 
Protein  
 
Microscopic (including RBCs and 
WBCs) 
 
Abbreviations: ABS = absolute; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; CO2 = carbon dioxide; GGT = gamma 
glutamyl transferase; LDH = lactate dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean 


 
 
 
 
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corpuscular hemoglobin concentration; MCV = mean corpuscular volume; RBC = red blood cell; TSH = thyroid 
stimulating hormone; WBC = white blood cell. 
*: HbA1c and TSH test (with free T-4 if TSH abnormal) will only be done during the screening period.  
 
 


 
 
 
 
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Appendix 11 Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences International 
Ethical Guidelines 
 Applicable ICH GCP Guidelines 
 Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator’s Brochure, and 
other relevant documents (e.g., advertisements) must be submitted to an Institutional Review 
Board (IRB)/Ethics Committee (EC) by the investigator and reviewed and approved by the 
IRB/EC before the study is initiated.  
 Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
The investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/EC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/EC. 
 Notifying the IRB/EC of serious adverse events or other significant safety findings as 
required by IRB/EC procedures. 
 Providing oversight of the conduct of the study at the site and adherence to requirements of 
21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study specific 
ICF giving details of the study drugs, procedures, and potential risks of the study. Subjects will 
be instructed that they are free to obtain further information from the investigator (or designee) 
and that their participation is voluntary, and they are free to withdraw from the study at any time. 


 
 
 
 
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Subjects will be given an opportunity to ask questions about the study prior to providing consent 
for participation.   
Subjects or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of local regulations, ICH guidelines, and the 
IRB/EC or study center, where applicable. The subject will be given a copy of the signed ICF, 
and the original will be maintained with the subject’s records.  
Subjects must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
Subject Data Protection 
Subjects will be assigned a unique identifier and will not be identified by name in electronic 
Case Report Forms (eCRFs), study-related forms, study reports, or any related publications. 
Subject and investigator personal data will be treated in compliance with all applicable laws and 
regulations. In the event the study protocol, study report, or study data are included in a public 
registry, all identifiable information from individual subjects or investigators will be redacted 
according to applicable laws and regulations.  
The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. The subject must also be informed that his/her medical records may be 
examined by Sponsor or Contract Research Organization (CRO) auditors or other authorized 
personnel appointed by the Sponsor, by appropriate IRB/EC members, and by inspectors from 
regulatory authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The investigator (or 
designee) agrees not to disclose such information in any way without prior written permission 
from the Sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
 All subject data relating to the study will be recorded on eCRFs unless directly transmitted to 
the Sponsor or designee electronically (e.g., laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by electronically signing the eCRF.  
 The investigator must maintain accurate documentation (source data) that supports the 


 
 
 
 
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information entered in the eCRF.  
 The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  
 The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. Pre-defined, agreed risks, monitoring thresholds, quality 
tolerance thresholds, controls, and mitigation plans will be documented in a risk 
management register. Additional details of quality checking to be performed on the data may 
be included in a Data Management Plan. 
 Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of subjects are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.  
 Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator in accordance with 21 CFR 312.62(c) unless local regulations 
or institutional policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.  
Investigator Documentation Responsibilities 
All individual, subject-specific study data will be entered into a 21 CFR Part 11-compliant 
electronic data capture (EDC) system on an eCRF in a timely fashion. All data generated from 
external sources (e.g., central laboratory, pharmacokinetics, pharmacodynamics, 
electrocardiogram central readers) and transmitted to the Sponsor or designee electronically will 
be integrated with the subject’s eCRF data in accordance with the Data Management Plan. 
An eCRF must be completed for each subject who signs an ICF and undergoes any pre-screening 
or screening procedures, according to the eCRF completion instructions. The Sponsor, or CRO, 
will review the supporting source documentation against the data entered into the eCRFs to 
verify the accuracy of the electronic data. The investigator will ensure that corrections are made 
to the eCRFs and that data queries are resolved in a timely fashion by the study staff.   
The investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the investigator reviewed and approved the data on 
the eCRF, the data queries, and the site notifications. 
 
 


 
 
 
 
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Publications 
If on completion of the study the data warrant publication, the investigator may publish the 
results in recognized (refereed) scientific journals subject to the provisions of the clinical study 
agreement (CSA). Unless otherwise specified in the CSA, the following process shall occur: 
The institution and investigator shall not publish or present data from an individual study center 
until the complete multicenter study has been presented in full or for 2 years after the termination 
of the multicenter study, whichever occurs first. Subsequent publications must refer to the 
multicenter findings. Thereafter, if the investigator expects to participate in the publication of 
data generated from this site, the institution and investigator shall submit reports, abstracts, 
manuscripts, and/or other presentation materials to the Sponsor for review before submission for 
publication or presentation. The Sponsor shall have 60 days to respond with any requested 
revisions, including (without limitation) the deletion of confidential information. The 
investigator shall act in good faith upon requested revisions, except the investigator shall delete 
any confidential information from such proposed publications. The investigator shall delay 
submission of such publication or presentation materials for up to an additional 90 days to have a 
patent application(s) filed. 
 
 


 
 
 
 
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Appendix 12 Study design (a larger version) 
 


 
 
 
 
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Appendix 13 Detailed Summary of Changes 
The below reflects changes made from protocol Version 5.0 to Version 6.0. Minor clarifications, formatting, grammatical and 
spelling errors have been corrected throughout Version 6.0 as needed and may not be outlined below. Corresponding updates 
have been reflected in the synopsis, appendices, and figures as applicable. 
 
Sections(s) affected 
Duration of subject participation in study, page 15 
 
Existing text 
The sequence and maximum duration of the study periods per subject will be as follows: 
• Screening: up to 14 days prior to the surgery  
• Treatment: on the day of surgery 
• Follow-up: 24 hours post study drug administration 
• Phone contact: 1 week [±2] days post-surgery 
Total duration for each subject is expected to be 22 [±2] days (including screening and 1 week follow up telephone call). 
Updated text 
The sequence and maximum duration of the study periods per subject will be as follows: 
• Screening: up to 14 days prior to the surgery and including the day of surgery (if needed) 
• Treatment: on the day of surgery 
• Follow-up: 24 hours post study drug administration 
• Phone contact: 1 week [±2 days] post-surgery 
Total duration for each subject is expected to be 22 [±2] days (including screening and 1 week follow up telephone call). 
 
Section(s) affected 
SCHEDULE OF ASSESSMENTS, pages 20-24 


 
 
 
 
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Existing text 
Screening 
Day -13 to Day 
0 
Updated text 
Screening 
Day -13 to Day 
1 p 
Existing text 
 
Screening 
Study 
treatment 
Follow-up visits 
Phone contact 
 
Day -13 to 
Day 0 
Day 1  
(day of 
surgery) 
6-hour and 
24 hour (Day 2) i follow-up after study drug 
administration  
Day 8 
1 week (±2 
days) post day 
of surgery 
 
 
 
PACU 
6 (±2) hours 
24 (±6) hours 
(Day 2) 
 
Clinical laboratory tests  
X l 
 
 
X k 
 
 
Serum pregnancy test 
(females)  
X l 
 
 
 
 
 
Updated text 


 
 
 
 
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Screening 
Study 
treatment 
Follow-up visits 
Phone contact 
 
Day -13 to 
Day 1p 
Day 1  
(day of 
surgery) 
6-hour and 
24 hour (Day 2) i follow-up after study drug 
administration  
Day 8 
1 week (±2 
days) post day 
of surgery 
Clinical laboratory tests  
X lp 
 
 
X k 
 
 
Serum pregnancy test 
(females)  
X lp 
 
 
 
 
 
Existing text 
No footnote p 
Updated text 
Footnote p added - In cases where a separate screening visit is not feasible or the central laboratory results are not available 
on Day 1, screening activities may be conducted on Day 1 prior to surgery. A study approved local laboratory may be used to 
confirm eligibility. In these cases, required screening laboratory samples must be drawn in parallel and sent to the central 
laboratory.     
Existing text 
Footnote l: Clinical laboratory tests (Appendix 10) include hematology, blood chemistry, and urinalysis; pregnancy tests for all 
women of childbearing potential (serum sample at screening and urine sample at baseline). HbA1c and TSH test (with free T-4 if 
TSH abnormal) will only be done during the screening period.  
Updated text 
Footnote l: Clinical laboratory tests (Appendix 10) include hematology, blood chemistry, and urinalysis; pregnancy tests for all 
women of childbearing potential (serum sample at screening and urine sample at baseline. If screening and baseline are both 


 
 
 
 
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conducted on Day 1, a urine sample for pregnancy testing is not required if eligibility is confirmed with an approved local lab 
as per footnote p). HbA1c and TSH test (with free T-4 if TSH abnormal) will only be done during the screening period.  
 
Sections(s) affected 
1.3 Benefit-risk Assessment, pages 33-34 
 
Existing text 
To date, 24 completed Phase I to III clinical studies of HSK3486 have been carried out and a total of 1072 subjects have been 
exposed to HSK3486. Analysis of data from 1072 subjects have been completed. 
Updated text 
To date, 26 completed Phase I to III clinical studies of HSK3486 have been carried out and a total of 1202 subjects have been 
exposed to HSK3486. Analysis of data from 1202 subjects has been completed. 
 
Section(s) affected 
3.1 Overall Study Design and Plan Description, page 38 
Existing text 
Before surgery, premedication is allowed except for sedative hypnotic or analgesic drugs. 
Updated text 
On Day 1, premedication is allowed prior to induction except for sedative hypnotics, analgesics (eg., opioids, NSAIDs, APAP) 
or any medications that relieve pain (eg., Gabapentin), unless otherwise specified in the protocol. Premedication should be 
recorded if used. 
 
Section(s) affected 
4.2 Exclusion Criteria, pages 43-44 
 
Existing text 
Exclusion criteria: 
Subjects will be excluded from the study if they satisfy any of the following criteria at the screening visit: 


 
 
 
 
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Sponsor Reference: HSK3486-305 
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Updated text 
Exclusion criteria: 
Subjects will be excluded from the study if they satisfy any of the following criteria at the screening or Day 1 visit: 
Existing text 
7) 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). 
Updated text 
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). 
 
Section(s) affected 
5.6 Preinduction Drugs, page 53 
 
Existing text 
All subjects will receive preinduction IV midazolam at dose 0.04 mg/kg, up to 3 mg maximum per subject over 15 [±2] seconds 
at 5 minutes [±30] seconds prior to initiating induction agents as premedication. And all subjects will receive preinduction IV 
fentanyl 1 mcg/kg rounded up to the nearest 25 mcg, up to 100 mcg maximum. Fentanyl and midazolam doses should be 
appropriately reduced in elderly patients as per the anesthetist’s discretion. Note: Administration of study drug must be initiated 
at 2 minutes [±10] seconds after preinduction fentanyl administration stop time. 
Updated text 
All subjects will receive preinduction IV midazolam at dose 0.04 mg/kg, up to 3 mg maximum per subject over 15 [±2] seconds 
at 5 minutes [±30 seconds] prior to initiating induction agents as premedication. And all subjects will receive preinduction IV 
fentanyl 1 mcg/kg rounded up to the nearest 25 mcg, up to 100 mcg maximum. Fentanyl and midazolam doses can be reduced 
according to patient’s age and comorbidities as per the anesthetist’s discretion. Note: Administration of study drug must be 
initiated at 2 minutes [±10 seconds] after preinduction fentanyl administration stop time. 


 
 
 
 
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Sections(s) affected 
6.2 Prohibited Therapies, pages 55 
 
Existing text: 
No sedative hypnotic, anesthetic drugs, analgesics, and systemic neuromuscular blocking agents other than those prescribed in 
the protocol are allowed from when the subjects are given preanesthetic medications until the completion of endotracheal 
intubation, including but not limited to the following: 
 Analgesics: morphine, methadone, codeine, pentazocine, tramadol, etc. 
Updated text: 
No sedative hypnotics, anesthetic drugs, analgesics, systemic neuromuscular blocking agents or any medications that relieve 
pain other than those prescribed in the protocol are allowed on Day 1 until the completion of endotracheal intubation, including 
but not limited to the following: 
 Analgesics: morphine, methadone, codeine, pentazocine, tramadol, NSAIDs, APAP etc. 
 Other drugs that relieve pain: Gabapentin 
 
Sections(s) affected 
7.1.1 Screening Period (Day -13 to Day 0), pages 56-57 
 
Existing text 
7.1.1 Screening Period (Day -13 to Day 0) 
Updated text 
7.1.1 Screening Period (Day -13 to Day 1) 
Existing text 
During screening, laboratory tests will be processed centrally to confirm eligibility.    
Updated text 


 
 
 
 
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During screening, the preference is for laboratory tests to be processed centrally to confirm eligibility. However, in cases where 
a separate screening visit is not feasible or the central laboratory results are not available on Day 1, a study approved local 
laboratory may be used to confirm eligibility. In these cases, required screening laboratory samples must be drawn in parallel 
and sent to the central laboratory.     
 
Section(s) affected 
7.1.2 Day of Surgery (Day 1), pages 57 - 61 
 
Existing text: 
 Premedication allowed except sedative-hypnotic or analgesic drugs. 
Updated text: 
 Premedication allowed except sedative-hypnotics, analgesic drugs or any medications that relieve pain. 
Existing text 
Prior to entering the operating room: 
 Measure vital signs (HR, RR, SpO2, SBP, DBP, MAP, Temp) to confirm consistent with eligibility criteria (after the subject 
has been resting supine for ≥5 minutes). 
Updated text 
Prior to entering the operating room: 
• Refer to 7.1.1 for certain cases where local labs may be drawn to confirm eligibility. 
 Measure vital signs (HR, RR, SpO2, SBP, DBP, MAP, Temp) to confirm consistent with eligibility criteria (after the subject 
has been resting supine for ≥5 minutes). 
Existing text 
Preinduction period: 


 
 
 
 
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CONFIDENTIAL 
Sponsor Reference: HSK3486-305 
Page 108 of 110 
• Subjects will receive IV midazolam at dose 0.04 mg/kg, up to 3 mg maximum over 15 [±2] seconds at 5 minutes [±30] 
seconds prior to initiation of induction agents as premedication. The start and end time of midazolam administration 
should be recorded. The end time of midazolam administration will begin the window.  
Updated text: 
Preinduction period: 
• Subjects will receive IV midazolam at dose 0.04 mg/kg, up to 3 mg maximum over 15 [±2] seconds at 5 minutes [±30 
seconds] prior to initiation of induction agents as premedication. The midazolam dose can be reduced according to 
patient’s age and comorbidities as per the anesthetist’s discretion. The start and end time of midazolam administration 
should be recorded. The end time of midazolam administration will begin the window to start of IP.  
Existing text 
Preinduction period: 
• Subjects will receive preinduction IV fentanyl at a dose of 1 mcg/kg rounded up to the nearest 25 mcg, up to 100 mcg 
maximum over 15 [±2] seconds at 2 minutes [±10] seconds prior to initiation of induction agents. The start and end time of 
fentanyl administration should be recorded. The end time of fentanyl administration will begin the window. 
Updated text: 
Preinduction period: 
• Subjects will receive preinduction IV fentanyl at a dose of 1 mcg/kg rounded up to the nearest 25 mcg, up to 100 mcg 
maximum over 15 [±2] seconds at 2 minutes [±10 seconds] prior to initiation of induction agents. The fentanyl dose can 
be reduced according to patient’s age and comorbidities as per the anesthetist’s discretion. The start and end time of 
fentanyl administration should be recorded. The end time of fentanyl administration will begin the window to start of IP. 
Existing text 
Induction period of general anesthesia: 
• Within 15 minutes post start of study drug administration, evaluate and record cardiac depression. 


 
 
 
 
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Page 109 of 110 
Updated text 
Induction period of general anesthesia: 
• Evaluate and record cardiac depression from start of study drug administration until the subject leaves the operating 
room. 
 
Section(s) affected 
7.3.5 Clinical Laboratory Evaluations, pages 69-70 
 
Existing text 
Laboratory tests are performed in the screening period and 6 (±2) hours post administration of study drug except for HbA1c and 
TSH (with free T-4 if TSH abnormal). HbA1c and TSH are only drawn at the screening visit.  
Updated text 
Laboratory tests are performed in the screening period and 6 (±2) hours post administration of study drug except for HbA1c and 
TSH (with free T-4 if TSH abnormal). HbA1c and TSH are only drawn at the screening visit. In cases where a separate 
screening visit is not feasible or the central laboratory results are not available on Day 1, a study approved local laboratory 
may be used to confirm eligibility. In these cases, required screening laboratory samples must be drawn in parallel and sent to 
the central laboratory. Local laboratory results will be maintained in the source documents but not be entered into the eCRF.     
For cases where central and local labs are drawn at the same time, blood volumes noted above in bullets 1 and 2 will be 
increased to approximately 15 mL total. Urine volume noted in bullet 3 will be increased to approximately 15 mL.  
 
Section(s) affected 
8.5 Safety Analysis, page 76 
 
Existing text 


 
 
 
 
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Laboratory test variables will be summarized by treatment group and visit using descriptive statistics. Shift tables between 
baseline and post-baseline time points will be presented by laboratory test and treatment group. Laboratory tests with categorical 
results that cannot be analyzed by change from baseline or shift table analysis will not be included in these summaries but will be 
listed. Data obtained from laboratory tests not required by the protocol will not be summarized but will be listed. 
Updated text 
Laboratory test variables will be summarized by treatment group and visit using descriptive statistics. Shift tables between 
baseline and post-baseline time points will be presented by laboratory test and treatment group. Laboratory tests with categorical 
results that cannot be analyzed by change from baseline or shift table analysis will not be included in these summaries but will be 
listed.  
 
 
 

SAP_001.pdf: 
Cover Page 
STATISTICAL ANALYSIS PLAN V2.0 HSK3486-305 
 
TITLE OF STUDY: 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 
 
NCT NUMBER: NCT05478174 
 
DOCUMENT DATE: 30 OCTOBER 2023 


Version:  HSK3486-305-SAP_v2.0.docx 
STATISTICAL ANALYSIS PLAN 
30 OCTOBER 2023 FINAL V2.0 
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 
PROTOCOL NUMBER HSK3486-305 
SPONSORED BY 
Haisco-USA Pharmaceuticals, Inc 
PREPARED BY 
This document is confidential and proprietary to Haisco-USA Pharmaceuticals, Inc.  Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein will be reproduced, 
published, or otherwise disclosed without the prior written approval of Haisco-USA Pharmaceuticals, Inc, except that 
this document may be disclosed to appropriate Institutional Review Boards under the condition that they keep the 
information confidential. 


Haisco-USA Pharmaceuticals, Inc 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. HSK3486-305 
 
30 October 2023 
Version:  HSK3486-305-SAP_v2.0.docx 
 
Page 2 of 68 
DOCUMENT VERSION CONTROL 
 
Version Number 
Date 
Comments/Changes 
1.0 
20 June 2023 
N/A 
2.0 
30 October 2023 
Added potential blood-
compatibility AEs and 
changed eyelash effect 
measurement timepoint to 
the start of the drug 
administration 
 
 
 
 
 
 
 
 


Haisco-USA Pharmaceuticals, Inc 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. HSK3486-305 
30 October 2023 
Version:  HSK3486-305-SAP_v2.0.docx 
Page 3 of 68 
APPROVALS 
Approved: 


Haisco-USA Pharmaceuticals, Inc 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. HSK3486-305 
 
30 October 2023 
Version:  HSK3486-305-SAP_v2.0.docx 
 
Page 4 of 68 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ........................................................................................... 6 
LIST OF IN-TEXT TABLES ............................................................................................ 7 
1. 
PURPOSE OF THE ANALYSES ............................................................................. 8 
2. 
PROTOCOL SUMMARY ......................................................................................... 9 
2.1 
Study Objectives........................................................................................... 9 
2.1.1 
Primary objective ................................................................................. 9 
2.1.2 
Secondary objectives .......................................................................... 9 
2.2 
Overall Study Design and Plan ..................................................................... 9 
2.2.1 
Preinduction Period ........................................................................... 10 
2.2.2 
Induction Period of General Anesthesia ............................................ 11 
2.2.3 
Maintenance Period of General Anesthesia....................................... 13 
2.2.4 
Follow-up period (6 hours Post Study Drug and 24-hours Post Study Drug 
Administration (Day 2); Day 8 Phone Contact) .................................. 14 
2.3 
Study Population ........................................................................................ 15 
2.4 
Treatment Regimens .................................................................................. 17 
2.4.1 
Test Product ...................................................................................... 17 
2.4.2 
Reference Therapy ............................................................................ 18 
2.5 
Sample Size Determination ........................................................................ 19 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS ................................. 20 
4. 
ANALYSIS POPULATIONS .................................................................................. 21 
4.1 
Full Analysis Set ......................................................................................... 21 
4.2 
Per Protocol Set ......................................................................................... 21 
4.3 
Safety Set ................................................................................................... 21 
5. 
STUDY SUBJECTS ............................................................................................... 22 
5.1 
Disposition of Subjects ............................................................................... 22 
5.2 
Protocol Deviations ..................................................................................... 22 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ........................ 23 
6.1 
Medical History ........................................................................................... 24 
6.2 
Surgical History .......................................................................................... 24 
6.3 
Allergy History ............................................................................................ 24 
6.4 
Planned Study Surgery ............................................................................... 24 
6.5 
Prior and Concomitant Medications/Therapies ........................................... 24 
7. 
MEASUREMENTS OF TREATMENT COMPLIANCE ........................................... 27 
8. 
EFFICACY EVALUATION ..................................................................................... 28 
8.1 
Overview of Efficacy Analysis Issues .......................................................... 28 
8.1.1 
Handling of Dropouts or Missing Data ............................................... 28 
8.1.2 
Multicenter Studies ............................................................................ 28 
8.1.3 
Assessment Time Windows .............................................................. 28 
8.1.4 
Multiple Comparisons/Multiplicity ....................................................... 28 
8.2 
Efficacy Variables ....................................................................................... 28 
8.2.1 
Primary Efficacy Endpoint ................................................................. 30 
8.2.1.1 
Primary Efficacy Analysis ..................................................... 30 
8.2.1.2 
Justification of the Non-inferiority Margin .............................. 31 
8.2.2 
Key Secondary Efficacy Analyses ..................................................... 31 


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8.2.2.1 
Composite Endpoint to Evaluate Desired Depth of Anesthesia31 
8.2.2.2 
Injection-site Pain ................................................................. 32 
8.2.3 
Other Secondary Efficacy Endpoints ................................................. 33 
8.2.3.1 
Time to Successful Anesthesia Induction .............................. 33 
8.2.3.2 
Time to Loss of Eyelash Reflex ............................................ 33 
8.2.3.3 
Successful Induction without Non-optimal Anesthetic Effects 34 
8.2.3.4 
Changes in the Bispectral Index ........................................... 34 
8.2.3.5 
Brice Awareness Questionnaire ............................................ 35 
8.3 
Examination of Subgroups .......................................................................... 35 
9. 
SAFETY EVALUATION ......................................................................................... 36 
9.1 
Overview of Safety Analysis Methods ......................................................... 36 
9.2 
Extent of Exposure ..................................................................................... 36 
9.3 
Adverse Events .......................................................................................... 37 
9.4 
Abuse-related AEsDeaths, Serious Adverse Events, and Other Significant 
Adverse Events .......................................................................................... 40 
9.4.1 
Serious Adverse Events .................................................................... 40 
9.4.2 
Adverse Events of Special Interest .................................................... 40 
9.4.3 
Abuse-Related Adverse Events of Interest ........................................ 42 
9.5 
Clinical Laboratory Evaluations ................................................................... 42 
9.6 
Vital Signs, Physical Findings, and Other Observations Related to Safety.. 43 
9.6.1 
Vital Signs ......................................................................................... 43 
9.6.2 
Physical Examinations ...................................................................... 43 
9.6.3 
12-lead ECG and 3-lead/5-lead ECG ................................................ 43 
10. OTHER ANALYSES .............................................................................................. 44 
11. INTERIM ANALYSES AND DATA MONITORING ................................................. 45 
12. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ....................... 46 
13. REFERENCES ...................................................................................................... 47 
14. APPENDICES ........................................................................................................ 48 
14.1 
Study Flow Chart ........................................................................................ 48 
14.2 
Schedule of Assessments .......................................................................... 49 
14.3 
Modified Observer’s Assessment of Awareness/Sedation (MOAA/S) Scale 54 
14.4 
Bispectral Index (BIS) ................................................................................. 55 
14.5 
Numerical Rating Scale (NRS) for Grading of Injection-site Pain ................ 57 
14.6 
Brice Awareness Questionnaire .................................................................. 58 
14.7 
Pharmacokinetic (PK) Blood Samples Collection Timetable ....................... 60 
14.8 
American Society of Anesthesiologists (ASA) Physical Status Grade ......... 61 
14.9 
Mallampati Classification ............................................................................ 62 
14.10 Adverse Event Definitions ........................................................................... 63 
14.11 Clinical Laboratory Evaluations ................................................................... 67 
 
 
 


Haisco-USA Pharmaceuticals, Inc 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. HSK3486-305 
 
30 October 2023 
Version:  HSK3486-305-SAP_v2.0.docx 
 
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LIST OF ABBREVIATIONS 
AESI 
Adverse Event of Special Interest 
BIS 
bispectral index 
BMI 
body mass index 
CNS 
central nervous system 
DBP 
diastolic blood pressure 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
HR 
heart rate 
KM 
Kaplan-Meier 
MAP 
mean arterial pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOAA/S 
Modified Observer’s Assessment of Awareness/Sedation 
NIM 
non-inferiority margin 
NRS 
Numeric Rating Scale 
PACU 
post-anesthesia care unit 
PK 
pharmacokinetic 
PT 
preferred term 
RR 
respiratory rate 
SAP 
Statistical Analysis Plan 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SOC 
system organ class 
SpO2 
oxygen saturation 
Temp 
temperature 
WHODrugG 
World Health Organization Global Drug Dictionary 
 
 
 
 
 
 


Haisco-USA Pharmaceuticals, Inc 
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Statistical Analysis Plan 
Protocol No. HSK3486-305 
 
30 October 2023 
Version:  HSK3486-305-SAP_v2.0.docx 
 
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LIST OF IN-TEXT TABLES 
Table 8-1 
Efficacy Variables and Analysis Methods ...................................... 29 
Table 9-1 
Exposure Variables ........................................................................ 36 
 


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Statistical Analysis Plan 
Protocol No. HSK3486-305 
 
30 October 2023 
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1. 
PURPOSE OF THE ANALYSES 
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. 
This statistical analysis plan (SAP) provides a detailed description of the strategy and statistical 
methodology to be used for analysis of data from the HSK3486-305 protocol. 
The purpose of the SAP is to describe the pre-specified statistical approaches to the analysis of 
study data prior to database lock. This analysis plan is meant to supplement the study protocol. If 
differences occur between analyses described in the SAP and the current protocol, those found in 
this SAP will assume primacy. Any deviations from this plan will be described in the Clinical 
Study Report. 


Haisco-USA Pharmaceuticals, Inc 
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Statistical Analysis Plan 
Protocol No. HSK3486-305 
 
30 October 2023 
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2. 
PROTOCOL SUMMARY 
2.1 
Study Objectives 
2.1.1 
Primary objective 
• To demonstrate HSK3486 0.4/0.2 mg/kg (0.4 mg/kg intravenous [IV] slow injection 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 for first dose, an additional 1.0 mg/kg if needed) in success 
of induction of general anesthesia in adults undergoing elective surgery. 
2.1.2 
Secondary objectives 
Key Secondary Objectives:  
• To confirm that HSK3486 0.4/0.2 mg/kg leads to statistically significant less injection-
site pain in all compared to propofol 2.0/1.0 mg/kg during the induction of general 
anesthesia in adults undergoing elective surgery.  
• To demonstrate HSK3486 0.4/0.2 mg/kg provides better anesthetic effects compared to 
propofol 2.0/1.0 mg/kg without significant cardiac and respiratory depression in 
conjunction with other routinely used preinduction and maintenance anesthetic agents in 
the induction of general anesthesia in adults undergoing elective surgery.  
Additional Efficacy Objectives:  
• To evaluate HSK3486 0.4/0.2 mg/kg induction time in general anesthesia compared to 
propofol.  
• To evaluate HSK3486 0.4/0.2 mg/kg time to the disappearance of eyelash reflex 
compared to propofol.  
• To confirm that HSK3486 0.4/0.2 mg/kg leads to statistically significant less moderate 
injection-site pain compared to propofol 2.0/1.0 mg/kg during the induction of general 
anesthesia in adults undergoing elective surgery.  
• To better characterize that HSK3486 0.4/0.2 mg/kg leads to statistically significant less 
average NRS scales in injection-site pain compared to propofol 2.0/1.0 mg/kg during the 
induction of general anesthesia in adults undergoing elective surgery.  
Safety:  
• To evaluate the overall safety profile of HSK3486 compared to propofol.  
Pharmacokinetic:  
• To characterize the HSK3486 population pharmacokinetic (PK) profile.  
2.2 
Overall Study Design and Plan 
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 


Haisco-USA Pharmaceuticals, Inc 
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Statistical Analysis Plan 
Protocol No. HSK3486-305 
 
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undergoing elective surgery with endotracheal intubation. The study design is described in detail 
below and outlined graphically in Appendix 14.1. The schedule of assessments can be found in 
Appendix 14.2. 
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 14.3) has been achieved and administration of neuromuscular 
blocking agent. 
On Day 1, premedication is allowed prior to induction except for sedative-hypnotics, analgesics 
(e.g., opioids, NSAIDs, APAP), or any medications that relieve pain (e.g., Gabapentin), unless 
otherwise specified in the protocol. 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. 
2.2.1 
Preinduction Period 
• Obtain vital signs (heart rate [HR], respiratory rate [RR], oxygen saturation [SpO2], 
systolic blood pressure [SBP], diastolic blood pressure [DBP], mean arterial pressure 
[MAP]), Temperature [Temp]; baseline value will be the measurement immediately prior 
to initiation of study drug administration. Attach 3-lead or 5-lead electrocardiogram 
(ECG) to subject and monitor continuously. In the event an abnormality is noted with 3-
lead or 5-lead ECG, clinical significance of an abnormality should be documented, and 
the investigators will decide whether to add a 12-lead ECG.  
• Attach bispectral index (BIS [Appendix 14.4]) monitor to subject. Record the three most 
recent BIS values preceding midazolam administration. 
• Subjects will receive IV midazolam at dose 0.04 mg/kg, up to 3 mg maximum over 15 
[±2] seconds at 5 minutes [±30] seconds prior to initiation of induction agents as 
premedication. The midazolam dose can be reduced according to patient’s age and 
comorbidities as per the anesthetist’s discretion. The start and end time of midazolam 
administration should be recorded. The end time of midazolam administration will begin 
the window to start of IP.  


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• Subjects will receive preinduction IV fentanyl at a dose of 1 mcg/kg rounded up to the 
nearest 25 mcg, up to 100 mcg maximum over 15 [±2] seconds at 2 minutes [±10] 
seconds prior to initiation of induction agents.  The start and end time of fentanyl 
administration should be recorded. The end time of fentanyl administration will begin the 
window to start of IP. 
Note: Throughout the preinduction and induction periods, a timing device must be used 
to allow accuracy and sequencing of necessary assessments. 
• Information about any adverse events (AEs) and concomitant medications will be 
recorded. 
2.2.2 
Induction Period of General Anesthesia 
The induction of general anesthesia will be performed as follows:  
• Monitor vital signs (HR, RR, SpO2, SBP, DBP, MAP, Temp) continuously. HR, RR, 
SBP, DBP, MAP, Temp should be recorded once every 2 minutes [±30 seconds], SpO2 
value should be recorded once every 1 minute [± 15 seconds] from the start of study drug 
administration (for every time point) for 30 minutes post start of study drug 
administration, for the judgment of key secondary endpoint.  
Note: Vital signs (HR, RR, SBP, DBP, MAP, Temp) monitor should be set to cycle every 
1 minute to obtain vitals at least every 2 minutes (in case cycle requires longer than 1 
minute).  
• Administer IV study drug (HSK3486 0.4 mg/kg or propofol 2.0 mg/kg) into vein located 
on the back of right or left hand (this IV location is strongly preferred rather than 
mandatory) at a port closest to the IV cannula (IV injection time: 30 [±5] seconds).  
• The MOAA/S will be evaluated every 30 [±10] seconds after end of study drug 
administration until MOAA/S ≤1 is reached.  
• If MOAA/S is still >1 at 1 minute [±10 seconds] post end of study drug 
administration, a top-up dose of 50% of the initial dose of study drug (either 
HSK3486 0.2 mg/kg or propofol 1 mg/kg depending on treatment group) will be 
given to the subject (IV injection time: 10 [±2] seconds).  Start and end times of 
top-up dose administration will be recorded. The MOAA/S will be evaluated 
every 30 [±10] seconds post end of the top-up dose administration. 
• If MOAA/S is still >1 at 2 minutes [±10 seconds] post end of the top-up dose 
administration, then the rescue drug, propofol, will be given (in both treatment 
groups). The rescue dose is prepared as the initial calculated propofol dose 
(100%) and administered per propofol guidelines. The MOAA/S will be evaluated 
every 30 [±10] seconds post end of rescue drug administration until MOAA/S ≤1 
is reached. 
• Administration of study drug must be initiated 5 minutes [±30 seconds] post 
midazolam preinduction medication administration stop time and at 2 minutes 
[±10 seconds] after preinduction fentanyl administration stop time. Top-up dose 
should be administered within 10 seconds once MOAA/S is evaluated >1. 


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• Injection-site pain is evaluated verbally by Numerical Rating Scale (NRS; Appendix 
14.5). Upon initiation of study drug administration, the investigator should immediately 
ask the subject to rate his or her pain at injection-site. As a general guidance, the 
evaluation should be done multiple times with the first evaluation occurring typically 
within 15 seconds after initiation of study drug injection and monitored until successful 
induction (MOAA/S ≤1).  Related information, such as the occurrence and severity of 
injection pain (NRS 0-10), shall be recorded. The maximum (highest value) injection-site 
pain will be recorded in EDC as NRS.  
• Post the end of initial study drug administration, the eyelash reflex will be evaluated 
every 30 [±10] seconds until loss of eyelash reflex. If there is a top-up dose, eyelash 
reflex will be evaluated every 30 [±10] seconds post end of the top-up dose 
administration until loss of eyelash reflex. If there is rescue drug given, eyelash reflex 
will be evaluated every 30 [±10] seconds post end of the rescue drug until loss of eyelash 
reflex.  The time of loss of eyelash reflex should be recorded. 
• BIS will be monitored continuously; record baseline BIS value prior to administering 
study drug. BIS values will be collected at the following timepoints post start of initial 
study drug administration: every 30 [±10] seconds for 5 minutes, and then every 2 
minutes [±30 seconds] for 30 minutes and then every 30 [±2] minutes for the duration of 
the surgery. 
• Monitor 3-lead or 5-lead electrocardiogram (ECG) continuously. Abnormalities that are 
clinically significant or not clinically significant should be recorded. The investigators 
will decide whether to add a 12-lead ECG.  
• When MOAA/S ≤1 is reached, then IV rocuronium bromide (0.6 mg/kg) is to be 
administered for neuromuscular blockade to perform endotracheal intubation. The start 
and end times of rocuronium bromide administration should be recorded.  RR should be 
collected until initiation of administration of rocuronium. 
Note: For subjects with BMI >40 kg/m2, the rocuronium dose may be modified per 
investigator discretion. 
Note: Additional IV rocuronium is allowed per investigator’s discretion only in response 
to clinical symptoms during tracheal intubation, such as gag reflex and movement et al, 
or during surgical procedures. The start and end times of additional rocuronium bromide 
administration should be recorded.   
• Intubate subject once neuromuscular blockade has taken effect; if using twitch monitor, 
intubate once no twitches are noted. The start and end times of first and subsequent 
intubation attempts should be recorded. 
• During endotracheal intubation, evaluate and record clinical symptoms and/or signs for 
inadequate depth of anesthesia, such as lacrimation, movement, vomiting, coughing, 
laryngospasm, bucking, swallowing reflex and/or bronchospasm, etc. for at least 15 
minutes from start of study drug administration. 
• Between start of study drug administration and prior to the administration of rocuronium 
bromide, evaluate and record respiratory depression.    


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Note: Respiratory depression includes apnea, defined as absence of thoracic movement 
lasting >30 seconds, prior to the administration of rocuronium bromide, or hypoxia, 
defined as SpO2 <90% lasting >30 seconds, or life-threatening apnea or hypoxia 
requiring immediate intervention. 
• Evaluate and record cardiac depression from start of study drug administration until the 
subject leaves the operating room. 
Note: Cardiac depression is defined as SBP <90 mmHg lasting >2 minutes plus requiring 
medical intervention such as inotropes, vasopressors, or IV fluid resuscitation, or life-
threatening hypotension requiring immediate intervention. 
• Sevoflurane (an inhalation anesthetic agent) will be used for maintenance of general 
anesthesia. Initiate sevoflurane within 60 seconds after successful endotracheal 
intubation. The end-tidal concentration of sevoflurane should be 1.5-2.0 % (The initial 
concentration that is set and start time of administration should be recorded).  
• Information about any AEs and concomitant medications will be recorded.  
2.2.3 
Maintenance Period of General Anesthesia 
• During the maintenance period of general anesthesia, the inhalational anesthetic agent 
sevoflurane will be used according to routine clinical practice, and the end-tidal 
concentration of sevoflurane should be 1.5-2.0 % within 15 minutes after initiation of 
study drug administration and can be adjusted to the desired effect after that. Propofol 
should not be used at any time all throughout the maintenance period.  
• During the maintenance period, end-tidal sevoflurane concentration will be monitored per 
standard of care.  
• The BIS will be monitored continuously per standard of care, and BIS values will be 
collected at the following timepoints from start of initial study drug administration: every 
30 [±10] seconds until 5 minutes, then every 2 minutes [±30 seconds] until 30 minutes 
and then every 30 [±2] minutes for the duration of the surgery.  
• Additional IV fentanyl or other analgesic drug may be administered for intraoperative 
analgesia only after initiation of sevoflurane, preferably after 15 minutes following the 
initiation of study drug administration, start time and end time of initial study drug 
administration should be recorded; if additional drug used, the start and end time of 
administration should be recorded. 
• Subject management during surgery needs to follow routine best practice which includes 
Antiemetics Ondansetron, or other 5 HT-3 antagonists and/or Dexamethasone. 
Antiemetics should be given during surgery and before subjects wake up unless otherwise 
contraindicated. The use of antiemetics should be recorded in concomitant medications. 
• Monitor 3-lead or 5-lead ECG continuously. Abnormalities of clinical significance and 
non-clinical significance should be recorded. The investigators decide whether to add a 
12-lead ECG based on the Subject's condition. Information about any adverse events 
(AEs) and concomitant medications will be recorded. 


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• Information about any adverse events (AEs) and concomitant medications will be 
recorded. 
 
2.2.4 
Follow-up period (6 hours Post Study Drug and 24-hours Post Study 
Drug Administration (Day 2); Day 8 Phone Contact) 
 Day 1 Visit: 
For the first 6 hours post study drug evaluation, study assessments and procedures will be 
assessed as indicated in the Schedule of Assessments: 
• After the surgery, vital signs (HR, RR, SpO2, SBP, DBP, MAP, Temp) will be assessed at 
6 [+2] hours post start study drug administration.  
Note: If surgery lasts >4 hours, vital signs, clinical laboratory tests and 12-ECG should 
be obtained 1[+1] hour after completion of surgery. Duration of surgery is defined as 
time from study drug administration to time of transfer from operating room to recovery 
room or post-anesthesia care unit (PACU). 
• Clinical laboratory tests (including hematology, blood chemistry, and urinalysis) will be 
obtained at 6[±2] hours post start study drug administration. 
• Obtain 12-lead ECG at 6 [±2] hours post start study drug administration. 
• In the post-anesthesia care unit (PACU), once the subject is alert and oriented, repeat 
NRS for recall of pain at time of study drug administration and assess surgical awareness 
with recall using the Brice Awareness Questionnaire (Appendix 14.6). The assessment 
time and result should be recorded.  
• Information about any AEs and concomitant mediations will be collected and recorded.  
• After the surgery, subjects may remain in the hospital or observation unit if required 
based on standard of care and the clinical situation; however, if the subject is clinically 
stable after the Day 1 follow-up assessments and appropriate to be discharged home per 
the judgement of the investigator and surgeon, the subject may be released with 
supervision by a family member or friend, and must return to the clinic for the 24-hour 
follow-up visit (Day 2). 
Day 2 Visit: 
For the 24-hour follow-up (Day 2) visit, study assessments and procedures will be assessed 
as indicated in the Schedule of Assessments: 
• 24 [±6] hours post study drug administration (Day 2), obtain vital signs (HR, RR, SpO2, 
SBP, DBP, MAP, Temp).  
• Information about any AEs and concomitant mediations will be collected and recorded. 
Day 8 Phone Contact: 
• Subjects will be evaluated by a follow-up telephone call 7 [±2] days after surgery. 


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• Surgical awareness with recall will be re-assessed using the Brice Awareness 
Questionnaire.  
• Information about any AEs and associated medications will be collected and recorded. 
2.3 
Study Population 
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 14.8). 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* and male subjects with female partners of childbearing potential must agree to use 
effective contraception as defined in the study protocol 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. Subjects 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: 


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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: 
a) 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.  
b) 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). 
c) Cerebrovascular disease: subject with a history of serious craniocerebral injury, 
convulsion, seizure disorder, intracranial hypertension, cerebral aneurysm, or stroke.  
d) Subjects 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. 
e) 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. 
f) Known glycosylated hemoglobin (HbA1c) greater than or equal to 10%. 
g) 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. 
h) 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).  
i) 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: 


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a) 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.  
b) History (or family history) of malignant hyperthermia. 
c) Any previous failure of tracheal intubation. 
d) 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 14.9], 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: 
a) Neutrophil count ≤1.5 x 109/L 
b) Platelet count <80 x 109/L 
c) Hemoglobin <90 g/L (without blood transfusion within 14 days) 
d) Alanine transaminase and/or aspartate transaminase ≥2.0 x upper limit of normal (ULN) 
e) Total bilirubin ≥2.0 x ULN 
f) 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. 
2.4 
Treatment Regimens 
2.4.1 
Test Product 
Name: HSK3486 injectable emulsion  
Dose, route, frequency: 0.4 mg/kg, IV slow injection over 30 [±5] seconds, preoperatively; 1 top 
up dose (0.2 mg/kg), IV injection over 10 [±2] seconds permitted if needed.  
For elderly subjects ≥65 years of age, the dose will be automatically adjusted to a 25% dose 
reduction. According to the judgment of the investigator, the dose can be further reduced up to 
50% of the calculated dose. The administration time should be extended to 1 minute for this 
population.  


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For ASA grade 3-4 subjects, the dose can be reduced by 25-50% per investigator discretion. The 
administration time should be extended to 1 minute for these populations. 
For subjects with BMI ≤40 kg/m2, total body weight (TBW) will be used to determine HSK3486 
dose; for subjects with BMI >40 kg/m2, lean body weight (LBW) will be used to determine 
HSK3486 dose, and rescue dose. LBW should be calculated using the Janmahasatian formula 
included below. 
The Janmahasatian Formula:  
• For males: estimated LBW = (9270 x TBW (kg))/ (6680 + (216 x BMI)) 
• For females: estimated LBW = (9270 x TBW (kg))/ (8780 + (244 x BMI)) 
HSK3486 injectable emulsion will be stored at ≤ 25 °C (77°F) away from light and should not be 
frozen. It should be shaken well before use. 
2.4.2 
Reference Therapy 
Name: Propofol injection 
Dose, route, frequency: 2.0 mg/kg, IV slow injection over 30[±5] seconds, preoperatively; 1 top 
up dose (1 mg/kg), IV injection over 10 [±2] seconds is permitted if needed.  
For elderly subjects ≥65 years of age, the dose will be automatically adjusted to a 25% dose 
reduction. According to the judgment of the investigator, the dose can be further reduced by up 
to 50% of the calculated dose. The administration time should be extended to 1 minute for this 
population. 
For ASA grade 3-4 subjects, the dose can be reduced by 25-50% per investigator discretion. The 
administration time should be extended to 1 minute for these populations. 
For subjects with BMI ≤40 kg/m2, TBW will be used to determine propofol dose; for subjects 
with BMI >40 kg/m2, LBW will be used to determine propofol dose, and Rescue dose. LBW 
should be calculated using the Janmahasatian formula included below. 
The Janmahasatian Formula:  
• For males: estimated LBW = (9270 x TBW (kg))/ (6680 + (216 x BMI)) 
• For females: estimated LBW = (9270 x TBW (kg))/ (8780 + (244 x BMI)) 
Propofol will be stored between 4°C and 25°C (40° to 77°F) away from light and should not be 
frozen. It should be shaken well before use.  
The rescue dose is prepared as 100% of the initial calculated dose and administered per propofol 
guidelines above.   


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2.5 
Sample Size Determination 
A total of 399 subjects (266 in HSK3486 0.4/0.2 mg/kg group and 133 in propofol 2.0/1.0 mg/kg 
group) need to be enrolled 2:1 into this study based on the following assumptions: 
• For the primary endpoint, a sample size of 215 subjects will give at least 90% power 
(providing the primary endpoint is statistically significant) assuming that type I error is 0.025 
(1-sided), the success rate of general anesthesia induction of HSK3486 and propofol are both 
97%, and non-inferiority margin (NIM) is -8%. 
• For the key secondary endpoint of incidence of injection-site pain, a sample size of 365 
subjects will give 90% power (providing the primary endpoint is statistically significant) 
assuming α= 0.015 (2-sided) and the proportion of subjects who meet the endpoint criteria of 
any injection-site pain are 6.8% and 20.5% for HSK3486 and propofol, respectively. 
• For the key secondary composite endpoint, a sample size of 338 subjects will give 90% 
power (providing the primary endpoint is statistically significant) to the superior testing, 
assuming α= 0.035 (2-sided), the proportion of subjects with successful induction, 
maintained desired depth of anesthesia for general elective surgery, without significant 
cardiac depression within the 15-minute post initiation start of study drug administration 
observation period and no significant respiratory depression  (prior to administration of 
rocuronium bromide) of HSK3486 and propofol are 82% and 65%, respectively (i.e., 17% 
treatment effect). 
To power statistical testing for all three endpoints at 90% and provide sufficient safety data, it is 
decided that 399 subjects will be randomized and treated in this study (266 in HSK3486 0.4/0.2 
mg/kg group and 133 in propofol 2.0/1.0 mg/kg group). 


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3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
The following is a list of general analysis and reporting conventions to be applied for this study.  
• Categorical variables will be summarized using the frequency of subjects/events and 
percentages. Percentages will be reported to one decimal place. 
• Continuous variables will be summarized descriptively, including the number of subjects 
(n), mean, standard deviation, median, minimum, and maximum. 
• The minimum and maximum will be reported to the same level of precision as the 
original observations.  The mean and median will be reported to 1 more significant digit 
than the precision of the original observations. Standard deviation will be reported to 2 
more significant digits than the precision of the original observations. 
• P values will be reported to 3 decimal places if greater than 0.001.  P values less than 
0.001 will be reported as ‘<0.001’.  Report P values and significant levels as 0.05 (with 
leading zero) rather than .05. 
• No preliminary rounding will be performed; rounding will only occur after analysis.  To 
round, consider the digit to the right of the last significant digit:  if < 5 then round down, 
if ≥5 then round up. 
• All listings will be sorted in order of treatment group (i.e., HSK3486, propofol), subject 
identifier, and time of assessment (e.g., visit, date, time, and/or event). Dates in listings 
will be displayed as YYYY-MM-DD (e.g., 2022-01-22). 
• All analysis will be performed using the SAS System version 9.4 or higher. 
If departures from these general conventions are present in the specific evaluations section of this 
SAP, then those conventions will take precedence over these general conventions.  


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4. 
ANALYSIS POPULATIONS 
4.1 
Full Analysis Set 
The Full Analysis Set (FAS) will include all randomized subjects who receive any dose of the 
study drug (HSK3486 or propofol). The FAS will be the primary population used for all efficacy 
endpoints. Subjects will be analyzed according to the study drug to which they are randomized. 
4.2 
Per Protocol Set 
All subjects from the FAS who have completed the primary efficacy endpoint measurement will 
be considered for the Per Protocol Set (PPS). Subjects with any important protocol deviations 
will be reviewed after database lock and prior to study unblinding and may be excluded from 
PPS if these important deviations will impact the efficacy evaluations. The PPS will be a 
secondary efficacy population, used only for certain efficacy analyses. Subjects will be analyzed 
according to the study drug to which they are randomized. 
4.3 
Safety Set 
The Safety Set (SS) will include all randomized subjects who receive any dose of the study drug 
and have post-dose safety assessment data. The SS will be the primary population used for all 
safety analyses. Subjects will be analyzed according to the study drug actually administered, 
regardless of the randomized assignment. Note that only the initial study drug administration will 
be taken into account, while rescue propofol will be ignored for the purposes of classification of 
treatment groups in safety analyses. 


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5.
STUDY SUBJECTS
5.1 
Disposition of Subjects
The number and percentage of subjects in each of the following categories will be summarized 
by treatment group and overall: 
•
Screen Failures (with reason for screen failure)
•
Enrolled (signed informed consent)
•
Randomized (has randomization record in the Interactive Web Randomization System)
•
Received Study Drug
•
Completed Primary Efficacy Measurement
•
Completed Study
•
Discontinued Study (with primary reason for discontinuation)
Disposition information will also be presented in a by-subject listing, including the variables 
listed above. Randomization information will be presented in a separate by-subject listing, 
including the randomization date and time, randomization number, and stratification factors) 
In addition, the number and percentage of subjects in each analysis population (FAS, PPS, SS) 
will be summarized by treatment group and overall. The analysis populations will also be 
presented in a by-subject listing, including the reason for exclusion when appropriate. 
5.2 
Protocol Deviations 
All protocol deviations in this study will be reported in      CTMS, as determined by clinical 
research associates during site monitoring or by medical reviewers. The CTMS can be exported 
as an Excel listing. 
No additional programmatic deviations will be derived. Subjects with any important protocol 
deviations will be reviewed after database lock and prior to study unblinding and may be 
excluded from PPS if these important deviations will impact the efficacy evaluations. 
The number and percentage of subjects with any protocol deviation will be summarized by 
treatment group and overall for the SS. The display will be sorted by descending frequency of 
overall subjects who incurred each deviation. The same summary will be repeated separately for 
non-important deviations only and for important deviations only. All protocol deviations will 
also be presented in a by-subject listing, including a column to indicate whether the deviation 
was considered important or not. 


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6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
The demographic variables and baseline characteristics listed below will be summarized by 
treatment group and overall for each of the FAS, PPS, and SS. For categorical variables, the 
possible responses are listed in parentheses. Demographics and baseline characteristics will also 
be presented in a by-subject listing. 
• Age, in years (from electronic Case Report Form [eCRF]; will not be re-derived) 
• Age Stratification Factor (<65 years, ≥65 years) 
• Sex (female, male) 
• Childbearing Potential (yes, no) 
Note: Denominator for percentages will exclude male subjects. 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, unknown) 
• Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Not Reported) 
• ASA-PS Score (I, II, III, IV, V) 
• ASA-PS Stratification Factor (I-II, III-IV) 
• Modified Mallampati Score (I, II, III, IV) 
• Ever Consumed Alcohol (never, current, former) 
• History of Drug Abuse in Last 3 Months (yes, no) 
• Any Relevant Anesthesia History (yes, no) 
• Post-Op Nausea and Vomiting (yes, no) 
• High Fevers with Anesthesia (yes, no) 
• History of Malignant Hyperthermia (yes, no) 
• Height, in cm 
• Weight, in kg 
• BMI, in kg/m2 
• BMI Stratification Factor (<35 kg/m2, ≥35 kg/m2) 


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6.1 
Medical History 
Medical history data for this study consists of log lines of self-reported medical conditions. Each 
event reported will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 25.0 system organ class (SOC) and preferred term (PT). Events will then be summarized 
by MedDRA SOC and PT, by treatment group and overall for the SS. The display will be sorted 
by descending frequency of overall subjects who incurred each SOC, and by descending 
frequency of PT within each SOC. 
The medical history data will also be presented in a by-subject listing, including the verbatim 
investigator description of the relevant medical condition, the coded terms (SOC, PT), start date, 
end date, and whether the condition is ongoing. 
6.2 
Surgical History 
Surgical history data for this study consists of log lines of self-reported surgical conditions. Each 
condition reported will be coded using the MedDRA version 25.0 system organ class (SOC) and 
preferred term (PT). Conditions will then be summarized by MedDRA SOC and PT, by 
treatment group and overall for the SS. The display will be sorted by descending frequency of 
overall subjects with a condition reported under each SOC, and by descending frequency of PT 
within each SOC. 
The surgical history data will also be presented in a by-subject listing, including the verbatim 
investigator description of the relevant condition, the coded terms (SOC, PT), whether the 
condition is controlled, date of first diagnosis, date of resolution, and whether the subject is 
taking any ongoing medications for the condition. 
6.3 
Allergy History 
Allergy history data will not be summarized, as the names of the allergic medicines/substances 
will not be coded. Allergy history data will be presented in a by-subject listing, including the 
allergen category, name of the allergic medicine/substance, name of the allergy condition, date of 
first diagnosis, whether the allergy is ongoing, and the severity of symptoms.  
6.4 
Planned Study Surgery 
Details of the planned study surgery will be summarized by treatment group and overall for the 
SS. The summary will include the number of subjects on whom surgery was performed, whether 
the subject fasted for 6 hours prior, type of surgery (Abdominal/Pelvic, Cosmetic and 
Reconstructive, Head and Neck, Orthopedic, or Other), location of surgery (Head and Neck, 
Upper Extremity, Lower Extremity, Abdomen, Chest/Thorax, Pelvis/Urogenital, Buttocks, 
Back/Spine, or other). Study surgery data will also be presented in a by-subject listing. 
6.5 
Prior and Concomitant Medications/Therapies 
Protocol-specified medications administered in the operating room (such as fentanyl, 
rocuronium, midazolam) will not be considered concomitant medications, and will instead be 
summarized along with the study drug and rescue medications, as described in Section 9.2. 


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All other medications and therapies recorded will be divided into 4 categories for the purposes of 
analysis: 
• Prior Medications will be any medications/supplements/vitamins used before the Day of 
Surgery, within 1 month before screening. 
• Intraoperative Analgesics will be any analgesic drugs administered in the operating 
room, excluding protocol-specified medications (collected via eCRF form “Intraoperative 
Administration”). 
• Concomitant Medications will be any medications/supplements/vitamins used by the 
subjects during Day of Surgery and after surgery until the end of the study (Day 8) 
(collected via eCRF page “Prior and Concomitant Medications”). Note that some 
medications can be considered both prior and concomitant if initiated before the Day of 
Surgery and continued on or past the Day of Surgery. 
• Concomitant Therapies will be any non-medication therapies used by the subjects 
during Day of Surgery and after surgery until the end of the study (collected via eCRF 
page “Concomitant Non-Medications Therapy”). 
All prior & concomitant medications/therapies will be coded to the World Health Organization 
Global Drug Dictionary (WHODrugG), March 2022 version. For prior and concomitant 
medications and therapies, the number and percentage of subjects receiving each 
medication/therapy will be summarized by WHODrug Anatomical Therapeutic Class (ATC) 
Level 4 Term, by treatment group and overall for the SS. 
In order to define concomitant medications, the start and end dates of each medication will be 
imputed as follows. The date of surgery will be compared to the start and end dates of 
medication in order to determine whether the medication was concomitant; therefore, times are 
not relevant for this comparison, and will not be imputed. 
Medication Start Dates: 
• If the medication start date is completely missing, then impute using the Date of Surgery. 
• If the year of medication start is available, but the month and day are missing: 
o If year of medication start is the same as year of Date of Surgery, then impute as 
the month and day or Date of Surgery. 
o If year of medication start is prior to year of Date of Surgery, then impute as 
December 31. 
o If year of medication start is after year of Date of Surgery, then impute as January 
01. 
• If the year and month of medication start are available, but the day is missing: 
o If year/month of medication start is the same as year/month of Date of Surgery 
then impute as the Date of Surgery. 
o If year/month of medication start is prior to year/month of Date of Surgery then 
impute as the last day of the month. 


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o If year/month of month is after year/month of Date of Surgery, then impute as the 
first day of the month. 
Medication Stop Dates: 
• If the medication stop date is completely missing or if the medication is ongoing, then 
impute using the subject’s last contact date. 
• If the year of medication stop is available, but the month and day are missing: 
o If year of medication stop is the same as year of Date of Surgery, then impute as 
the subject’s last contact date. 
o If year of medication stop is prior to or after year of Date of Surgery, then impute 
as December 31. 
• If the year and month of medication stop are available, but the day is missing: 
o If year/month of medication stop is the same as year/month of Date of Surgery 
then impute as the subject’s last contact date. 
o If year/month of medication stop is prior to or after year/month of Date of Surgery 
then impute as the last day of the month. 
 
Medication/therapy data will also be presented in four by-subject listings, in accordance with the 
categories specified above. 


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7. 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Treatment compliance is not applicable for this protocol. Analyses of study drug exposure, 
doses, and durations are described in Section 9.2. 


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8. 
EFFICACY EVALUATION 
8.1 
Overview of Efficacy Analysis Issues 
8.1.1 
Handling of Dropouts or Missing Data 
Handling of missing data for each endpoint is discussed in the specific sections for those 
endpoints. 
8.1.2 
Multicenter Studies 
The success rate of general anesthesia induction in both treatment groups (counts and 
proportions) will be reported in a separate display by site (out of the FAS population at that site). 
No inferential statistics will be reported at the site level due to expected small sample sizes. For 
all other analyses described in this document, data from all sites will be pooled for the purpose of 
analyses. 
8.1.3 
Assessment Time Windows 
No analysis windowing will be performed. 
8.1.4 
Multiple Comparisons/Multiplicity 
The primary endpoint of non-inferiority to propofol for successful induction of general 
anesthesia will be tested first. If the null hypothesis fails to be rejected, the testing will stop. If 
the primary endpoint is statistically significant, then the key secondary endpoints will be tested 
in parallel using a weighted Bonferroni-Holm step-down approach with weights w1=0.7 for the 
proportion of subjects who maintain the desired depth of anesthesia, and w2=0.3 for the 
incidence of injection-site pain. In this procedure, the p-values for the secondary endpoints are 
divided by their respective alpha levels, then the endpoint for which this calculation is smaller 
(i.e., test pj < αj for j=arg min (p1/0.035, p2/0.015)) is tested. If the first test is rejected, then the 
other endpoint will be tested at α=0.05; otherwise testing will stop. This procedure controls the 
familywise Type I error rate at the overall α=0.05 level for the key secondary endpoints. The 
analyses for all other secondary endpoints will be descriptive, and any testing that may be done 
will not be adjusted to maintain Type I error [4]. 
8.2 
Efficacy Variables 
Table 8-1 below presents a summary of the study efficacy variables and types of analyses used to 
evaluate them.


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Table 8-1 
Efficacy Variables and Analysis Methods 
Efficacy Variables 
NIa 
CMHb 
KMc 
ANOVAd 
Descriptivee 
Primary 
 
 
 
 
 
Proportion of Subjects with Successful Induction 
X 
 
 
 
 
 
 
 
 
 
 
Secondary 
 
 
 
 
 
Proportion of Subjects Meeting Successful Induction Secondary 
Composite Endpoint 
 
X 
 
 
 
Proportion of Subjects with Any Injection Site Pain (NRS ≥1) 
 
X 
 
 
 
Proportion of Subjects with Moderate Injection Site Pain (NRS ≥4) 
 
X 
 
 
 
Mean NRS Pain Score 
 
 
 
X 
 
Time to Successful Induction of General Anesthesia 
 
 
X 
 
 
Time to Disappearance of Eyelash Reflex 
 
 
X 
 
 
Proportion of Subjects with Successful Induction of General 
Anesthesia without Non-optimal Anesthetic Effects 
 
X 
 
 
 
Change of BIS During the Period of Anesthesia Post Study Drug 
Administration up to 15 Minutes 
 
 
 
 
X 
Brice Awareness Questionnaire 
 
 
 
 
X 
ANOVA = analysis of variance; ASA-PS = American Society of Anesthesiologists Physical Status; BIS = bispectral index; BMI = body mass index; CI = confidence 
interval; CMH = Cochran-Mantel-Haenszel; KM = Kaplan Meier; NI = Non-inferiority; NRS = numerical rating scale. 
a The lower limit of the Farrington-Manning 95% CI for the risk difference will be compared with the NI margin of -8%. 
b CMH Chi-squared test controlling for the stratification factors in the study randomization. 
c The median time and its 95% CI will be provided by treatment group using the Kaplan-Meier (KM) method. The KM estimates and 95% CIs at selected time 
points will also be reported. A Cox regression model controlling for the stratification factors in the study randomization will be used to compare treatment groups. 
d Mean treatment differences will be compared via ANOVA, controlling for the stratification factors in the study randomization. 
e Endpoints will be summarized descriptively, with no inferential statistics computed. 


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8.2.1 
Primary Efficacy Endpoint 
Success rate of anesthesia induction: The proportion of subjects with successful anesthesia 
induction in all subjects of the group. 
A successful anesthetic induction should meet both of following conditions: 
1. Successful induction of anesthesia (MOAA/S ≤ 1) after the dosing of the study drug, and 
2. One or less top-up dose required without using any rescue drugs. 
Scoring criteria: According to the MOAA/S scale (Appendix 14.3), observation and evaluation 
will be carried out stepwise, and the cross-level evaluation will not be carried out. 
MOAA/S scoring: The subject's name will be called during induction to observe the subject's 
response to name calling with a normal tone. The subject will be lightly stimulated or shaken 
after the subject falls asleep, and the subject's response to painful stimulation will be observed. If 
the subject does not respond to the light stimulus or shaking but responds to painful stimulation 
(by squeezing the trapezius muscle), the MOAA/S score is 1 and the time from the end of the 
dosing of the study drug to when MOAA/S is ≤1 will be recorded. 
8.2.1.1 
Primary Efficacy Analysis 
The primary efficacy  analysis will compare the success rate of anesthesia induction (defined as 
the proportion of subjects with MOAA/S ≤ 1 after the dosing of the study drug, with one or less 
top-up dose required, and without using any rescue drugs) between the HSK3486 group and the 
propofol group using a difference of proportions (HSK3486 minus propofol) among all subjects 
in the FAS (all randomized subjects who receive any dose of the study drug), analyzed as 
randomized. The FAS subjects who are non-evaluable for anesthesia success will be counted as 
treatment failures in the primary analysis. No additional sensitivity analysis is planned, as 
minimal missing data is expected for this study design. 
The statistical null hypothesis to be tested is: 
𝐻𝐻0: 𝑝𝑝𝑡𝑡 – 𝑝𝑝𝑐𝑐 ≤ 𝛿𝛿 
With the alternative hypothesis: 
𝐻𝐻1: 𝑝𝑝𝑡𝑡 – 𝑝𝑝𝑐𝑐 > 𝛿𝛿 
Where pt and pc are the anesthesia success rates for the HSK3486 and propofol arms, 
respectively, and δ is the NIM. This hypothesis will be tested at the 1-sided α=0.025 level. 
Success rate of general anesthesia induction in both groups and rate difference between groups 
and its 95% confidence interval (CI) will be estimated by Farrington-Manning method in the 
FAS. The lower limit of 95% CI of rate difference will be compared with the NIM of -8% to 
confirm the establishment of non-inferiority. The FAS subjects who are non-evaluable for 
anesthesia success will be counted as treatment failures in the primary analysis. 


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In addition, the primary endpoint analysis described above will be repeated using the PPS to test 
the robustness of the primary endpoint when removing subjects with important protocol 
deviations. 
Grades and times from all MOAA/S assessments will also be presented in a by-subject listing, 
including the datetime of induction of anesthesia, and the datetime of loss of eyelash reflex. 
8.2.1.2 
Justification of the Non-inferiority Margin 
The NIM for this study is based on the expectation that the active control, propofol, and 
HSK3486 will both perform similarly to historical evidence, achieving ≥97% efficacy for 
induction of general anesthesia, defined as achieving MOAA/S ≤1 after 1 dose, with no more 
than 1 top-up dose if needed. Since the expected response rates are ≥97%, there is little concern 
for loss of assay sensitivity (i.e., loss of efficacy) from historical performance or loss of the 
“constancy assumption.” Furthermore, the exercise of attempting to identify the M1 based on 
historical literature would lead to an unacceptably large margin, then applying clinical judgement 
to establish the M2 (often 50% of the M1) (Food and Drug Administration Guidance for 
Industry: Non-Inferiority Clinical Trials to Establish Effectiveness, 2016) would lead to a NIM 
>10%, which permits too much uncertainty to be acceptable or useful. Using a NIM of 8% is 
clinically relevant and meaningful for this indication. 
8.2.2 
Key Secondary Efficacy Analyses 
8.2.2.1 
Composite Endpoint to Evaluate Desired Depth of Anesthesia 
Successfully induced subjects treated with HSK3486 compared to propofol who maintain the 
desired depth of anesthesia for general elective surgery, and without significant cardiac and 
respiratory depression within 15 minutes post initiation of start of study drug administration, or 
up to the start of second tracheal intubation attempt if it is a difficult condition and not beyond 15 
minutes post initiation start study drug initiation are defined as meeting all of the following 
criteria: 
a) Desired depth of anesthesia for general elective surgery is defined if all following criteria 
are met: 
o No clinical signs of inadequate depth of anesthesia, such as lacrimation, movement, 
vomiting, coughing, laryngospasm, bucking, swallowing reflex or bronchospasm etc. 
o 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. 
o Subjects maintain desired depth of anesthesia for general elective surgery with BIS as 
an objective assessment (after reaching the initial lowest value, BIS remains 
sustainable level at not more than 60) 
Note: Target BIS 40 to 60 for general anesthesia (see Appendix 14.4). 
The BIS sustainable level at not more than 60 is defined as not more than 1 episode with 
BIS value observed >60 after reaching initial lowest value, in defined period. 


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b) No significant respiratory depression, such as apnea, prior to the administration of 
rocuronium bromide. 
Note: For the composite endpoint, respiratory depression includes apnea, defined as 
absence of thoracic movement lasting >30 seconds, or hypoxia, defined as SpO2 <90% 
lasting >30 seconds, or life-threatening apnea or hypoxia requiring immediate 
intervention. 
c) No significant cardiac depression indicated by blood pressure decrease that requires 
intervention, i.e., vasopressors and/or IV fluid resuscitation. 
Note: For the composite endpoint, cardiac depression is defined as SBP <90 mmHg 
lasting >2 minutes plus requiring medical intervention such as inotropes, vasopressors, or 
IV fluid resuscitation, or life-threatening hypotension requiring immediate intervention. 
The proportion of FAS subjects meeting the composite endpoint criteria for the proportion of 
successfully induced subjects will be calculated for both groups. The FAS subjects who are non-
evaluable for anesthesia success will be counted as treatment failures in the secondary composite 
endpoint. The difference between groups will be calculated as the difference in proportions 
(HSK3486 minus propofol). The same analysis will be repeated for the PPS subjects. 
The 95% CI will also be reported. The p-value for comparison between groups will be obtained 
based on the Cochran-Mantel-Haenszel (CMH) test using the stratification factors 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). 
8.2.2.2 
Injection-site Pain 
Injection-site pain is evaluated verbally during study drug administration using the NRS, ranging 
from 0 (no pain) to 10 (worse imaginable pain) (see Appendix 14.5). Recollection of pain during 
study drug administration will be assessed in the PACU once the subject is awake and oriented. 
During the baseline visit, the subject will be oriented to the NRS for the evaluation of injection-
site pain. Upon initiation of study drug administration, the investigator will immediately ask the 
subject to rate his or her pain. As a general guidance, the evaluation will be done multiple times 
with the first evaluation occurring typically within 15 seconds after initiation of study drug 
administration and monitored until successful induction (MOAA/S ≤1). Related information 
such as the occurrence and severity of injection pain (NRS 0-10) will be recorded. The maximum 
(highest value) injection-site pain will be recorded. Pain during the injection of study drug in the 
hand/arm will be distinguished from unrelated puncture pain from the IV site or due to adhesive 
tape at the IV site. When injection pain occurs, the subject’s pain will be graded verbally using 
the NRS (0-10) and will be recorded. The subject will be asked to rate the pain on a scale from 0, 
which is no pain, to 10, which is the worst pain imaginable. The subject will point to the number 
on the scale that best represents the intensity of the pain now. In the PACU, once the subject is 
alert and oriented, the NRS for recall of pain at time of study drug administration will be 
repeated. 


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During induction of anesthesia, the maximum NRS pain score collected will be used for all 
analysis detailed below. If no NRS pain score is collected during this time, the NRS recall pain 
score collected in the PACU will be used for analysis. All injection site pain analyses will be 
based on the FAS and repeated in the PPS. 
The proportion of subjects with any injection-site pain (NRS ≥1) will be analyzed using the same 
CMH methods described in Section 8.2.2.1 for the composite secondary endpoint. 
The proportion of subjects with moderate injection-site pain (NRS ≥4) will be analyzed using the 
same CMH methods described in Section 8.2.2.1 for the composite secondary endpoint. 
The mean injection-site NRS pain score will be analyzed using an analysis of variance 
(ANOVA). The model will contain treatment as a fixed effect, with the stratification factors in 
the study randomization included as factors. Descriptive statistics will be provided for the NRS 
pain scores by treatment group, along with the least squares (LS) means, standard errors, 95% 
CIs by treatment group, and LS means, standard errors, and 95% CIs for the difference between 
treatment groups. The difference between groups will be calculated as the difference in LS 
means (HSK3486 minus propofol). 
All injection-site NRS pain scores will also be presented in a by-subject listing. 
8.2.3 
Other Secondary Efficacy Endpoints 
8.2.3.1 
Time to Successful Anesthesia Induction 
The time to successful anesthesia induction is evaluated during the induction period and is 
defined as the time from the start of the first administration of the study drug to the time when 
MOAA/S ≤1. If anesthesia induction requires rescue medication, the subject will be counted as 
an anesthesia induction failure at the time of the rescue medication. If the subject dies prior to 
successful anesthesia induction, the subject will be censored at the time of death. The median 
and its 95% CI of time to successful induction of general anesthesia will be provided by 
treatment group using the KM method. The KM estimates and 95% CIs at selected time points 
will also be reported. 
In addition, a Cox proportional hazards model will be utilized to compare the time to successful 
anesthesia between treatment groups. The model will control for the stratification factors in the 
study randomization. The hazard ratio (HSK3486/propofol) will be reported, along with the 95% 
CI for the hazard ratio, and the p-value to test if the hazard ratio is equal to 1. 
The time to successful anesthesia induction will also be displayed in a KM plot by treatment 
group. 
8.2.3.2 
Time to Loss of Eyelash Reflex 
The time to loss of eyelash reflex is evaluated during the induction period and defined as the 
time from the start of the first administration of the study drug to the time when eyelash reflex is 
lost. Analyses will use the same KM and Cox methods described for the time to successful 
anesthesia induction in Section 8.2.3.1. If rescue medication is required, the subject will be 


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counted as a failure for time to loss of eyelash reflex at the time of the rescue medication. If the 
subject dies prior to successful anesthesia induction, the subject will be censored at the time of 
death. 
The time to loss of eyelash reflex will also be displayed in a KM plot by treatment group. 
8.2.3.3 
Successful Induction without Non-optimal Anesthetic Effects 
Non-optimal anesthetic effects are defined as those subjects experiencing any of the following: 
a) Any clinical symptoms in response to tracheal intubation, such as lacrimation, movement, 
vomiting, coughing, laryngospasm, bucking, swallowing reflex or bronchospasm etc. 
b) An event where 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. 
c) Subjects do not maintain desired depth of anesthesia for general elective surgery with 
BIS as an objective assessment (i.e., after reaching initial lowest value, BIS sustainable 
level at more than 60). 
d) Significant respiratory depression. 
e) Cardiac depression indicated by blood pressure decreases that requires intervention (i.e., 
vasopressors and/or IV fluid resuscitation). 
The proportion of subjects with successful induction without non-optimal anesthetic effects 
within 15 minutes post initiation of administration of study drugs will be analyzed using the 
same CMH methods described for the secondary composite efficacy endpoint in Section 8.2.2.1. 
8.2.3.4 
Changes in the Bispectral Index 
From the start of study drug administration to the end of the surgery, the subjects are 
continuously monitored for their BIS, which is recorded at specified time points to understand 
the changes in the BIS of the subjects throughout the entire anesthesia period (see Appendix 
14.4) for BIS guidance). The BIS is measured prior to midazolam administration, prior to study 
drug administration, every 30 (±10) seconds from study drug administration until 5 minutes post 
study drug administration, and every 2 minutes (±30 seconds) from 5 minutes post study drug 
administration until 30 minutes post study drug administration.  
The BIS values and changes from baseline will be summarized descriptively by treatment group 
for all timepoints collected prior to administration of rescue medication. The average of 3 BIS 
measurements collected immediately prior to study drug administration (after midazolam 
administration) will be considered the baseline value for analysis purposes. Any values collected 
within the appropriate time windows will be included in analysis. No timepoint windowing will 
be performed. Values collected outside of the appropriate time windows will be excluded from 
analysis. If multiple measurements are collected within any given time window for post-baseline 
timepoints, the average measurement within said window will be used for analysis. 


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The BIS values will also be presented in a by-subject listing, including a column to indicate 
which values were collected after administration of rescue medication Additionally, figures will 
be constructed providing the BIS actual values and mean change from baseline over time per 
treatment arm. 
8.2.3.5 
Brice Awareness Questionnaire 
Recall of awareness during surgery, assessed postoperatively, will be evaluated using the Brice 
Awareness Questionnaire (see Appendix 14.6). The questionnaire will be administered in the 
PACU once the subject is alert and oriented. The questionnaire is repeated at Day 8. The results 
of each question will be summarized descriptively by treatment group and timepoint, for all 
timepoints collected prior to administration of rescue medication. 
The Brice Awareness Questionnaire scores will also be presented in a by-subject listing. 
8.3 
Examination of Subgroups 
The primary endpoint for success rate of general anesthesia induction will be repeated for each 
of the following subgroups in the FAS: 
• Age Stratification Factor (<65 years, ≥65 years) 
• ASA-PS Stratification Factor (I-II, III-IV) 
• BMI Stratification Factor (<35 kg/m2, ≥35 kg/m2) 
• Sex (female, male) 
• Race (Asian, Black or African American, White, or Other) 
• Surgery Type (abdominal/pelvic, cosmetic and reconstructive, head and neck, orthopedic, 
or other) 






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o If year of onset is prior to year of initial study drug administration, then impute as 
December 31 at 11:59:59pm. 
o If year of onset is after year of initial study drug administration, then impute as 
January 01 at 12:00:01am. 
• If the year and month of AE onset are available, but the day and time are missing: 
o If year/month of onset is the same as year/month of initial study drug 
administration, then impute as the day and time of initial study drug 
administration. 
o If year/month of onset is prior to year/month of initial study drug administration, 
then impute as the last day of the month at 11:59:59pm. 
o If year/month of onset is after year/month of initial study drug administration, 
then impute as the first day of the month at 12:00:01am. 
• If the date of AE onset is available, but the time is completely missing: 
o If date of onset is the same as date of initial study drug administration, then 
impute as the time of initial study drug administration. 
o If date of onset is prior to date of initial study drug administration, then impute as 
11:59:59pm. 
o If date of onset is after date of initial study drug administration, then impute as 
12:00:01am. 
• If the date and hour of AE onset are available, but the minutes are missing: 
o If date/hour of onset is the same as date/hour of initial study drug administration, 
then impute as the time of initial study drug administration. 
o If date/hour of onset is prior to date/hour of initial study drug administration, then 
impute minutes:seconds as :59:59. 
o If date/hour of onset is after date/hour of initial study drug administration, then 
impute minutes:seconds as 00:01. 
• If the date, hour, and minute of AE onset are available, but the seconds are missing: 
o If date/hour/minute of onset is the same as date/hour/minute of initial study drug 
administration, then impute as the time of initial study drug administration. 
o If date/hour/minute of onset is prior to date/hour/minute of initial study drug 
administration, then impute seconds as :59. 
o If date/hour/minute of onset is after date/hour/minute of initial study drug 
administration, then impute seconds as :01. 
Note that AE stop dates/times will not be imputed since the stop date does not affect the 
determination of treatment emergence. Note also that any listings of AEs will display onset dates 
as collected in the EDC system but will not display imputed dates. 


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All AEs will be coded according to the MedDRA version 25.0 and graded for severity according 
to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
A tabular overview of adverse events will be presented by treatment group and overall, including 
a row for each of the following categories: 
• Number of subjects with any TEAE 
• Total number of TEAEs 
• Number of subjects with any serious TEAE 
• Total number of serious TEAEs 
• Number of subjects with any TEAE of CTCAE grade 2 or higher 
• Total number of TEAEs of CTCAE grade 2 or higher 
• Number of subjects with any AESIs 
• Total number of AESIs 
• Number of subjects with any TEAE related to study drug 
• Total number of TEAEs related to study drug 
• Number of subjects with any TEAE leading to treatment discontinuation 
• Number of subjects with any TEAE leading to study discontinuation 
• Number of subjects with any TEAE leading to death 
In addition, the incidence of TEAEs will be summarized by treatment group and overall, for the 
following categories of AEs: 
• TEAEs by SOC and PT 
• Serious TEAEs by SOC and PT 
• TEAEs related to study drug by SOC and PT 
• Serious TEAEs related to study drug by SOC and PT 
• TEAEs of CTCAE grade 2 or higher by SOC, PT 
• TEAEs leading to treatment discontinuation by SOC and PT 
• TEAEs leading to study discontinuation by SOC and PT 
• TEAEs leading to death by SOC and PT 
• TEAEs by SOC, PT, and maximum severity 
• TEAEs by SOC, PT, and maximum relationship to study drug 
• Common TEAEs (≥2% of subjects in any treatment group) by PT 
• TEAEs of special interest (hypoxemia, bradycardia, hypotension) by PT 
• Abuse-related TEAEs of interest by PT 


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If a subject experiences more than one episode of an AE, the subject will be counted once for the 
given PT. If a subject has more than 1 AE in a SOC, the subject will be counted only once in that 
SOC. The summary tables will include incidence estimates for overall SOC, as well as for PTs 
within each SOC. The displays will be sorted by descending frequency of overall subjects with 
an AE reported under each SOC, and by descending frequency of PT within each SOC. 
The AE data will also be presented in by-subject listings. Separate by-subject listings will be 
generated for each of the following categories of AEs, with a column to indicate whether each 
AE was treatment emergent: 
• All AEs 
• Serious AEs (SAEs) 
• AEs leading to treatment discontinuation 
• AEs leading to study discontinuation 
• AEs leading to death 
• AEs of special interest (AESIs) 
9.4 
Abuse-related AEsDeaths, Serious Adverse Events, and Other 
Significant Adverse Events 
Deaths, SAEs, AESIs and abuse-related AEs of interest will be summarized and listed as 
described in Section 9.3. The type of events that will fall into these categories are described in 
more detail below. 
In addition, any potential blood compatibility-related AEs will be summarized in the same 
manner. 
9.4.1 
Serious Adverse Events 
An SAE is any AE occurring at any dose that meets 1 or more of the following criteria: 
• Results in death 
• Is life-threatening 
• Requires subject hospitalization or prolongation of an existing hospitalization 
• Results in a persistent or significant disability or incapacity 
• Results in a congenital anomaly or birth defect 
• Results in an important medical event. 
9.4.2 
Adverse Events of Special Interest 
The AESIs due to pharmacological effect of an anesthetic agent include hypoxemia, bradycardia, 
severe hypotension, allergy/anaphylaxis, cardiac arrhythmia and QTc prolongation which are 
defined as follows: 


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• Hypoxemia due to respiratory depression is defined as SpO2 <90% with duration of >30 
seconds. Hypoxemia is evaluated from the initial dose of study drug until the subject leaves 
the operating room. Those occurring within 15 minutes from the end of the last dose of 
study drug will be categorized as drug related unless an obvious cause is ascertained.   
• Bradycardia is defined as a heart rate of <45 beats/minute that lasts >30 seconds requires 
intervention (treatment). Bradycardia is evaluated from the initial dose of study drug until 
the subject leaves the operating room. Those occurring within 15 minutes from the end of 
the last dose of study drug will be categorized as drug related unless an obvious cause is 
ascertained.  
• Severe hypotension is defined as an SBP <90 mmHg that lasts >2 minutes requiring 
treatment. Severe hypotension is evaluated from the initial dose of study drug until the 
subject leaves the operating room. Those occurring within 15 minutes from the end of the 
last dose of study drug will be categorized as drug related unless an obvious cause is 
ascertained.  
• Allergy/anaphylaxis may include angioedema, bronchospasm, erythema, and hypotension.  
Allergy/anaphylaxis is evaluated from the initial dose of study drug until visit Day 2.  
• Cardiac arrhythmia is any rhythm not arising from the sinus node (atrial fibrillation, atrial 
flutter, Torsade de pointes). Cardiac arrythmia is evaluated from the initial dose of study 
drug until visit Day 2.  
• QTc prolongation: QTc intervals of > 450 ms in males and > 470 ms in females occurring 
within 15 minutes from the end of the last dose of study drug are considered QTc 
prolongation. Patients who reach an absolute QT interval of more than 500 ms upon QTc 
correction for rate should be reassessed, and immediate action should be taken to correct any 
possible concomitant risk factors [2, 3]. 
AESI start time, end time (both should be accurate to the second and the duration should be 
calculated) and treatment measures should be recorded (if any).  
Note: Vital sign values out of range (or suspected as being erroneous) should be confirmed 
with a second measurement before recording as the confirmed value. 
Note: Since injection-site pain has been recorded and analyzed in the efficacy endpoints, it 
is no longer recorded in the Safety endpoints (see section 2.1.2) for injection-site pain 
evaluation. 
Note: The list and definitions of AESIs as modified in protocol version 5.0 will be 
implemented retroactively to include applicable events for all study subjects. The list 
and definitions were modified primarily based on the background rates of adverse 
events in previously completed studies and include those events that were uncommon, 
rare, or very rare (> 1/1,000; >1/10,000; <1/10,000 respectively) that are clinically 
significant. 
 


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9.4.3 
Abuse-Related Adverse Events of Interest 
Both HSK3486 and propofol cross the blood-brain barrier and have central nervous system 
(CNS) effects, which are the intended pharmacological action of the drug (e.g., sedation, 
anesthesia/unconsciousness). Any untoward change from baseline that is not the intended or 
desired effect of the study drug will be reported as an AE. Investigators and site personnel will 
monitor for and report abuse-related AEs of interest, which include: euphoria, dissociative 
effects, hallucinations, psychosis, changes in mood, impaired cognition, attention and 
psychomotor effects, and inappropriate affect; overdoses, abuse, and misuse. 
9.5 
Clinical Laboratory Evaluations 
The laboratory analytes to be assessed in this study are listed in Appendix 14.11. Blood draws 
for central laboratory evaluations are collected at Screening and at 6 (±2) hours post 
administration of study drug. Summaries of actual values and the changes from baseline to each 
time point will be presented by treatment group and overall for all quantitative laboratory 
parameters (e.g., white blood cell count, lymphocyte count). Summary laboratory values will be 
reported using the International System of Units only. Only data from the central laboratory will 
be summarized. Data collected from local labs will be utilized to address eligibility concerns and 
otherwise at investigators’ discretion but will not be included in summaries. 
Baseline is defined as the last measurement taken on or prior to the initial study drug 
administration. Note that the Day 1 assessment can be included in the evaluation of baseline if 
the sample is drawn prior to dosing. Otherwise, the baseline value would come from the 
screening assessment. 
Quantitative laboratory test results will be classified by the central lab according to whether the 
value was below (L), within (N), or above (H) the laboratory parameter reference range. A 
summary of treatment-emergent shifts will compare the baseline L/N/H classification for each 
laboratory test to the highest and/or lowest L/N/H classification obtained after initial 
administration of study drug. 
Qualitative laboratory test results will be reported using categories such as Abnormal/Normal, 
Positive/Negative, etc. A summary of treatment-emergent shifts will compare the baseline 
classification for each laboratory test to the worst classification obtained after initial 
administration of study drug. 
Laboratory tests with categorical results that cannot be analyzed by change from baseline or shift 
table analysis will not be included in these summaries but will be listed. 
All laboratory evaluation data will be presented in by-subject listings, separated into the 
following 4 groups of analytes: 
• Chemistry (including Glycosylated Hemoglobin and Hormones) 
• Hematology 
• Urinalysis 


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• Pregnancy Test Results 
9.6 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety 
9.6.1 
Vital Signs 
The vital signs collected in this study include RR, HR, SpO2, Temp, SBP, DBP, and MAP. Vital 
signs are assessed at screening, at Day 1 preinduction, continuously during the induction of 
general anesthesia, as well as 6 (±2) hours and 24 (±6) hours post administration of study drug. 
Summaries of actual values and the changes from baseline to each time point will be presented 
by treatment group and overall. 
Baseline is defined as the last measurement taken on or prior to the initial study drug 
administration. Note that the Day 1 assessment will be included in the evaluation of baseline if 
the assessment is performed prior to dosing. Otherwise, the baseline value will come from the 
screening assessment. 
The number of subjects with blood pressure (SBP, DBP, or MAP) with ≥30% decrease from 
baseline will be summarized for each post-baseline time point by treatment group and overall.  
Vital sign data will also be presented in a by-subject listing. Mean change from baseline over 
time for vital sign data will also be presented in a figure for 1) baseline to 30 minutes on Day 1 
and 2) baseline to 6 hours and 24 hours. 
9.6.2 
Physical Examinations 
Physical examinations include skin, head, neck, cardiovascular system, respiratory system, 
gastrointestinal system, psychological and neurological system, and musculoskeletal system. 
These assessments will be completed at screening, and a focused physical exam will be repeated 
as needed to assess AEs. Physical examination data will not be tabulated but will be presented in 
a by-subject listing. 
9.6.3 
12-lead ECG and 3-lead/5-lead ECG 
The 12-Lead ECG parameters collected in this study include PR, QRS, QT, QTcF, and RR. 
These measurements are collected via 12-Lead ECG at screening, at 6 hours (±2 hours) post 
study drug administration, and as clinically indicated.  Summaries of actual values and the 
changes from baseline to each time point will be presented by treatment group and overall. 
In addition, 3-Lead or 5-Lead ECGs are monitored continuously during the surgery. Using the 
normality assessment from all 12-Lead, 3-Lead, and 5-Lead ECGs collected during the course of 
the study, a summary of treatment-emergent shifts will compare the baseline ECG normality 
assessment to the worst ECG normality assessment obtained after initial administration of study 
drug. Normality assessments will be categorized by the PIs at each site as normal, abnormal 
clinically significant, or abnormal not clinically significant. 
All 12-Lead, 3-Lead, and 5-Lead ECG data will also be presented in a by-subject listing. 


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10. 
OTHER ANALYSES 
Not applicable. 


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11. 
INTERIM ANALYSES AND DATA MONITORING 
No formal interim analyses will be conducted. 
An independent data monitoring committee (DMC) will be involved in the conduct of the study 
to ensure the safety of all subjects who have been administered study drug. The DMC will 
consist of 3 unblinded members: 2 anesthesiologists with appropriate clinical expertise and 1 
statistician. The DMC will review all available unblinded safety information at approximately 
30% enrollment. Additionally, enrollment will be immediately stopped after one death during the 
study where a clear alternative cause is not readily apparent (i.e., deemed definitely or likely 
related to study drug); after 4 (4/399 [1%] ) non-fatal serious adverse events (SAEs) where a 
clear alternative cause is not readily apparent (i.e., deemed definitely or likely related to study 
drug); or after 8 (8/399 [2%]) severe AEs of special interest (AESIs; Common Terminology 
Criteria for Adverse Events [CTCAE] Grade 3 or 4) of severe hypotension, bradycardia, hypoxia 
due to respiratory depression, or QTc prolongation occurring within 15 minutes of study drug 
administration, where a clear alternative cause is not readily apparent (i.e., deemed definitely or 
likely related to study drug), and lasting ≥10 minute duration despite routine interventions. 
AESIs of allergy/anaphylaxis or cardiac arrhythmia occurring from the initial dose of study drug 
until Day 2 where a clear alternative cause is not readily apparent will be evaluated as part of the 
stopping criteria. If these criteria are met, enrollment will be temporarily suspended while the 
DMC convenes to review all available unblinded data. Based on recommendations from the 
DMC, the Sponsor can terminate the study or resume enrollment if measures can be taken to 
effectively address (i.e., mitigate) the risk to safely continue the study, such as revising 
inclusion/exclusion criteria or study procedures. The final decision to suspend enrollment or 
proceed will be made by the Sponsor after consultation with the DMC members and taking into 
consideration their recommendations. Conduct of the DMC is described in the DMC Charter.  


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12. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
 In order to avoid using negative numbers in the analysis, the definition of time to successful 
anesthesia induction has been changed from the end of the first administration of the study drug 
to the start of the first administration of the study drug. The ending point of the measurement, 
MOAA/S ≤1, remains unchanged. 
A corresponding change has been made in the definition of the time to loss of eyelash reflex. It 
will be measured from the start of the first administration of the study drug, instead of the end of 
the administration. 
An additional summary table will be added to the analysis, containing any potential blood 
compatibility-related AEs. The PT terms of the AEs will be summarized in the table in a similar 
manner to the AESI output. 


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13. 
REFERENCES 
1. Food and Drug Administration, Center for Drug Evaluation and Research and 
Center for Biologics Evaluation and Research. Guidance for Industry: Non-
Inferiority Clinical Trials to Establish Effectiveness. Food and Drug 
Administration, November 2016. 
2. Kishida H, Cole JS, Surawicz B. Negative U wave: a highly specific but poorly 
understood sign of heart disease. Am J Cardiol. 1982 Jun;49(8):2030-6. doi: 
10.1016/0002-9149(82)90225-9. PMID: 6211085. 
3. Document E 14: Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential of Non-Antiarrhythmic Drugs, Rockville, Md: US 
Department of Health and Human Services, Food and Drug Administration; 
October 2005. 
4. Zhang J, Quan H, Nh J, Stepanavage ME. Some Statistical Methods for Multiple 
Endpoints in Clinical Trials. Elsevier Science Inc. 1997. 
 


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14. 
APPENDICES 
14.1 
Study Flow Chart 
 


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14.2 
Schedule of Assessments 
 
Screening 
Study 
treatment 
Follow-up visits 
Phone 
contact 
 
Day -13 to 
Day 1p 
(prior to 
surgery) 
Day 1  
(day of 
surgery) 
6-hour and 
24 hour (Day 2) i follow-up after 
study drug administration  
Day 8 
1 week (±2 
days) post 
day of 
surgery 
 
 
 
PACU 
6 (+2) hours 24 (+6) hours 
(Day 2) 
 
Written informed 
consent 
X 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
Verify 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Modified Mallampati 
score assessment 
X 
 
 
 
 
 
Physical exam a 
X  
 
 
 
 
 
Vital signs  
X 
X j 
 
X k 
X k 
 
Height, weight, and 
BMI 
X 
X 
 
 
 
 
12-lead ECG 
 
X 
X f 
 
X f 
 
 
Clinical laboratory 
tests  
X lp 
 
 
X k 
 
 
Serum pregnancy test 
(females)  
X lp 
 
 
 
 
 
Urine pregnancy test 
(females)  
 
X l 
 
 
 
 
Instruct subject to fast 
minimum of 6 hours 
before surgeryo 
X 
 
 
 
 
 
Confirm preoperative 
readiness b 
 
X 
 
 
 
 


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Screening 
Study 
treatment 
Follow-up visits 
Phone 
contact 
 
Day -13 to 
Day 1p 
(prior to 
surgery) 
Day 1  
(day of 
surgery) 
6-hour and 
24 hour (Day 2) i follow-up after 
study drug administration  
Day 8 
1 week (±2 
days) post 
day of 
surgery 
 
 
 
PACU 
6 (+2) hours 24 (+6) hours 
(Day 2) 
 
Randomization  
 
X 
 
 
 
 
Start maintenance IV 
infusion (NS, LR, or 
5% dextrose) 
 
X 
 
 
 
 
Administration of 
preinduction IV 
midazolam 
 
X 
 
 
 
 
Administration of 
preinduction IV 
fentanyl 
 
X 
 
 
 
 
Administer oxygen via 
face mask (≥4 L/min)  
 
X 
 
 
 
 
Administration of 
study drug c 
 
X 
 
 
 
 
Pain NRS d 
 
X 
X 
 
 
 
Monitor BIS e 
 
X 
 
 
 
 
Monitor eyelash reflex 
 
X 
 
 
 
 
Monitor MOAA/S 
 
X 
 
 
 
 
Monitor 3-lead or 5-
lead ECG 
continuously f 
 
X 
 
 
 
 
Administration of IV 
rocuronium g 
 
X 
 
 
 
 
Endotracheal 
intubation g 
 
X 
 
 
 
 


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Screening 
Study 
treatment 
Follow-up visits 
Phone 
contact 
 
Day -13 to 
Day 1p 
(prior to 
surgery) 
Day 1  
(day of 
surgery) 
6-hour and 
24 hour (Day 2) i follow-up after 
study drug administration  
Day 8 
1 week (±2 
days) post 
day of 
surgery 
 
 
 
PACU 
6 (+2) hours 24 (+6) hours 
(Day 2) 
 
General anesthesia 
maintenance per 
routine practice 
(sevoflurane must be 
used as inhalational 
agent; record use of 
any alternative drugs) h 
 
X 
 
 
 
 
Blood sample 
collection for 
population PK study 
 
X m 
 
 
 
 
Brice Awareness 
Questionnaire 
 
 
X n 
 
 
X n 
Adverse events and 
prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
Abbreviations: ASA-PS = American Society of Anesthesiologists Physical Status; BIS = bispectral index; BMI = 
body mass index; DBP = diastolic blood pressure; ECG = electrocardiogram; HR = heart rate; IV = intravenous; 
LR = lactated ringer’s; MAP = mean arterial pressure; MOAA/S = Modified Observer’s Assessment of 
Awareness/Sedation; NRS = Numeric Rating Scale; NS = normal saline; OR = operating room; PACU = post-
anesthesia care unit; PK = pharmacokinetic; RR = respiratory rate; SBP = systolic blood pressure; SpO2 = 
peripheral capillary oxygen saturation. 
a. 
Physical examination will include ASA-PS score (Appendix 14.8). 
b. Subject is hemodynamically stable and has followed preoperative instructions, and there is no evidence of acute 
illness such as fever. 
c. 
Administer IV study drug (HSK3486 0.4 mg/kg or propofol 2.0 mg/kg) on the back of right or left hand vein 
(this IV location is strongly preferred rather than mandatory) at a port closest to the IV cannula (IV injection 
time: 30 [±5] seconds). The MOAA/S will be evaluated every 30 [±10] seconds after end of injection until 
MOAA/S ≤1 is reached. If MOAA/S is still >1 at 1 minute [±10 seconds] post end of study drug administration, 
a top-up dose of 50% of the initial dose of study drug (either HSK3486 0.2 mg/kg or propofol 1 mg/kg 
depending on treatment group) will be given to the subject (IV injection time: 10 [±2] seconds) and start and 
end time of administration will be recorded. The MOAA/S will be evaluated every 30 [±10] seconds post end of 


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the top-up dose. If MOAA/S is still >1 at 2 minutes [±10 seconds] post end of the top-up dose, then the rescue 
drug, propofol (100% of the initial calculated dose), will be given (in both treatment groups). The MOAA/S will 
be evaluated every 30 [±10] seconds post end of rescue drug administration until MOAA/S ≤1 is reached. 
Administration of study drug must be initiated 5 minutes [±30 seconds] post midazolam preinduction 
medication administration stop time. Top-up doses should be administered within 10 seconds once MOAA/S is 
evaluated >1. 
d. Prior to entering the OR, orient the subject to the use of the NRS assessment. Upon initiation of study drug 
administration, the investigator should immediately ask the subject to rate his or her pain. As a general 
guidance, the evaluation should be done multiple times with the first evaluation occurring typically within 15 
seconds after initiation of study drug injection and monitored until successful induction (MOAA/S ≤1). Related 
information such as the occurrence and severity of injection pain (NRS 0-10) shall be recorded. The maximum 
(highest value) injection-site pain should be recorded. Pain during the injection of study drug in the hand/arm 
should be distinguished from unrelated puncture pain from the IV site or due to adhesive tape at the IV site.  
When injection pain occurs, the subject’s pain should be graded verbally using the NRS (0-10) and should be 
recorded. The subject should be asked to rate the pain on a scale from 0, which is no pain, to 10, which is the 
worst pain imaginable. Ask the subject to point to the number on the scale that best represents the intensity of 
the pain now. In the PACU, once the subject is alert and oriented, repeat NRS for recall of pain at time of study 
drug administration. 
e. 
At preinduction, attach BIS monitor to subject. Record the three most recent BIS values before midazolam 
administration. Also, record baseline BIS value prior to administering study drug. The BIS values will be 
collected at the following timepoints at start of initial study drug administration: every 30 [±10] seconds until 5 
minutes, then every 2 minutes [± 30 seconds] until 30 minutes and then every 30 [±2] minutes for the duration 
of the surgery. 
f. 
Obtain 12-lead ECG at Day 1 visit only if the screening ECG is more than 1 week from the Day 1 visit. During 
the surgery, 3-lead or 5-lead ECG will be monitored continuously and the investigators will decide whether to 
add a 12-lead ECG. A 12-lead ECG will be obtained at 6 [±2] hours post study drug administration and as 
clinically indicated. 
g. When MOAA/S ≤1 is reached, IV rocuronium bromide (0.6 mg/kg) is to be administered for neuromuscular 
blockade to perform endotracheal intubation. RR collected until initiation of administration of rocuronium. 
Intubate subject once neuromuscular blockade (rocuronium) has taken effect; if using twitch monitor, intubate 
once no twitches are noted. The start and end of first and subsequent intubation attempt time should be 
recorded. 
h. An inhalational anesthetic agent, Sevoflurane (an inhalation anesthetic agent) will be used for maintenance of 
general anesthesia. Initiate sevoflurane within 60 seconds after successful endotracheal intubation. The end-tidal 
concentration of sevoflurane should be 1.5-2.0% (The initial concentration that is set and start time of 
administration should be recorded). 
i. 
After the surgery, subjects may remain in the hospital or observation unit if required based on standard of care 
and the clinical situation; however, if the subject is clinically stable after the Day 1 follow-up assessments and 
appropriate to be discharged home per the judgement of the investigator and surgeon, the subject may be 
released with supervision by a family member or friend, and must return to the clinic for the 24-hour follow-up 
visit (Day 2). 
j. 
On the day of surgery prior to entering the operating room (after the subject has been resting supine for ≥5 
minutes), vital signs (HR, RR, SpO2, SBP, DBP, MAP, Temp) will be collected. During preinduction, obtain 


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baseline vital signs (baseline value will be the measurement immediately prior to initiation of study drug 
administration). During the induction of general anesthesia, monitor vital signs (HR, RR, SpO2, SBP, DBP, 
MAP, Temp) continuously. HR, RR, SBP, DBP, MAP, Temp should be recorded once every 2 minutes [±30] 
seconds, SpO2 value should be recorded once every 1 minute [± 15 seconds] from the start of study drug 
administration (for every time point) for 30 minutes post start of study drug administration, for the judgment of 
key secondary endpoint. After the surgery, vital signs (HR, RR, SpO2, SBP, DBP, MAP, Temp) will be 
assessed at 6 [±2] hours post study drug administration. 
k. At 6 [±2] hours post study drug administration, obtain vital signs (HR, RR, SpO2, SBP, DBP, MAP, Temp) and 
clinical laboratory tests (including hematology, blood chemistry, and urinalysis). At 24 [±6] hours post study 
drug administration (Day 2), obtain vital signs (HR, RR, SpO2, SBP, DBP, MAP, Temp). 
l. 
Clinical laboratory tests (Appendix 14.12) include hematology, blood chemistry, and urinalysis; pregnancy tests 
for all women of childbearing potential (serum sample at screening and urine sample at baseline. If screening 
and baseline are both conducted on Day 1, a urine sample for pregnancy testing is not required if serum 
pregnancy eligibility is confirmed with an approved local lab as per footnote p). HbA1c and TSH test (with free 
T-4 if TSH abnormal) will only be done during the screening period.  
m. The blood collection time points for population PK analysis are listed (Appendix 14.7). Approximately 2 mL of 
venous blood is collected at each time point. 
n. The Brice Awareness Questionnaire is administered in the PACU once the subject is alert and oriented. The 
questionnaire is repeated at Day 8. 
o. Per investigator discretion, in otherwise healthy patients, clear liquids may be ingested for up to 2 hours prior to 
surgery. These liquids should not include alcohol. Examples of clear liquids include, but are not limited to, 
water and fruit juices without pulp, carbonated beverages, carbohydrate-rich nutritional drinks, clear tea, and 
black coffee. 
p. In cases where a separate screening visit is not feasible, or the central laboratory results are not available on Day 
1, screening activities may be conducted on Day 1 prior to surgery. A study approved local laboratory may be 
used to confirm eligibility. In these cases, required screening laboratory samples must be drawn in parallel and 
sent to the central laboratory.  
 


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14.3 
Modified Observer’s Assessment of Awareness/Sedation (MOAA/S) 
Scale 
The assessment for MOAA/S is performed stepwise and skipping of any grade is not allowed. 
The judgment of recovery can be based on a reverse order of scoring. 
Grade 
Description 
Grade 5 
Completely awake; responds readily to name spoken in normal 
tone 
Grade 4 
Lethargic response to name spoken in normal tone 
Grade 3 
Responds only after name is called loudly and repeatedly 
Grade 2 
Responds only after mild prodding or shaking 
Grade 1 
Responds only after painful trapezius squeeze (including 
active and reflex withdrawals) 
Grade 0 
No response after painful stimulus (trapezius squeeze) 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.4 
 Bispectral Index (BIS) 
The BIS Index is a number between 0 and 100 scaled to correlate with important clinical 
endpoints and electroencephalogram (EEG) states during administration of anesthetic agents 
(Figure 2). The BIS values near 100 represent an “awake” clinical state while 0 denotes the 
maximal electroencephalogram (EEG) effect possible (i.e., an isoelectric EEG). 
Figure 2  
The BIS Index is scaled to correlate with important clinical 
endpoints during administration of anesthetic agent. 
 
It should be noted that the BIS Index range represents a continuum that correlates to the clinical 
state and expected responses (Figure 3). 
This chart below reflects a general association between clinical state and BIS values. Ranges are 
based on results from a multicenter study of the BIS involving the administration of specific 
anesthetic agents. The BIS values and ranges assume that the EEG is free of artifacts that can 
affect its performance. Titration of anesthetics to BIS ranges should be dependent upon the 
individual goals established for each subject. These goals and associated BIS ranges may vary 
over time and in the context of subject status and treatment plan. 
 


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Figure 3  
BIS Index Range: A Continuum of Clinical State and EEG 
Changes 
 


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14.5 
Numerical Rating Scale (NRS) for Grading of Injection-site Pain 
 


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14.6 
Brice Awareness Questionnaire 
1) What is the last thing you remember before going to sleep? 
-Being in the pre-op area 
-Seeing the operating room 
-Being with family 
-Hearing voices 
-Feeling mask on face 
-Smell of gas 
-Burning or stinging in the IV line 
-Other [Free Text]: 
 
2) What is the first thing you remember after waking up? 
-Hearing voices 
-Feeling breathing tube 
-Feeling mask on face 
-Feeling pain 
-Seeing the operating room 
-Being in the recovery room 
-Being with family 
-Being in ICU 
-Nothing 
-Other [Free Text]: 
 
3) Do you remember anything between going to sleep and waking up? 
-No 
-Yes: 
-Hearing voices 
-Hearing events of the surgery 
-Unable to move or breathe 
-Anxiety/stress 
-Feeling pain 
-Sensation of breathing tube 
-Feeling surgery without pain 
-Other [Free Text]: 
 
4) Did you dream during your procedure? 
-No 
-Yes: 
-What about [Free Text]: 
 
5) Were your dreams disturbing to you? 
-No 
-Yes 
6) What was the worst thing about your operation? 
-Anxiety 


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-Pain 
-Recovery process 
-Functional limitations 
-Awareness 
-Other [Free Text] 
 
 


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14.7 
Pharmacokinetic (PK) Blood Samples Collection Timetable 
Phase  
Time  
Allowed Time 
Window  
PK Blood Sample 
Collection2  
Before dosing study drug  
 
Before the 1st dose of 
study drug 
administration  
Within 10 minutes 
prior to study drug 
administration  
X  
After the end of last dose of study drug1  
 
2 minutes3  
±30 seconds  
X  
 
3 ~ 30 minutes  
Not applicable  
X  
 
60 ~ 120 minutes  
Not applicable  
X  
 
 
 


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14.8 
American Society of Anesthesiologists (ASA) Physical Status Grade 
Before anesthesia, the ASA classifies subjects into 5 grades according to their physical 
conditions and the risk of surgery:  
 ASA I: Normal and healthy. No systemic diseases other than local lesions. 
 ASA II: A subject with mild systemic disease. 
 ASA III: A subject with severe systemic disease that results in functional limitations but not 
incapacity. 
 ASA IV: A subject with severe systemic disease that is a constant threat to life and results in 
incapacity. 
 ASA V: A moribund subject who is not expected to survive without the operation. If it is an 
emergency surgery, mark "Emergency" or "E" before the evaluated level shown above.  
Subjects assessed as ASA I or ASA II have good tolerability to anesthesia and surgery, and the 
process of anesthesia is smooth. Subjects assessed as ASA Ⅲ are under certain risks of 
anesthesia. The pre-anesthetic preparation should be adequate. Effective measures should be 
taken to prevent complications that may occur during anesthesia. Subjects assessed as ASA IV 
are under particularly high risks of anesthesia. Subjects assessed as ASA V are under extremely 
high risks of anesthesia and surgery for their extremely critical conditions, extremely poor 
tolerability to anesthesia, and death that may occur at any time. Thus, pre-anesthetic preparation 
is more important and shall be adequate, careful, and comprehensive.


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14.9 
Mallampati Classification 
 
The Modified Mallampati classification is a simple scoring system to help predict difficult 
intubation. It relates the amount of mouth opening to the size of the tongue and provides an 
estimate of space available for oral intubation by direct laryngoscopy. Class I is present when the 
soft palate, uvula, and pillars are visible; Class II when the soft palate and uvula are visible; 
Class III when only the soft palate and base of the uvula are visible; and Class IV when only the 
hard palate is visible. Mallampati Class I and II predict easy laryngoscopy, Class III predicts 
difficulty, and Class IV predicts extreme difficulty. 


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14.10 
Adverse Event Definitions 
Definitions 
An AE is:  
 Any untoward medical occurrence in a study subject, regardless of whether or not 
considered drug-related. The examples are as follows: 
 Any clinically significant recurrence or worsening of a pre-existing condition. 
 An AE occurring from overdose of a Sponsor study drug whether accidental or intentional 
(i.e., a dose higher than that prescribed by a healthcare professional for clinical reasons). 
 A treatment-emergent AE is defined as：an AE that occurs after the subject starts treatment 
with the IMP. 
A pre-existing condition is a clinical condition (including a condition being treated) that is 
diagnosed before the subject signs the Informed Consent Form and that is documented as part of 
the subject’s medical history. 
Note: A procedure is not an AE, but the reason for a procedure may be an AE. 
The diagnosis should be recorded, in preference to listing the individual signs and symptoms. For 
example, symptoms of fever, cough, and elevated white blood cells should be reported as 
pneumonia rather than the individual signs and symptoms. Abnormal laboratory values are 
typically not reported as AEs by themselves, but rather are included with the underlying 
diagnosis. For example, a low serum hemoglobin value associated with gastrointestinal bleeding 
should not be reported separately from the underlying diagnosis of gastrointestinal hemorrhage. 
Reporting of Adverse Events 
At each visit, the investigator, or delegate, will determine whether or not any AEs have occurred. 
Non-leading questions such as “How are you feeling today?” or “Have you had any health 
concerns since your last visit?” should be used to elicit the subject to report any possible AEs. If 
any AEs have occurred, they will be recorded in the AE section of the eCRF and in the subject’s 
source documents.  
AEs will be collected from the time of informed consent until the final study visit. AEs that are 
related to the investigational drug and continue beyond the normal collection period (i.e., are 
ongoing at the time a subject exits the study) will be followed until resolution or stabilization. 
Assessment of Severity 
The investigator will be asked to provide an assessment of the AE severity using the CTCAE 
Version 5.0 classification. This study will enroll subjects undergoing elective surgeries requiring 


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general anesthesia using endotracheal intubation; however, not all subjects will be healthy 
volunteers. Elective surgery does not necessarily mean optional surgery. Elective means the 
surgery can be scheduled in advance, and it can still be associated with serious conditions. The 
intent is to exclude emergent surgeries for life-threatening conditions, while still including a 
diverse, heterogenous subject population such as ASA-PS III-IV, elderly and morbidly obese 
subjects with comorbidities.  The CTCAE Version 5 severity classification is as follows:  
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
 Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activity of daily living (preparing meals, shopping for groceries or 
clothes, using the telephone, managing money). 
 Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activity of daily living (bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden). 
 Grade 4: Life-threatening consequences; urgent intervention indicated. 
 Grade 5: Death related to AE. 
 
Relationship to Study Treatment 
The investigator will make a determination of the relationship of the AE to the study drug using 
a 4-category system according to the following guidelines: 
 Not related: When the AE is definitely caused by the subject’s clinical state, or the study 
procedure/conditions. There is no association between the study drug and the reported event; 
there is a clear alternative explanation; a causal relationship is non plausible. 
 Unlikely Related: Underlying or concurrent disease or other drugs/exposures provide 
plausible alternative explanations. Temporal relationship to study drug administration makes 
a causal relationship improbable. 
 Likely Related: There is a reasonable possibility that the drug caused the AE; the event is 
unlikely attributed to underlying or concurrent disease or other drugs/exposures (i.e., 
alternative explanation). There is a reasonable time sequence to administration of the study 
drug. 
 Definitely Related: A definite causal relationship exists between the drug administration and 
the AE; including a plausible time relationship to drug administration, and it cannot be 
explained by underlying or concurrent disease or other drugs/exposures; abates upon 
discontinuation of the drug, follows a known or hypothesized cause-effect relationship, and 
(if appropriate) reappears when the drug is reintroduced. 


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Action Taken for Adverse Events 
The investigator or designee will record the action taken for the AE in the eCRF. Actions taken 
will include: 
 Dose increased: The medication schedule was modified by addition, either by changing the 
frequency, strength, or amount. 
 Dose not changed: The medication schedule was not changed. 
 Dose reduced: The medication schedule was modified by subtraction, either by changing the 
frequency, strength, or amount. 
 Drug interrupted: The medication schedule was modified by temporarily terminating the 
prescribed regimen of medication. 
 Drug withdrawn: The medication schedule was modified through termination of the 
prescribed regimen of medication. 
 Not applicable 
 Unknown 
 
Follow-up of Adverse Events 
All SAEs that are ongoing at the time of discontinuation, or that develop prior to the final 
Follow-up Telephone Call, will be followed for 30 days, or until resolution or stabilization. 
Serious Adverse Events 
An SAE is any AE occurring at any dose that meets 1 or more of the following criteria: 
 Results in death 
 Is life-threatening (see below) 
 Requires subject hospitalization or prolongation of an existing hospitalization (see below) 
 Results in a persistent or significant disability or incapacity (see below) 
 Results in a congenital anomaly or birth defect 
 Results in an important medical event (see below). 
Additionally, important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered SAEs when, based on appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed above. Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room, blood dyscrasias or convulsions that do not require 
hospitalization, or development of drug dependency or drug abuse. 


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A life-threatening adverse event is any AE that places the subject at immediate risk of death 
from the event as it occurred. A life-threatening event does not include an event that might have 
caused death had it occurred in a more severe form but that did not create an immediate risk of 
death as it actually occurred. For example, drug-induced hepatitis that resolved without evidence 
of hepatic failure would not be considered life-threatening, even though drug-induced hepatitis 
of a more severe nature can be fatal. Hospitalization is to be considered only as an overnight 
admission.  
Hospitalization or prolongation of a hospitalization is a criterion for considering an AE to be 
serious.  
The following circumstances should not be considered an AE/SAE: 
 Planned hospitalization for the surgery required for study participation. 
 Hospitalization or prolongation of hospitalization is part of a routine procedure followed by 
the study center (e.g., stent removal after surgery). This should be recorded in the study file. 
 Hospitalization for surgical follow-up required as routine standard of care. 
In addition, a hospitalization planned before the start of the study for a pre-existing condition that 
has not worsened does not constitute an SAE (e.g., elective hospitalization for a total knee 
replacement due to a pre-existing condition of osteoarthritis of the knee that has not worsened 
during the study).   
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions (i.e., the AE resulted in a significant, persistent, or permanent change, impairment, 
damage, or disruption in the subject’s bodily function/structure, physical activities, or quality of 
life).   
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
those situations where important medical events may not be immediately life-threatening or 
result in death, hospitalization, disability, or incapacity. These include events that may jeopardize 
the subject or may require medical intervention to prevent one or more outcomes listed in the 
definition of serious. Such events should usually be considered as serious. 
 


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14.11 
Clinical Laboratory Evaluations 
The following clinical laboratory analytes will be assessed: 
Chemistry (Chem-20): 
Hematology (CBC): 
Albumin 
Hematocrit 
ALP 
Hemoglobin 
ALT 
MCH 
AST 
MCHC 
BUN 
MCV 
Calcium 
Platelet count 
Chloride 
RBC count 
Cholesterol (TC, LDL, HDL, TG) 
WBC count 
Creatinine 
WBC differential 
GGT 
(% & ABS count) 
Glucose 
Basophils 
LDH 
Eosinophils 
Phosphorus 
Lymphocytes 
Potassium 
Monocytes 
Sodium 
Neutrophils 
Bilirubin (Total and Indirect) 
Total CO2 (measured as bicarbonate) 
 Hormone: 
Total protein 
Urine pregnancy test  local laboratory 
only (For females only) 
Uric acid 
Serum pregnancy test (For females only) 
TSH* (free T-4 if TSH abnormal) 
Complete Urinalysis (UA): 
Glycosylated Hemoglobin 
Color and appearance 
HbA1c* 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Microscopic (including RBCs and 
WBCs) 
Abbreviations: ABS = absolute; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; CO2 = carbon dioxide; GGT = gamma 
glutamyl transferase; LDH = lactate dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean 
corpuscular hemoglobin concentration; MCV = mean corpuscular volume; RBC = red blood cell; TSH = thyroid 
stimulating hormone; WBC = white blood cell. 


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*: HbA1c and TSH test (with free T-4 if TSH abnormal) will only be done during the screening period.