A 2-Part, Dose-Finding and Human Abuse Potential Study Of HSK3486 Injection In Nondependent, Recreational Central Nervous System Depressant Users
Phase: PHASE1
Conditions: General Anesthesia
Sponsor: Haisco-USA Pharmaceuticals, Inc.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 1 of 84
CLINICAL STUDY PROTOCOL
A 2-PART, DOSE-FINDING AND HUMAN ABUSE POTENTIAL STUDY OF HSK3486 
INJECTION IN NONDEPENDENT, RECREATIONAL CENTRAL NERVOUS SYSTEM 
DEPRESSANT USERS
CONFIDENTIAL
Sponsor code: HSK3486-110
Investigational product: 
HSK3486
Clinical phase: 
Phase 1 study
Sponsor:
Haisco-USA Pharmaceuticals, Inc
Contract Research
Organization
Clinical Site
Principal Investigator:
 
 
Version 2.0, 04-Nov-2022 
This study will be performed in compliance with the principles of Good Clinical Practice.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 3 of 84
AUTHORIZATION OF CLINICAL STUDY PROTOCOL BY CONTRACT 
RESEARCH ORGANIZATION
The Sponsor and the Contract Research Organization agree to conduct the study as outlined in this 
clinical study protocol. Any modification of the clinical study protocol must be agreed upon by the 
Sponsor and the Contract Research Organization and must be documented in writing.
Name/Position:
Date:
Signature:

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 4 of 84
SERIOUS ADVERSE EVENT CONTACT INFORMATION
In case of a serious adverse event (see Appendix 8.2), the Principal Investigator will send a 
report within 24 hours of notification to:

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 5 of 84
SUMMARY OF CHANGES
The following changes have been introduced in this Version 2.0 of the protocol (dated 04-Nov-2022).
Updates are either described below, or pictured below with double underlined/italic text for additions 
and strikethrough for deletions. Additionally, clarifications from previously approved Administrative 
Letters are incorporated in this protocol amendment.
Location: Synopsis, Table 2 footnote n, Table 3 footnote q, and Section 3.1.3.2
o
Addition/Deletion: approximately at least 48 hours
o
Rationale: To improve the specificity of the washout verbiage used between Qualification Phase 
and the Treatment Phase. 
Location: Synopsis, Table 2: Part 2 Schedule of Assessments — Screening and Qualification Phase / 
Table 3: Part 2 Schedule of Assessments — Treatment Phase (Periods 1-4) and Safety Follow-up/Early 
Withdrawal (table body), Section 3.5.3.2
o
Update Description: Global VAS evaluations were planned for 8 and 24 hours postdose. The 
evaluation at 8 hours is changed to 12 hours
o
Rationale: Global VAS evaluations typically occur at 12 and 24 hours.
Location: Synopsis and Section 3.3.1 (Inclusion 7)
o
Deletion: Remove opiates from inclusion list of 
psychoactive effects) with CNS depressants.
o
Rationale: Inclusion of subjects with nontherapeutic experiences with opioids may decrease 
reliability and interpretability of the study results.
Location: Synopsis, Section 3.5.3.2; Section 3.5.1.2.9
o
Update Description: Updated the endpoints for Part 2 of the study. The secondary endpoints for 
statistical hypothesis testing are: Take Drug Again VAS; High VAS; Overall Drug Liking VAS. The 
secondary endpoints for descriptive analysis are: Good Drug Effects; Bad Drug Effects, 
sick-nausea; Unknown: Any Drug Effects, Drowsiness/Alertness, and Drug Similarity. 
o
Rationale: To clarify the secondary endpoints. These measures intend to evaluate subjective 
responses after peak drug effects (Emax) have occurred, as well as next-day responses utilizing 
the unipolar and bipolar VAS.
Location: Synopsis, Section 3.6.3
Update Description:  Revised the power calculation for sample size. Changes to the Synopsis 
and Section 3.6.2.3 are indicated below: 
For the validity comparison, a sample size of 36 subjects will provide 95% power to detect a mean 
difference in the Drug Liking VAS Emax between 0.6 mg/kg propofol and placebo that is greater 
than a margin of 
1=15 in a 1-sided, alpha=0.025 test for study validity. And with alpha=0.05, a 
sample size of 36 subjects will provide at least 98% power to detect a mean difference in the Drug 
Liking VAS Emax between 0.6 mg/kg propofol and placebo that is greater than a margin of 15-point 
in a 1-sided test. This assumes Drug Liking Emax mean (SD) of 74.4 (14.99) for propofol and 
50 (0.33) for placebo, and correlation of 0.5. 5 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 6 of 84
For the primary treatment comparison, evaluating the difference between propofol and HSK3486, 
a sample size of 27 will provide 95% power to reject the null hypothesis that HSK3486 has greater 
abuse potential than propofol, in favor of similarity with less than 11-point difference in a 1-sided 
t-test, alpha=0.025 t-test. This assumes a mean (SD) of the difference in Drug Liking Emax between 
HSK3486 and propofol of 0 (15).
Rationale: The power calculation for sample size was revised based on the correct hypothesis. 
Location: Table 1: Schedule of Assessments — Screening and Qualification Phase / Table 2: Part 2 
Schedule of Assessments — Screening and Qualification Phase
o
Update Description and Additions: Weight will be collected at Admission to the clinic in Part 1
(from the date of this protocol amendment) and Part 2. An X was added to the relevant column of 
the “Demographics, Height, Weight, BMI” row in Tables 1 and 2. Footnotes were added Table 1 
(footnote p) and Table 2 (footnote u) to clarify that only weight will need to be redone at admission. 
footnote q - Weight only will be collected on Day -1.
footnote u - Weight only will be collected on Day -4.
o
Rationale: Participants’ weight  at admission is needed to calculate the correct dose in 
accordance with the Pharmacy Manual. Refer to memo to file for participants’ enrolled prior to 
this protocol amendment.
Location: Table 1: Schedule of Assessments — Screening and Qualification Phase / Table 2: Part 2 
Schedule of Assessments — Screening and Qualification Phase / Table 3: Part 2 Schedule of 
Assessments — Treatment Phase (Periods 1-4) and Safety Follow-up/Early Withdrawal / 
Section 3.5.1.3.7
o
Update Description: Pulse oximetry and telemetry measurements were planned to 8 hours 
postdose. This has been decreased to 4 hours postdose. For participants in Part 1, this change 
will apply from the date of this protocol amendment.
o
Rationale: This change was to decrease burden on the site staff, and given that patients who 
receive treatment doses of these medications in outpatient procedures are routinely discharged 
home within 4 hours, there is no expected increase in risk to the study subject.
Location: Table 2: Part 2 Schedule of Assessments — Screening and Qualification Phase (footnotes I 
and k) / Table 3: Part 2 Schedule of Assessments — Treatment Phase (Periods 1-4) and Safety 
Follow-up/Early Withdrawal (footnotes k and n)
o
Update Description: Added Drug High VAS and Nausea to list of Drug Specific VAS. Added 
Drug Similarity to list of Other VAS.
o
Rationale: These parameters were inadvertently not included in the Schedules of Assessments 
for Part 2.
Location: Table 3: Part 2 Schedule of Assessments — Treatment Phase (Periods 1-4) and Safety Follow-
up/Early Withdrawal (table body and footnote j)
o
Update Description: The 1 min and 5 min collections will be changed to 2 min and 6 min, 
respectively; in footnote j the +3 min sampling window prior to 15 min will be changed +1 min; 
and an 8 hour postdose blood sampling will be added for PK collections. 
o
Rationale: To update and expand the PK sampling window to improve accuracy of PK
assessments. 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 7 of 84
Location: Section 3.5.1.3.2
o
Update Description and Addition: Added description of Adverse Events of Special Interest 
(AESI).
Part 2 only: AESIs are AEs for a particular product or class of products that a Sponsor 
may wish to monitor carefully. AESIs may be serious or nonserious. The AESIs due to 
pharmacological effect of an anesthetic agent include hypoxemia, bradycardia, 
hypotension, allergy/anaphylaxis, and cardiac arrhythmia, 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 
1 hour postdose. 
Symptomatic bradycardia, where bradycardia is defined as a heart rate of 
<45 beats/minute that lasts >30 seconds and requiring intervention. Bradycardia 
is evaluated from the initial dose of study drug until 1 hour postdose. 
Hypotension defined as an SBP <90 mmHg that lasts >2 minutes and requiring 
treatment. Hypotension is evaluated from the initial dose of study drug until 
1 hour postdose. 
Allergy/anaphylaxis may include angioedema, bronchospasm, erythema, and 
hypotension.  Allery/anaphylaxis is evaluated from the initial dose of study drug 
until 4 hours postdose. 
Clinically significant cardiac arrhythmia, as judged by the Investigator. Cardiac 
arrhythmia is evaluated from the initial dose of study drug until 4 hours postdose. 
QTc prolongation: QTc intervals of >450 ms in males and >470 ms in females 
occurring within 15 minutes of study drug. Participants 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. 
Start time, end time, and duration should be calculated, and treatment measures (if any) 
should be recorded. Additionally, AESIs will be categorized as drug related for those 
occurring within 15 minutes from the initial dose of study drug.
Rationale: To ensure proper collection and categorization of AEs associated with anesthetic 
agent administration. 
Location: Section 3.6.2.2
o
Update Description: Revised the relative abuse potential hypothesis testing. Changes to Section 
3.6.2.2 are indicated below:
The treatment comparison for relative abuse potential of HSK3486 will be the comparison of Drug 
Liking Emax between each dose level of HSK3486 (Treatment A and Treatment B) and propofol 
(Treatment C). The following hypothesis will be tested for each comparison:
1.
A: HSK3486 dose 1 vs. C: propofol 
2.
B: HSK3486 dose 2 vs. C: propofol 
The hypothesis can be expressed as:
Ho
C – 
T
2 vs. Ha
C – 
T
2,

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 8 of 84
with 
2 =11,
0 and
C is the mean of Drug Liking Emax for propofol (Treatment C), 
T
is mean for Drug Liking Emax for each dose level of HSK3486 (Treatment A and Treatment B). 
Primary comparison will be the highest dose at which the subjects can complete all the 
assessments. If the treatment difference is statistically significant with the (less than11-point (
2) 
in a 1-sided test at a 5% level of significance, this will demonstrate that the abuse potential of 
propofol is greater than that of HSK3486 is no greater than propofol by at least 11 points. The 1-
sided 95% CIs of the mean difference will be calculated. P-values will be provided for the 
treatment comparisons. And the 2-sided 95% CIs will be also derived for the exploratory result.  
o
Rationale: To clarify the hypothesis for comparing Drug Liking Emax between each dose level of 
HSK3486 and propofol; to clarify how statistical significance will be evaluated.
Location: Section 3.6.2.2
Update Description: Revised the hypothesis test for each dose of HSK3486 compared to 
placebo and provided a preselected value of margin 
3. Changes to Section 3.6.2.2 are indicated 
below: 
The evaluation of absolute abuse potential of HSK3486 will be the comparison of HSK3486 
versus placebo. The following hypothesis will be tested for each dose level of HSK3486 compared 
to placebo:
1.
A: HSK3486 dose 1 vs. D: placebo
2.
B: HSK3486 dose 2 vs. D: placebo
The hypothesis can be expressed as:
Ho
C – 
T
2 vs. Ha
C – 
T
2
Ho
T – 
D
3 vs. Ha
T – 
D
3
With 
3=11 
2
T is the mean of Drug Liking Emax for each dose level of HSK3486 
(Treatments A and B)
D is the mean of Drug Liking Emax for placebo (Treatment D). If the 
treatment difference is statistically significantly less than 11-
3) in a 1-sided test at a 5% 
level of significance, this will suggest that HSK3486 does not produce a greater abuse-related 
response than placebo. The 1-sided 95% CIs of the mean difference will be calculated. P-values 
will be provided for the treatment comparisons. And the 2-sided 95% CIs will be also derived for 
the exploratory result.
Analyses  similar to those described for the primary endpoint (Drug Liking Emax) will be performed 
on the secondary endpoints (Take Drug Again VAS 12- and 24-hour scores; High VAS Emax; and 
Overall Drug Liking VAS 12- and 24-hour scores) in the treatment phase. The same hypothesis 
tests and difference margins as noted above for hypotheses will be evaluated for the secondary 
endpoints.
o
Rationale: To correct the hypothesis for absolute abuse potential testing. To clarify how 
secondary endpoints will be evaluated.
Location: Section 7
Update Description:  Added Chen and Bonson, 2013, to list of references.
Rationale: Reference added in support of the formula used for evaluation of absolute abuse 
potential.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 9 of 84
The following changes were added per Administrative Letter 1 dated 29 June 2022:
Location: Table 2: Part 2 Schedule of Assessments — Screening and Qualification Phase / Table 3: Part 
2 Schedule of Assessments — Treatment Phase (Periods 1-4) and Safety Follow-up/Early Withdrawal
o
Update Description and Additions: All 24-hour postdose assessments of Day -3 or during
Periods 1, 2, and 3 can be recorded also as predose assessments of Day -2 and Periods 2, 3, 
and 4, respectively, without the need to redo the assessment. Clarifications will be made by 
adding footnote t to Table 2 and updating footnote t in Table 3. Additionally, footnote m of Table 3 
is currently only used for the 24-hour assessment of drug-specific VAS but can also be applied to 
vital signs, the global VAS, and other VAS assessments.
footnote t - The 24-hour postdose assessments of Day -3 can be recorded also as the 
predose assessment of Day -2 without the need to redo the assessment.
footnote t - Day 2 for Periods 1, 2, and 3 will also be Day 1 for Periods 2, 3, and 4, 
respectively. The 24-hour postdose assessments of Periods 1, 2, and 3 can be recorded 
also as predose assessments of Periods 2, 3, and 4, respectively, without the need to 
redo the assessment.
o
Rationale: In the qualification phase of Part 2 the 24-hour postdose assessments of vital signs 
and all VAS assessments of Day -3 will coincide with the predose assessments of vital signs and 
all VAS assessments of Day -2. Similarly for the treatment phase of Part 2 the 24-hour postdose 
assessments of vital signs and all VAS assessments of Periods 1-3 will coincide with the predose 
assessments of vital signs and all VAS assessments of Periods 2-4, respectively.
The following changes were added per Administrative Letter 2 dated 23 Aug 2022:
Location: Synopsis and Section 3.2.5
o
Additions: The Investigator and Haisco will determine the doses of HSK3486 and propofol to be 
used in Part 2 of the study using the following criteria as monitored through the first hour postdose: 
Maximum dose at which subjects are able to adequately complete the battery of human 
abuse potential assessments over most of the 1-hour period 
Level of consciousness generally remains at a MOAA/S score 4 (Section 3.5.1.2.3)
Minute ventilation does not decrease more than 30% for one minute with verbal 
stimulation
Oxygen saturation does not fall below 90% for more than 30 sec with verbal stimulation
o
Rationale: The dose determination criteria used in Part 1 for selection of doses in Part 2 were 
found to be unnecessarily stringent due to unclear wording in the protocol.
The following changes were incorporated per Administrative Letter 3 dated 01 September 2022:
Location: Synopsis and Section 3.2.4 
o
Additions: Dose finding will be halted, pending discussion between sponsor and investigator, in 
Part 1 if 1 subject out of 4 demonstrates 1 or more of the below changes in vital signs sustained 
for >2 minutes with verbal stimulation as monitored through the first hour postdose: 
Heart rate <40 bpm
Systolic blood pressure (BP) <80 mmHg
Respiratory rate <6 breaths per minute

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 10 of 84
Pulse oximetry O2 sat <87% with verbal stimulation
Respiratory minute ventilation <60% of baseline
If the sponsor and investigator agree that the vital signs changes noted above were 
unlikely related to study drug and/or that there is no significant safety concern, then dose 
finding may proceed at an increased, decreased, or repeated dose level. 
o
Rationale: The dose finding stopping criteria used in Part 1 were found to be unnecessarily 
stringent due to unclear wording in the protocol.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 11 of 84
SYNOPSIS 
Study Title
A 2-PART, DOSE-FINDING AND HUMAN ABUSE POTENTIAL STUDY OF HSK3486 INJECTION IN 
NONDEPENDENT, RECREATIONAL CENTRAL NERVOUS SYSTEM DEPRESSANT USERS 
Study Codes
Sponsor code
: HSK3486-110
Study Rationale
HSK3486 is a new intravenous (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, with an anesthetic induction dose of 
0.4 mg/kg for HSK3486 that has been shown comparable to the approved 2.5 mg/kg dose of propofol. This 
higher potency could potentially result in less site pain and cardiopulmonary instability. Substantial Phase 1 to 
3 clinical trials were conducted in Australia and China. Currently, one of two pivotal Phase 3 trial is ongoing in 
US. This human abuse potential study is planned to address the Food and Drug Administration (FDA) 
requirement that any new chemical entity that targets central nervous system (CNS) needs to be evaluated on 
substance abuse potential in humans.
Objectives - Part 1
Primary
: To determine the doses of IV HSK3486 and propofol for use in Part 2, the abuse 
potential part of the study
Secondary
: To evaluate the safety and tolerability of HSK3486 in healthy, nondependent, 
recreational CNS depressant drug users 
Objectives - Part 2
Primary
: To evaluate the abuse potential of HSK3486 compared with propofol when 
administered IV to healthy nondependent, recreational CNS depressant drug users 
Secondary
: To evaluate the safety and tolerability of HSK3486 compared to propofol when 
administered IV to healthy nondependent, recreational CNS depressant drug users
To evaluate the pharmacokinetic (PK) profile of HSK3486 when administered IV to 
healthy nondependent, recreational CNS depressant drug users

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 12 of 84
Design and Treatments
This single center study will consist of 2 parts. Part 1 will be an open-label, dose-finding study of HSK3486 and 
propofol conducted in up to 48 recreational users of CNS depressants to determine the appropriate doses to be 
used in Part 2 of the study. Part 2 will be a randomized, double-blind, placebo- and active-controlled 4-period, 
4-way crossover, in approximately 42 healthy volunteers with prior recreational CNS depressant exposure. Both 
Part 1 and Part 2 of the study will consist of an outpatient Screening Visit, an in-clinic Treatment Phase, and 
Follow-up; Part 2 will also include a Qualification Phase. 
A schematic summary of the study is shown in Figure 1. 
Figure 1: 
Study Diagram
N=number of subjects
The doses to be used in Part 2 will be determined during dose finding in Part 1. Groups of 4 subjects will receive 1 dose 
level. Enrollment will be halted after the doses to be used in Part 2 will have been determined. 
The Drug Discrimination Test will ensure subjects can differentiate between the effects of active control (propofol) and 
placebo.
A naloxone challenge will ensure subjects are not opioid dependent. 
A naloxone challenge will be administered on the day of admission. 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 13 of 84
Part 1
Part 1 will consist of 2 separate arms: Part 1A and Part 1B. Up to 48 subjects may be enrolled to participate in 
Part 1 with up to 24 subjects in each arm. Screening will occur up to 28 days before drug administration. All 
subjects who have given their written informed consent and who satisfy all study entry criteria will be screened 
for eligibility to participate in the study. Subjects will be admitted to the clinic on Day -1 and administered a 
naloxone challenge to assess opioid dependence, on Day 1 they will be administered study drug (either 
HSK3486 or propofol) following a minimum 8-hour fast, and on Day 2 they will be discharged at least 24 hours 
after study drug administration and upon completion of study assessments. A follow-up visit will be conducted 
via a telephone call 3 to 7 days after study drug administration. Subjects who participate in a given group in 
Part 1 cannot participate in a subsequent group in Part 1; however, subjects in Part 1 may participate in Part 2 
of the study at the discretion of the Investigator. If a subject is admitted to the clinic in Part 1 within the 28 day 
screening window of Part 2 they must be reconsented but do not need to be rescreened. 
Part 1A: For HSK3486 dose determination, groups of 4 eligible subjects will receive 1 dose of study drug. On 
Day 1, subjects in the first group will receive IV HSK3486 0.1 mg/kg (starting dose) administered as a bolus over 
30 seconds (+5 seconds) from a syringe. The dose used for succeeding groups will be based on the 
pharmacodynamic (PD) and safety results of the prior group. The dose used in the next group may be increased, 
decreased or repeated; the magnitude of change for a new dose will be no greater than 0.025 mg/kg (increase 
or decrease) relative to previously administered doses. It is anticipated that 4 dose levels will be sufficient to 
identify the doses that should be used in Part 2 of the study; however, enrollment can be halted prior to 
completing all planned groups once doses for Part 2 have been identified based on dose selection criteria listed 
below. If necessary, up to 2 additional groups of 4 subjects each may be enrolled up to a total of 24 subjects.  
Part 1B: Likewise, for propofol dose determination, groups of 4 eligible subjects will receive 1 dose of propofol. 
On Day 1, subjects in the first group will receive IV propofol 0.5 mg/kg (starting dose) administered as a bolus 
over 30 seconds (+5 seconds) from a syringe. The dose used for succeeding groups will be based on the 
pharmacodynamic (PD) and safety results of the prior group. The dose used in the next group may be increased, 
decreased, or repeated; the magnitude of change for a new dose will be no greater than 0.125 mg/kg (increase 
or decrease) relative to previously administered doses. It is anticipated that 4 dose levels will be sufficient to 
identify the dose of propofol that should be used in Part 2 of the study; however, enrollment can be halted prior 
to completing all planned groups once the dose for Part 2 has been identified using the dose selection criteria
listed below. If necessary, up to 2 additional groups of 4 subjects each may be enrolled up to a total of 24 
subjects.
All subjects will receive a 2 cc pre-treatment of 1% lidocaine at the injection site to minimize pain associated with 
study drug administration prior to administration of either HSK3486 or propofol. 
Dose finding will be halted, pending discussion between sponsor and investigator, in Part 1 if 1 subject out of 4 
demonstrates 1 or more of the below changes in vital signs sustained for >2 minutes with verbal stimulation as 
monitored through the first hour postdose:  
1)
Heart rate <40 bpm
2)
Systolic blood pressure (BP) <80 mmHg
3)
Respiratory rate <6 breaths per minute
4)
Pulse oximetry O2 sat <87% with verbal stimulation
5)
Respiratory minute ventilation <60% of baseline

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 14 of 84
If the sponsor and investigator agree that the vital signs changes noted above were unlikely related to study drug 
and/or that there is no significant safety concern, then dose finding may proceed at an increased, decreased, or 
repeated dose level.
Safety and PD assessments will be performed at defined timepoints including Drug Liking (“at this moment”), 
Drowsiness/Alertness visual analog scale (VAS), and the Modified Observer’s Assessment of 
Alertness/Sedation (MOAA/S). Subjects will be rated on their ability to complete the full battery of abuse potential 
questions for up to 1 hour. Safety assessments will include continuous oxygen saturation, BP, and 12-lead 
electrocardiogram (ECG). Respiratory minute ventilation of subjects will be monitored using the ExSpiron®
device. An anesthesiologist or advanced cardiovascular life support (ACLS)-certified physician capable of 
performing intubation will remain at the clinical research unit (CRU) to support site staff during study drug 
administration and for at least 0.5 hours following study drug administration.
The Investigator and Haisco will determine the doses of HSK3486 and propofol to be used in Part 2 of the study 
using the following criteria as monitored through the first hour postdose:
1)
Maximum dose at which subjects are able to adequately complete the battery of human abuse potential 
assessments over most of the 1-hour period
2)
Level of consciousness generally remains at a MOAA/S score 4 
3)
Minute ventilation does not decrease more than 30% for one minute with verbal stimulation
4)
Oxygen saturation does not drop below 90% for more than 30 sec with verbal stimulation
For both HSK3486 and propofol, the highest doses tested in Part 1 meeting these criteria will be used in Part 2, 
Treatments A and C, respectively. The second dose of HSK3486 to be used in Part 2 will be the second highest 
dose tested in Part 1 (Treatment B) that meets these criteria.
Part 2
Part 2 will be a randomized, double-blind, placebo- and active-controlled 4-period, 4-way crossover design to 
assess the abuse potential of HSK3486 in nondependent, recreational CNS depressant drug (e.g., 
benzodiazepines, barbiturates, zolpidem, zopiclone, propofol/fospropofol, gamma-hydroxybutyrate) users. The 
abuse potential of single administration of 2 different presumed subtherapeutic doses of HSK3486 will be 
compared with that of propofol (active control) and placebo.
Screening will occur up to 28 days before drug administration. All subjects who have given their written informed 
consent and who satisfy all of the inclusion and exclusion criteria will be screened for eligibility to participate in 
the study. 
Subjects will be admitted to the CRU on Day -4 for the Qualification Phase. Upon admission on Day -4, each 
subject will be administered a naloxone challenge to assess opioid dependence. During the Qualification Phase,
subjects will undergo a Drug Discrimination Test to ensure that they can differentiate between the effects of 
active control (propofol) and placebo. During the Drug Discrimination Test, subjects will receive IV propofol (dose 
to be determined in Part 1) administered over 30 seconds (Treatment X) or matching placebo (Treatment Y) 
after an overnight fast in a randomized, double-blind, crossover manner with each drug administration separated 
by approximately 24 hours (Day -3 and Day -2). Subjects who do not meet Drug Discrimination criteria will be 
discharged from the CRU approximately 24 hours after the second drug administration. Subjects who 
successfully complete the Qualification Phase will be eligible to enter the Treatment Phase. A washout interval 
of at least 48 hours will be required between the last drug administration in the Qualification Phase and the first 
drug administration in the Treatment Phase. In both Qualification and Treatment phases of the study, the 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 15 of 84
Investigator will instruct subjects when answering questions after drug administration, not to make comparisons 
with previous treatments received in the study.
All subjects will be randomized to 1 of 8 treatment sequences according to two 4×4 William squares in the 
Treatment Phase. Subjects will receive each of the following 4 treatments in a randomized, double-blind, 4-way 
crossover manner following an overnight fast:
Treatment A: HSK3486 dose 1 (IV bolus over 30 seconds [+5 seconds] from a syringe; dose to be 
determined in Part 1)
Treatment B: HSK3486 dose 2 (IV bolus over 30 seconds [+5 seconds] from a syringe; dose to be 
determined in Part 1)
Treatment C: Propofol (IV bolus over 30 seconds [+5 seconds] from a syringe; dose to be determined 
in Part 1)
Treatment D: Placebo (Treatment A matched) (IV bolus over 30 seconds [+5 seconds] from a syringe)
To assist with blinding of subjects all study treatments in Part 2 will be administered by an unblinded dosing 
team, which will use a blindfold and curtain to obscure visible differences between treatments for the subject 
dosed, any blinded study team members, and neighboring subjects. In effort to further maintain the blind, within 
5 minutes before each treatment (test, active control, or placebo; Qualification Phase and Treatment Phase) 
subjects will be administered 2 cc of 1% lidocaine at the injection site in order to block the stinging sensation 
that can occur with propofol injection. 
Each treatment administration in the Treatment Phase will be separated by approximately 24 hours. Serial PD 
assessments will be performed, including Drug Liking, level of sedation, and ability to respond to questions. 
Subjects will also undergo safety assessments while housed in the CRU.
Subjects will receive a follow-up phone call approximately 3 to 7 days after either last drug administration or 
early withdrawal from the study.
Naloxone Challenge 
During the naloxone challenge administered in Parts 1 and 2, all participants will receive IV naloxone 0.2 mg 
dose as an IV bolus, followed by an assessment for signs of opioid withdrawal. If there are no signs of opioid 
withdrawal within 30 seconds after administration, a second dose of 0.6 mg IV will be administered within 
5 minutes of the first dose, followed by another assessment for signs of opioid withdrawal 5 minutes after the 
second naloxone dose. Only participants who do not have signs and symptoms of opioid withdrawal, as 
assessed by the Clinical Opioid Withdrawal Scale (COWS score <5), will be eligible to proceed with the study. 
Any participant demonstrating evidence of withdrawal (COWS score >5) on any assessment will not be eligible 
for further participation in the trial. The participant will be released from the study center when medically stable, 
as determined by the Investigator. Symptoms reported in the COWS as a consequence of opioid withdrawal will 
not be collected as AEs unless they meet the criteria for a new AE or serious adverse event (SAE).
Study Schedule
Part 1
Screening
: Between Day -28 and Day -2.
Confinement Period 
: A single period of approximately 2 days in the clinic from Day -1 (admission) to 
approximately 24 hours after study drug administration.
Follow-up 
: 3 to 7 days after drug administration. 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 16 of 84
Part 2
Screening
: Between Day -28 and Day -5.
Confinement Period
: An anticipated period of approximately 9 days in the clinic from Day -4 (admission) 
to approximately 24 hours after the last study drug administration in Period 4.
Follow-up
: 3 to 7 days after either last drug administration or early withdrawal from the study.
Subjects
Part 1
An adequate number of subjects will be screened such that up to 32 subjects (16 subjects for HSK3486 dose 
determination [4 groups of 4 subjects each] and 16 subjects for propofol dose determination [4 groups of 
4 subjects each]) may be enrolled in Part 1 of the study. Up to an additional 16 subjects (2 groups of 4 each for 
HSK3486 dose determination and 2 groups of 4 each for propofol dose determination) may be enrolled in Part 1, 
if necessary.
Part 2
An adequate number of subjects will be screened such that a sufficient number of subjects are randomized into 
the Qualification Phase with the intention of qualifying and randomizing approximately 42 subjects into the 
Treatment Phase, with the intention of completing 36 subjects. Subjects who participated in Part 1 of the study 
may be eligible for Part 2 of the study at the Investigator’s discretion.
Inclusion Criteria
The following criteria must be met for a subject to be eligible for inclusion in the study:
1.
Willing to participate in the study, give written informed consent, and comply with the study restrictions.
2.
Gender: male or female; females may be of childbearing potential, of nonchildbearing potential, or 
postmenopausal.
3.
Age: 18 years to 55 years, inclusive, at Screening.
4.
Body mass index (BMI): 18.0 kg/m2 to 30.0 kg/m2, inclusive.
5.
6.
Healthy subject, defined by the absence of evidence of any clinically significant, in the opinion of the 
Investigator, active or chronic disease following a detailed medical and surgical history, a complete physical 
examination including vital signs, 12-lead ECG, hematology, blood chemistry, serology, and urinalysis.
7.
Subject must be a nondependent, nontreatment-seeking recreational CNS depressant user, defined as 
follows:
•
i.e., for psychoactive effects) with CNS depressants (e.g., 
benzodiazepines, barbiturates, zolpidem, zopiclone, propofol/fospropofol, gamma-hydroxybutyrate).
•
rapeutic use of a CNS depressant within the 8 weeks prior to Screening.
•
8.
Ability and willingness to abstain from alcohol-, caffeine-, and xanthine-containing beverages or food (e.g., 
coffee, tea, cola, chocolate, energy drinks) from 48 hours (2 days) prior to first admission to the CRU, 
throughout the entire study, and until discharge.
9.
All values for hematology and clinical chemistry tests of blood and urine within the normal range or show no 
clinically relevant deviations, as judged by the Investigator.
10. Females of childbearing potential, and males with female partner(s) of childbearing potential, as judged by 
the Investigator, must agree to use 2 forms of contraception, 1 of which must be a barrier method, during the 
study and for 90 days after the last drug administration. Acceptable barrier forms of contraception are 
condom, cervical cap, and diaphragm. Acceptable non barrier forms of contraception for this study are an 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 17 of 84
study treatment), and/or spermicide.
11. For females: a negative pregnancy test at Screening and Admission.
12. Postmenopausal females: defined as 12 months with no menses prior to Screening and a serum 
follicle-stimulating hormone (FSH) >40 IU/L at Screening.
13. All nonregular medication (including over-the-counter medication, health supplements, and herbal remedies 
such as St. John’s Wort extract) must have been stopped at least 14 days prior to (the first) admission to the 
CRU. An exception is made for acetaminophen, which is allowed up to admission to the CRU.
14. All prescribed medication must have been stopped at least 30 days prior to (first) admission to the clinical 
research center. An exception is made for hormonal contraceptives, which may be used throughout the 
study.
15. Able to speak, read, and understand English sufficiently to allow completion of all study assessments.
Exclusion Criteria
A subject who meets any of the following criteria will not be eligible for inclusion in the study:
1.
An employee of the Sponsor or research site personnel directly affiliated with this study or their immediate 
family member (defined as a spouse, parent, child, or sibling, whether biological or legally adopted).
2.
Drug or alcohol dependence within the 2 years prior to Screening (except nicotine and caffeine), as defined 
by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR), 
and/or has ever participated or plans to participate in a substance or alcohol rehabilitation program to treat 
their substance or alcohol dependence.
3.
Opioid dependence as judged by the Investigator after a naloxone challenge. 
4.
Women who are pregnant, lactating, or planning to attempt to become pregnant during this study or within 
90 days of last study drug administration.
5.
Males with female partners who are pregnant, lactating, or planning to attempt to become pregnant during 
this study or within 90 days of last study drug administration.
6.
Positive drug and alcohol screen (tetrahydrocannabinol [THC], morphine/opiates, methadone, oxycodone, 
phencyclidine, cocaine, amphetamines, methamphetamines, ecstasy, barbiturates, benzodiazepines, 
tricyclic antidepressants, and alcohol) at each admission to the CRU. For THC, subjects should ideally test 
negative. However, eligibility decision with regards to THC use will be considered on a case by case basis, 
at the discretion of the Investigator.
7.
Treatment with an investigational drug or device within 5 times the elimination half-life, if known (e.g., a 
marketed product) or within 30 days (if the elimination half-life is unknown) prior to first drug administration 
or is concurrently enrolled in any research judged not to be scientifically or medically compatible with this 
study. An exception may be made for subjects who participated in Part 1 of the study.
8.
History or presence of clinically significant abnormality (e.g., obstructive sleep apnea) as assessed by 
physical examination, medical history, ECG, vital signs, or laboratory values, which, in the opinion of the 
Investigator, would jeopardize the safety of the subject or the validity of the study results.
9.
Any disease which, in the opinion of the Investigator, poses an unacceptable risk to the subjects.
10. Mallampati intubation score >2. 
11. History of clinically significant drug allergy diagnosed by a physician. Confirmatory circumstances would 
include treatment with epinephrine or in an emergency department.
12. Any personal or family history of issues with succinylcholine, such as malignant hyperthermia or 
pseudocholinesterase deficiency.
13. History of allergy, adverse reaction (including significant agitation, etc.), or hypersensitivity to propofol, 
lidocaine, other injected anesthetic agents, or related drugs.
14. History of allergy to eggs, egg products, soybeans or soy products.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 18 of 84
15. Heavy smoker (>20 cigarettes per day) and/or is unable to abstain from smoking and/or the use of prohibited 
nicotine-containing products (including e-cigarettes, pipes, cigars, chewing tobacco, nicotine topical patches, 
nicotine gum, or nicotine lozenges) from 2 hours prior to dosing until at least 4 hours postdose during the 
in-clinic periods.
16. Routine or chronic use of more than 3000 mg of acetaminophen daily.
17. Strenuous activity (such as exercise), sunbathing, and contact sports within 48 hours (2 days) prior to
admission to the CRU, during the study, and until after discharge in the last study period.
18. History of donation of more than 450 mL of blood within 60 days prior to dosing in the CRU or planned 
donation before 30 days has elapsed since last intake of study drug.
19. Plasma or platelet donation within 7 days of dosing and throughout the entire study.
20. Average intake of more than 14 units of alcohol per week (1 unit of alcohol equals approximately 250 mL of 
beer, 100 mL of wine, or 35 mL of spirits). Alcohol consumption will be prohibited 48 hours prior to first 
admission to the CRU and throughout the entire study until the Follow-up visit (including washout period).
21. Positive screening test for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) antibodies, or 
anti-HIV 1 and 2 antibodies.
22. History of peripheral vasculopathy, including Raynaud’s phenomenon.
23. History of seizures, seizure disorder, or known electroencephalogram (EEG) abnormalities.
24. History of mental illness, which, in the opinion of the Investigator, would jeopardize the safety of the subject 
or the validity of the study results.
25. Subject with a history of clinically significant head injury, ongoing seizure disorder, chronic tics, or diagnosis 
or family history of Tourette's syndrome.
26. Subjects with a history of serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm 
abnormalities, coronary artery disease, advanced arteriosclerosis, symptomatic cardiovascular disease, 
hypertension, or other cardiac problems.
27. Any history of clinically significant suicidality as assessed by the Investigator based upon clinical history, 
source documents, or scores on the Columbia-Suicide Severity Rating Scale (C-SSRS).
28. History or presence of clinically significant hepatic or renal disease.
29. History of hyperthyroidism.
30. Difficulty with venous access or unsuitable or unwilling to undergo catheter insertion.
31. Use of a cytochrome P450 (CYP)2D6-inhibiting drug or a serotonergic drug within 14 days prior to first drug 
administration in the Qualification Phase.
32. Consumption of any nutrients known to modulate CYP enzymes activity (e.g., grapefruit or grapefruit juice, 
pomelo juice, star fruit, or Seville [blood] orange products) within 14 days prior to administration of study 
medication and during the study (including washout period) until after discharge in the last study period.
33. A subject who, in the opinion of the Investigator or designee, is considered unsuitable or unlikely to comply 
with the study protocol for any reason.
34. A subject who has pending legal charges or is on probation.
Study Drug
Test preparation (HSK3486)
Active substance 
: HSK3486 injectable emulsion 
Activity
: CNS depression through gamma-aminobutyric acid receptor subtype A (GABAA) 
mediation
In development for 
: General anesthesia and sedation
Strength
: 2.5 mg/mL (total dose: 0.05 g in 20 mL)
Dosage forms
: Injection

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 19 of 84
Reference medication (Propofol injectable emulsion)
Active substance 
: Propofol 
Activity
: Positive modulation of the inhibitory function of the neurotransmitter GABA through 
the ligand-gated GABAA receptors
Indication
: General anesthesia and sedation
Strength
: 10 mg/mL
Dosage form
: Injection 
Placebo
Substance
: Intralipid®
Activity
: Not applicable
Strength
: Not applicable
Dosage form
: 20% IV fat emulsion
Masking drug (xylocaine)
Substance
: Lidocaine HCl
Activity
: Local anesthetic
Strength
: 1%
Dosage form
: Injection
Criteria for Evaluation
Pharmacodynamics 
: PD parameters in Part 1 will include:
Drug Liking (“at this moment”) VAS Emax
Drug Liking (“at this moment, I feel high”) Emax High VAS (secondary endpoint) 
Drowsiness/Alertness VAS (Emin [secondary endpoint], TEmin, TA_AUE0-1, and 
TA_AUE0-2) 
MOAA/S score
Ability to complete battery of abuse potential assessment questions for 1 hour 
PD parameters in Part 2 will include:
Drug Liking (“at this moment”) VAS Emax  
Drug Liking (“at this moment, I feel high”) Emax High VAS
Drowsiness/Alertness VAS (Emin, TEmin, TA_AUE0-1, and TA_AUE0-2) 
MOAA/S score
Ability to complete battery of abuse potential assessment questions for 1 hour 
Overall Drug Liking VAS – 12- and 24-hour score 
Take Drug Again VAS – 12- and 24-hour score
Drug Liking VAS (TEmax, TA_AUE, Emin, TEmin, and %reduction)
Drug Effects Questionnaire (DEQ) – Any Drug Effect VAS (Emax, TEmax, and 
TA_AUE0-1) 
DEQ – Good Drug Effects VAS (Emax, TEmax, and TA_AUE0-1) 
DEQ – Bad Drug Effects VAS, sick-nausea (Emax, TEmax, and TA_AUE0-1) 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 20 of 84
Relaxation/Agitation VAS (Emax, TEmax, Emin, TEmin, and TA_AUE0-1) 
Drug Similarity (“How similar is the drug you most recently received 
[drug 1] to drug you just took [drug 2]?”) VAS
Part 2 endpoints:
The primary endpoint is Drug Liking VAS (Emax).
The secondary endpoints for statistical hypothesis testing are: Take Drug Again VAS
(12- and 24-hour scores); High VAS (Emax); and Overall Drug Liking VAS (12- and 
24-hour scores). 
The secondary endpoints for descriptive analysis are: Good Drug Effects; Bad Drug 
Effects, sick-nausea; Unknown: Any Drug Effects, Drowsiness/Alertness, and Drug 
Similarity.
The following scale will be used for MOAA/S scoring:
5 = responds readily to name spoken in normal tone
4 = lethargic response to name spoken in normal tone
3 = responds only after name is called loudly and/or repeatedly
2 = responds only after mild prodding or shaking
1 = responds only after painful trapezius squeeze
0 = does not respond to painful trapezius squeeze
Pharmacokinetics 
: Plasma HSK3486 concentrations
Plasma PK parameters estimated using noncompartmental analysis, as 
appropriate: maximum observed plasma concentration (Cmax), time to attain 
maximum observed plasma concentration (Tmax), area under the plasma 
concentration-time curve (AUC) from time 0 to 1 hour postdose (AUC0-1), AUC from 
time 0 to 2 hours postdose (AUC0-2) AUC from time 0 to 4 hours postdose (AUC0-4), 
AUC up to the last point with concentrations above the lower limit of quantification 
(AUClast,), AUC from time 0 to infinity (AUC0-inf), percent of estimated part for the 
calculation of AUC0-inf (%AUCextra), terminal elimination rate constant (kel), terminal 
elimination half-life (t½), and abuse quotient (Cmax/Tmax) 
  
Safety
: Adverse events (AEs), clinical laboratory assessments, vital signs, pulse oximetry, 
12-lead ECG, continuous cardiac monitoring, physical examination, and C-SSRS.
Respiratory volume of subjects will be monitored using the ExSpiron® device.
Statistical Methods
Sample size calculation 
: For assessment of abuse potential, the sample size will be considered the 
maximum of the sample sizes for the validity comparison and primary treatment 
comparison. Assuming a 10% dropout rate, approximately 42 subjects will be 
randomized to the Part 2 Treatment Phase, with the intention of completing 
36 subjects. 
For the validity comparison, a sample size of 36 subjects will provide 95% power to 
detect a mean difference in the Drug Liking VAS Emax between 0.6 mg/kg propofol 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 21 of 84
and placebo that is greater than a margin of 
1=15 in a 1-sided, alpha=0.025 test 
for study validity. With alpha=0.05, a sample size of 36 subjects will provide at least 
98% power to detect a mean difference in the Drug Liking VAS Emax between 
0.6 mg/kg propofol and placebo that is greater than a margin of 15-point in a 1-sided 
test. This assumes Drug Liking Emax mean (SD) of 74.4 (14.99) for propofol and 50 
(0.33) for placebo, and correlation of 0.5. 
For the primary treatment comparison, evaluating the difference between propofol
and HSK3486, a sample size of 27 will provide 95% power to reject the null 
hypothesis that HSK3486 has greater abuse potential than propofol, in favor of 
similarity with less than a margin of 
2=11 in a 1-sided, alpha=0.025 t-test. With 
alpha=0.05, a sample size of 27 will provide 98% power to reject the null hypothesis 
that HSK3486 has greater abuse potential than propofol, in favor of similarity with 
2=11 in a 1-sided t-test. This assumes a mean (SD) of the 
difference in Drug Liking Emax between HSK3486 and propofol of 0 (15).
PD parameters
: PD data and derived PD parameters from the Treatment Phase will be summarized 
using descriptive statistics by treatment (and by time point as applicable). PD 
endpoints for the Treatment Phase will be analyzed using a mixed-effect model if 
the residuals are normally distributed. The model will include treatment, period, 
sequence, and first-order carryover effect (if significant) as fixed effects, baseline 
(where applicable) as a covariate, and subject as a random effect. Treatment 
variance will be evaluated and adjusted as needed. Step-wise hypothesis testing 
will be conducted for the treatment differences following the FDA guidance. 
PK parameters
: Descriptive statistics will be calculated and presented for each time point by 
treatment for plasma concentrations. PK parameters will be calculated and will be 
summarized by treatment using descriptive statistics. The natural log-transformed, 
dose-normalized PK exposure parameters: Cmax and AUC, will be analyzed using a 
mixed-effect model with treatment, period, and sequence as fixed effects and 
subject nested in sequence as a random effect. The geometric means of each 
treatment, geometric mean ratio of the treatment comparisons, and 90% confidence 
intervals will be reported. The relationship between PK and PD may be evaluated 
using correlational analysis or similar methodology. 
Safety parameters
: Descriptive statistics or incidence/frequency counts (where applicable)
Exploratory parameters
: Descriptive statistics

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 30 of 84
TABLE OF CONTENTS
TITLE PAGE........................................................................................................................1
SPONSOR AUTHORIZATION OF CLINICAL STUDY PROTOCOL.................................. 2
AUTHORIZATION OF CLINICAL STUDY PROTOCOL BY CONTRACT RESEARCH 
ORGANIZATION .......................................................................................................... 3
SERIOUS ADVERSE EVENT CONTACT INFORMATION ................................................ 4
SUMMARY OF CHANGES................................................................................................. 5
SYNOPSIS........................................................................................................................ 11
TABLE OF CONTENTS.................................................................................................... 30
TABLE OF TABLES......................................................................................................... 34
TABLE OF FIGURES ....................................................................................................... 34
LIST OF ABBREVIATIONS.............................................................................................. 35
1.
INTRODUCTION ........................................................................................................ 37
1.1
Background.................................................................................................................37
1.1.1
Nonclinical Summary.........................................................................................37
1.1.2
Clinical Summary...............................................................................................38
1.2
Risk-benefit Assessment and Risk Management .....................................................39
1.3
Study Rationale...........................................................................................................39
2.
OBJECTIVES ............................................................................................................. 41
2.1
Part 1............................................................................................................................41
2.2
Part 2............................................................................................................................41
3.
INVESTIGATIONAL PLAN ........................................................................................ 42
3.1
Overall Study Design and Plan ..................................................................................42
3.1.1
Type of Study ....................................................................................................42
3.1.2
Screening Period ...............................................................................................43

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 31 of 84
3.1.3
Treatment Period...............................................................................................44
3.1.3.1
Part 1.................................................................................................44
3.1.3.2
Part 2.................................................................................................45
3.2
Discussion of Study Design.......................................................................................47
3.2.1
Subjects and Qualification .................................................................................47
3.2.2
Propofol as Comparator.....................................................................................47
3.2.3
Study Design .....................................................................................................47
3.2.4
Part 1 Stopping Rules for Dose Finding.............................................................47
3.2.5
Part 2 Dose Selection Criteria............................................................................48
3.2.6
Qualification Criteria ..........................................................................................48
3.2.7
Naloxone Challenge ..........................................................................................48
3.3
Selection of Study Population....................................................................................49
3.3.1
Inclusion Criteria................................................................................................49
3.3.2
Exclusion Criteria...............................................................................................50
3.3.3
Removal of Subjects from Assessment..............................................................52
3.4
Treatments...................................................................................................................53
3.4.1
Treatments Administered...................................................................................53
3.4.2
Identity of Investigational Products ....................................................................54
3.4.3
Method of Assigning Subjects to Treatment Groups ..........................................55
3.4.4
Selection of Doses in the Study .........................................................................55
3.4.5
Timing of Doses in the Study .............................................................................55
3.4.6
Meals During the Study......................................................................................56
3.4.7
Blinding..............................................................................................................56
3.4.8
Concomitant Medication and Other Restrictions During the Study.....................56
3.4.9
Treatment Compliance.......................................................................................57
3.5
Pharmacokinetic, Pharmacodynamic, and Safety Variables....................................58
3.5.1
Pharmacokinetic, Pharmacodynamic, and Safety Assessed..............................58
3.5.1.1
Pharmacokinetic Measurements........................................................58
3.5.1.1.1 Blood Sampling..................................................................................58
3.5.1.2
Pharmacodynamic Measurements.....................................................58
3.5.1.2.1 Drug Liking (“at this moment”) VAS....................................................58
3.5.1.2.2 Drowsiness/Alertness VAS ................................................................58
3.5.1.2.3 MOAA/S Score ..................................................................................58
3.5.1.2.4 Ability to Complete Battery of Abuse Potential Assessment Questions for 1 
Hour...................................................................................................59
3.5.1.2.5 Overall Drug Liking VAS ....................................................................59
3.5.1.2.6 Take Drug Again VAS........................................................................59
3.5.1.2.7 Drug Effects Questionnaire................................................................59
3.5.1.2.8 Relaxation/Agitation VAS...................................................................59
3.5.1.2.9 Drug Similarity VAS ...........................................................................60
3.5.1.3
Safety and Tolerability Measurements ...............................................60
3.5.1.3.1 Adverse Events..................................................................................60

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 32 of 84
3.5.1.3.2 Adverse Events of Special Interest ....................................................61
3.5.1.3.3 Clinical Laboratory .............................................................................61
3.5.1.3.4 Vital Signs..........................................................................................62
3.5.1.3.5 Pulse Oximetry ..................................................................................62
3.5.1.3.6 Respiratory Volume ...........................................................................63
3.5.1.3.7 Electrocardiogram..............................................................................63
3.5.1.3.8 Continuous Cardiac Monitoring..........................................................63
3.5.1.3.9 Physical Examination.........................................................................63
3.5.1.3.10Columbia-Suicide Severity Rating Scale............................................63
3.5.1.3.11Mallampati Score...............................................................................64
3.5.1.4
Total of Blood Volume........................................................................64
3.5.2
Appropriateness of Measurements ....................................................................65
3.5.2.1
Timing of Assessments......................................................................65
3.5.3
Pharmacokinetic, Pharmacodynamic, and Safety Variables ..............................65
3.5.3.1
Pharmacokinetic Variables.................................................................65
3.5.3.2
Pharmacodynamic Variables .............................................................66
3.5.3.3
Safety Variables.................................................................................67
3.5.4
Drug Concentration Measurements ...................................................................67
3.5.5
Retention of Blood and Urine Samples ..............................................................68
3.6
Statistical Procedures and Determination of Sample Size.......................................68
3.6.1
Analysis Sets.....................................................................................................68
3.6.1.1
Safety Set..........................................................................................68
3.6.1.2
Qualification Safety Set......................................................................68
3.6.1.3
Pharmacokinetic Set..........................................................................68
3.6.1.4
Completer Set....................................................................................68
3.6.1.5
Modified Completer Set .....................................................................68
3.6.2
Statistical and Analytical Plan for Pharmacokinetic, Pharmacodynamic, and Safety 
Evaluation..........................................................................................................68
3.6.2.1
Pharmacokinetic Evaluation...............................................................69
3.6.2.2
Pharmacodynamic Evaluation............................................................69
3.6.2.3
Evaluation of Safety and Tolerability ..................................................71
3.6.2.3.1 Adverse Events..................................................................................71
3.6.2.3.2 Clinical Laboratory .............................................................................71
3.6.2.3.3 Vital Signs, Pulse Oximetry, Respiratory Volume, and Electrocardiograms
..........................................................................................................71
3.6.2.3.4 Continuous Cardiac Monitoring..........................................................71
3.6.2.3.5 Physical Examination.........................................................................71
3.6.2.3.6 Columbia-Suicide Severity Rating Scale............................................72
3.6.3
Determination of Sample Size............................................................................72
3.7
Data Quality Assurance..............................................................................................72
4.
ETHICS....................................................................................................................... 74

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 33 of 84
4.1
Institutional Review Board .........................................................................................74
4.2
Ethical Conduct of the Study .....................................................................................74
4.3
Subject Information and Consent ..............................................................................75
4.4
Privacy.........................................................................................................................75
5.
STUDY DOCUMENTATION....................................................................................... 76
5.1
Archiving .....................................................................................................................76
5.2
Recording of Data in Source Documents and Electronic Case Report Forms .......76
6.
CONFIDENTIALITY AND PUBLICATION POLICY ................................................... 77
7.
REFERENCES ........................................................................................................... 78
8.
APPENDICES............................................................................................................. 79
8.1
Drug Accountability....................................................................................................79
8.2
Adverse Events and Serious Adverse Events Evaluation and Reporting...............79
8.2.1
Adverse Events .................................................................................................79
8.2.2
Serious Adverse Events.....................................................................................81
8.2.3
Suspected Unexpected Serious Adverse Reactions ..........................................82
8.2.4
Follow-up of Adverse Events .............................................................................82
8.3
Pregnancy....................................................................................................................82
8.4
Clinical Opioid Withdrawal Scale...............................................................................83

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 34 of 84
TABLE OF TABLES
Table 1
Part 1 Schedule of Assessments — Dose Determination
22
Table 2
Part 2 Schedule of Assessments — Screening and Qualification Phase
25
Table 3
Part 2 Schedule of Assessments — Treatment Phase (Periods 1-4) and Safety 
Follow-up/Early Withdrawal
28
Table 4
Number and Volume of Blood Samples and Total Blood Volume Collected per Subject –
Part 1
64
Table 5
Number and Volume of Blood Samples and Total Blood Volume Collected per Subject –
Part 2
65
Table 6
Pharmacokinetic Parameters
65
Table 7
Pharmacodynamic Parameters
67
TABLE OF FIGURES
Figure 1: Study Diagram
12
Figure 2: Study Diagram
43

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 35 of 84
LIST OF ABBREVIATIONS
ACLS
advanced cardiovascular life support
AE
adverse event 
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
BMI
body mass index
BP
blood pressure 
CHMP
Committee for Medicinal Products for Human Use 
CK
creatine kinase
CNS
central nervous system 
CRO
contract research organization
CRU
clinical research unit
CSP
clinical study protocol
CSR
clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450
DEQ
drug effects questionnaire
DSM-IV-IR
Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision
ECG
electrocardiogram
eCRF
electronic case report form
EDS
Early Development Services
EEG
electroencephalogram
EMA
European Medicines Agency
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GABAA
gamma-aminobutyric acid receptor subtype A 
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HDL
high-density lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
IB
Investigator’s brochure
ICF
informed consent form
ICH
International Council for Harmonisation 
INR
international normalized ratio
IRB
Institutional Review Board
IUD
intrauterine device
IV
intravenous
LC-MS/MS
liquid chromatography with tandem mass spectrometry
LDL
low-density lipoprotein
LORR
loss of righting reflex
MedDRA
Medical Dictionary for Regulatory Activities
MOAA/S
Modified Observer’s Assessment of Alertness/Sedation
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PT
prothrombin time
QTc
prolonged corrected QT-interval
SAE
serious adverse event
SAP
statistical analysis plan
SOP
standard operating procedure

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 36 of 84
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
THC
tetrahydrocannabinol
TSH
thyroid stimulating hormone
VAS
visual analog scale 
WMA
World Medical Association
Note: Definitions of pharmacokinetic (PK) and pharmacodynamic (PD) parameters are provided in 
Section 3.5.3.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 37 of 84
1.
INTRODUCTION
1.1
Background
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 
patients to recover quickly, and it is widely used in the induction and maintenance of general 
anesthesia for surgery. However, propofol also comes with pronounced shortcomings, in
particular, pain on injection,1 propofol-induced decrease in diastolic blood pressure (BP) and 
mean arterial BP, respiratory depression,2 and, with prolonged use, excessive lipid intake 
causing patients to suffer from disorders of lipid metabolism.3  
HSK3486 is a chemical entity similar to propofol; however, is unique in that it is a 
single-configuration chiral compound with 1 R-designated chiral center and a terminal 
cyclopropyl group. HSK3486 has been engineered such that the structural design aims to 
enhance the pharmacological and physicochemical properties of drug-receptor binding in a 
systematic manner. These structural improvements result in increased potency, therefore a 
smaller amount of drug required, less injection-site pain, and may reduce the occurrence of 
side effects caused by propofol.
For further information on the investigational product, including preclinical and clinical 
information, refer to the HSK3486 Investigator's Brochure (IB).4
1.1.1
Nonclinical Summary
Nonclinical pharmacology studies, including a loss of righting reflex (LORR) study in rats 
and anesthesia evaluation studies in dogs and minipigs, showed that HSK3486 achieved a 
similar depth of anesthesia as propofol with HSK3486 having up to 6-fold higher anesthetic 
potency than propofol.
The results of nonclinical safety pharmacology studies showed that HSK3486 had no 
significant effect on central nervous system (CNS) function in rats recovered from 
anesthesia, suggesting that HSK3486 has no residual effect in this organ system. 
Observed changes in electrocardiogram (ECG), BP, respiratory rate, and body 
temperature after HSK3486 injection were expected changes associated with 
anesthetic drugs; were mild and transient; and returned to normal when the animals 
regained consciousness. Both HSK3486 and propofol were found to shorten action 
potential duration in rabbit cardiac Purkinje fibers; however, the effect of HSK3486 was 
found to be less than that of propofol.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 38 of 84
Results from single- and repeat-dose toxicity and toxicokinetic studies in Sprague 
Dawley rats and Beagle dogs showed that the depth and duration of anesthesia in 
animals increased proportionally with HSK3486 dose, and multiple doses did not result 
in drug accumulation, with the exception of certain animals in the high-dose group which 
may have died from respiratory depression due to their individual sensitivity to 
anesthesia; this is not an unusual finding at higher doses in preclinical anesthesia 
studies or in other preclinical studies involving anesthesia. All other animals displayed 
no significant toxicity and no specific target organs were identified during the 
administration and recovery periods. HSK3486 was not shown to have mutagenicity. 
Reproductive toxicity study showed no significant toxicity to rat fertility and early embryo 
development by HSK3486. At 2.5 mg/kg and 5 mg/kg, fetal resorption was observed to 
increase due to the amplification of the pharmacological action of the test article, 
suggesting the need to pay attention to the respiratory management of the user 
population. No significant embryo-fetal developmental toxicity or teratogenicity was 
observed. No significant toxicity was observed in birth and lactation of F0 females; the 
growth, neurobehavioral development, and fertility of F1 generation; or the survival of F2 
generations. No significant embryo-fetal developmental toxicity or teratogenicity was 
observed in New Zealand White rabbits. Results of local irritation, hemolytic, and allergic 
tests were negative, indicating the safety of the formulation. The precipitated withdrawal 
test in mice, spontaneous withdrawal test in rats, and conditioned place preference tests 
in rats suggested that HSK3486 has no physical nor psychological dependence 
potential in the corresponding animal models; while in the self-administration rat model, 
the potential for drug dependency of HSK3486 was predicted not to be higher than that 
of propofol.
1.1.2
Clinical Summary 
As of 30 Oct 2020, 21 Phase 1 to 3 clinical studies have been initiated or planned for 
HSK3486; 17 have been completed, and 4 are ongoing or planned. Among the 
17 completed studies, a total of 671 subjects were exposed to HSK3486, including 
228 healthy subjects, 16 subjects with hepatic impairment, 20 subjects with renal 
impairment, 236 subjects who underwent colonoscopy, 15 subjects who underwent 
gastroscopy, and 156 subjects who underwent induction of general anesthesia for 
elective surgery. Results showed that HSK3486 exhibited quick onset and rapid 
regaining of consciousness, and had approximately 4 to 5 times the potency of propofol.
The types of drug-related adverse events (AEs) in subjects exposed to HSK3486 were 
consistent with those in subjects exposed to propofol. Cardiovascular-related AEs 
including hypotension, bradycardia, and prolonged corrected QT-interval (QTc) with 
HSK3486 were comparable to those with propofol. However, incidences of injection-site 
pain and respiratory-related AEs (respiratory depression, apnea, and hypoxia), and the 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 39 of 84
proportion of subjects requiring assistance in ventilation were slightly lower with 
HSK3486 than propofol.
Phase 1 pharmacokinetic (PK) studies showed that HSK3486 was widely distributed after a 
single IV administration, the plasma exposure level increased approximately proportionally 
to the dose, and the clearance did not change in a dose-dependent manner. The plasma
concentration of HSK3486 was characterized by 3-phase elimination, with corresponding 
half-lives of 0.54 min (t1/2
t1/2
t1/2
14C]HSK3486, the total recovery of 
radioactivity was approximately 87.24% within 10 days; the majority was excreted by kidney 
(84.59%), and the minority was excreted by feces (2.65%). UDP-glucuronosyltransferase 
and cytochrome P450 (CYP)2B6 were predicted to be the primary metabolizing enzymes of 
HSK3486, contributing 54.0% and 24.5%, respectively, with each of the other metabolizing 
enzymes contributing less than 10%.
1.2
Risk-benefit Assessment and Risk Management
Propofol has the potential for respiratory and BP depression as a common side effect, and 
HSK3486 has been shown to elicit lower or comparable rates, respectively, of these AEs. 
Risk of these AEs is low in the current study due to the planned use of subtherapeutic doses 
for assessment of abuse potential. Additionally, an anesthesiologist or advanced 
cardiovascular life support (ACLS)-certified physician capable of performing intubation will 
remain at the clinical research unit (CRU) to support site staff during and for an appropriate 
time after study drug administration, to ensure subject safety. 
Due to nonclinical mutagenicity, reproductive, developmental, and fetal development 
studies there is no perceived risk to women of childbearing potential, who will be included 
in this study.
There is no expected clinical benefit for the healthy subjects who will participate in this study. 
The information obtained in this study can be used for the further clinical development of 
HSK3486.
Overall, on the basis of the available nonclinical and clinical data, and prior knowledge, the 
risk-benefit profile of study treatments is judged acceptable for the proposed clinical study.
1.3
Study Rationale
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,
with an anesthetic induction dose of 0.4 mg/kg for HSK3486 that has been shown 
comparable to the approved 2.5 mg/kg dose of propofol. This higher potency could
potentially result in less site pain and cardiopulmonary instability. Substantial Phase 1 to 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 40 of 84
3 clinical trials were conducted in Australia and China. Currently, one of two pivotal Phase 3 
trial is ongoing in US. This human abuse potential study is planned to address the Food and 
Drug Administration (FDA) requirement that any new chemical entity that targets CNS needs 
to be evaluated on substance abuse potential in humans.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 41 of 84
2.
OBJECTIVES
2.1
Part 1
Primary
To determine the doses of IV HSK3486 and propofol for use in Part 2, the abuse 
potential part of the study
Secondary
To evaluate the safety and tolerability of HSK3486 in healthy, nondependent, 
recreational CNS depressant drug users
2.2
Part 2
Primary
To evaluate the abuse potential of HSK3486 compared with propofol when 
administered IV to healthy nondependent, recreational CNS depressant drug users
Secondary
To evaluate the safety and tolerability of HSK3486 compared to propofol when 
administered IV to healthy nondependent, recreational CNS depressant drug users
To evaluate the PK profile of HSK3486 when administered IV to healthy 
nondependent, recreational CNS depressant drug users

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 42 of 84
3.
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan
3.1.1
Type of Study
This single center study will consist of 2 parts. Part 1 will be an open-label, dose-finding 
study of HSK3486 and propofol conducted in up to 48 recreational users of CNS 
depressants to determine the appropriate doses to be used in Part 2 of the study. Part 2 will 
be a randomized, double-blind, placebo- and active-controlled 4-period, 4-way crossover, 
in approximately 42 healthy volunteers with prior recreational CNS depressant exposure. 
The abuse potential of single administration of 2 different presumed subtherapeutic doses 
of HSK3486 will be compared with a dose of propofol (active control) determined in Part 1,
and placebo. Both Part 1 and Part 2 of the study will consist of an outpatient Screening Visit, 
an in-clinic Treatment Phase, and Follow-up; Part 2 will also include a Qualification Phase.
The treatments planned in this study are described in Section 3.4.1. 
Additional coronavirus disease 2019 (COVID–19) related precautions and procedures 
(including 
SARS-CoV-2
[severe 
acute 
respiratory 
syndrome 
coronavirus 
2]
testing/screening) may be implemented based on the prevailing situation during study 
conduct, at the Investigator’s discretion; the instructions will be provided in a separate 
document. Any procedure implemented will be in accordance with the local and national 
regulations and shall be documented appropriately.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 43 of 84
Figure 2:
Study Diagram
N=number of subjects
The doses to be used in Part 2 will be determined during dose finding in Part 1. Groups of 4 subjects will 
receive 1 dose level. Enrollment will be halted after the doses to be used in Part 2 will have been determined. 
The Drug Discrimination Test will ensure subjects can differentiate between the effects of active control 
(propofol) and placebo.
A naloxone challenge will ensure subjects are not opioid dependent. 
A naloxone challenge will be administered on the day of admission.
3.1.2
Screening Period
Subjects will report to the medical screening facility/clinical site for the eligibility screening 
(see Section 3.2.6 for inclusion and exclusion criteria) within 28 days prior to drug 
administration. If a subject participates in Part 1 and is admitted to the clinic for Part 1 within 
the 28 day screening window for Part 2, they will be reconsented but do not need to be 
rescreened. 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 44 of 84
Subjects will sign the study-specific informed consent form (ICF) prior to any study-specific 
screening procedures being performed. The written informed consent will be obtained for 
all subjects, regardless of their eligibility for the study; the signed ICFs will be retained and 
archived, and a copy will be provided to the subject.
Eligibility screening will consist of the assessments as presented in the schedule(s) of 
assessments (Table 1 or Table 2).
3.1.3
Treatment Period
3.1.3.1
Part 1
Part 1 will consist of 2 separate arms: Part 1A and Part 1B. Up to 48 subjects may be 
enrolled to participate in Part 1 with up to 24 subjects in each arm. Subjects will be admitted 
to the clinic on Day -1 and administered a naloxone challenge (Section 3.2.7) to assess 
opioid dependence, on Day 1 they will be administered study drug (either HSK3486 or 
propofol) following a minimum 8-hour fast, and on Day 2 they will be discharged at least 
24 hours after study drug administration and upon completion of study assessments. 
Subjects who participate in a given group in Part 1 cannot participate in a subsequent group 
in Part 1; however, subjects in Part 1 may participate in Part 2 of the study at the discretion 
of the Investigator.  
Part 1A: For HSK3486 dose determination, groups of 4 eligible subjects will receive 1 dose 
of study drug. On Day 1, subjects in the first group will receive IV HSK3486 0.1 mg/kg 
(starting dose) administered as a bolus over 30 seconds (+5 seconds) from a syringe. The 
dose used for succeeding groups will be based on the pharmacodynamic (PD) and safety 
results of the prior group. The dose used in the next group may be increased, decreased. 
or repeated; the magnitude of change for a new dose will be no greater than 0.025 mg/kg 
(increase or decrease) relative to previously administered doses. It is anticipated that 4 dose 
levels will be sufficient to identify the doses that should be used in Part 2 of the study; 
however, enrollment can be halted prior to completing all planned groups once doses for 
Part 2 have been identified based on dose selection criteria listed in Section 3.2.5. If 
necessary, up to 2 additional groups of 4 subjects each may be enrolled up to a total of 24 
subjects. These additional groups will be used if doses have not been identified that meet 
the dose selection criteria, or if the Investigator and Sponsor agree that higher or 
intermediate doses may be of value to Part 2, even if previously tested doses meet dose 
selection criteria. All dose increases during dose finding are subject to stopping rules defined 
in Section 3.2.4. 
Part 1B: Likewise, for propofol dose determination, groups of 4 eligible subjects will receive 
1 dose of propofol. On Day 1, subjects in the first group will receive IV propofol 0.5 mg/kg 
(starting dose) administered as a bolus over 30 seconds (+5 seconds) from a syringe.5 The 
dose used for succeeding groups will be based on the pharmacodynamic (PD) and safety 
results of the prior group. The dose used in the next group may be increased, decreased, 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 45 of 84
or repeated; the magnitude of change for a new dose will be no greater than 0.125 mg/kg 
(increase or decrease) relative to previously administered doses. It is anticipated that 4 dose 
levels will be sufficient to identify the dose of propofol that should be used in Part 2 of the 
study; however, enrollment can be halted prior to completing all planned groups once the 
dose for Part 2 has been identified based on dose selection criteria listed in Section 3.2.5. 
If necessary, up to 2 additional groups of 4 subjects each may be enrolled up to a total of 
24 subjects. These additional groups will be used if a dose has not been identified that 
meets the dose selection criteria, or if the Investigator and Sponsor agree that a higher or 
intermediate dose may be of value to Part 2, even if previously tested doses meet dose
selection criteria. All dose increases during dose finding are subject to stopping rules defined 
in Section 3.2.4.
All subjects will receive a 2 cc pre-treatment of 1% lidocaine at the injection site to minimize 
pain associated with study drug administration prior to administration of either HSK3486 or 
propofol. 
Safety and PD assessments will be performed at defined timepoints including Drug Liking
(“at this moment”), drowsiness/alertness visual analog scale (VAS), and the Modified 
Observer’s Assessment of Alertness/Sedation (MOAA/S) (Section 3.5.1.2.3). Subjects will 
be rated on their ability to complete the full battery of abuse potential questions for up to 
1 hour. Safety assessments will include continuous oxygen saturation, vital signs, 
continuous telemetry, and 12-lead electrocardiogram (ECG). Respiratory minute ventilation
of subjects will be monitored using the ExSpiron® device. An anesthesiologist or 
ACLS-certified physician capable of performing intubation will remain at the CRU to support 
site staff during study drug administration and for at least 0.5 hours following study drug 
administration.
Dose-finding stopping rules are described in Section 3.2.4, and Part 2 dose selection criteria 
are described in Section 3.2.5.
Subjects will be discharged approximately 24 hours following study drug administration. A 
telephone follow-up assessment will be performed 3 to 7 days after drug administration.  
Assessments for follow-up will be performed as presented in Table 1 or Table 3.
3.1.3.2
Part 2 
Subjects will be admitted to the CRU on Day -4 for the Qualification Phase. Upon admission 
on Day -4, each subject will be administered a naloxone challenge to assess opioid 
dependence (Section 3.2.7). During the Qualification Phase, subjects will undergo a Drug 
Discrimination Test to ensure that they can differentiate between the effects of active control 
(propofol) and placebo; qualification criteria described in Section 3.2.6. During the Drug 
Discrimination Test, subjects will receive IV propofol (dose to be determined in Part 1) 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 46 of 84
administered over 30 seconds (Treatment X) or matching placebo (Treatment Y) after an 
overnight fast in a randomized, double-blind, crossover manner with each drug 
administration separated by approximately 24 hours (Day -3 and Day -2). Subjects who do 
not meet Drug Discrimination criteria (Section 3.2.6) will be discharged from the CRU
approximately 24 hours after the second drug administration. Subjects who successfully 
complete the Qualification Phase will be eligible to enter the Treatment Phase. A washout 
interval of at least 48 hours will be required between the last drug administration in the 
Qualification Phase and the first drug administration in the Treatment Phase. In both 
Qualification and Treatment phases of the study, the Investigator will instruct subjects when 
answering questions after drug administration, not to make comparisons with previous
treatments received in the study.
All subjects will be randomized to 1 of 8 treatment sequences according to two 4×4 William 
squares in the Treatment Phase. Subjects will receive each of the following 4 treatments in 
a randomized, double-blind, 4-way crossover manner following an overnight fast:
Treatment A: HSK3486 dose 1 (IV bolus over 30 seconds [+5 seconds] from a 
syringe; dose to be determined in Part 1 [Section 3.2.5]) 
Treatment B: HSK3486 dose 2 (IV bolus over 30 seconds [+5 seconds] from a 
syringe; dose to be determined in Part 1 [Section 3.2.5]) 
Treatment C: Propofol (IV bolus over 30 seconds [+5 seconds] from a syringe; dose 
to be determined in Part 1 [Section 3.2.5]) 
Treatment D: Placebo (Treatment A matched) (IV bolus over 30 seconds 
[+5 seconds] from a syringe)
To assist with blinding of subjects all study treatments in Part 2 will be administered by an 
unblinded dosing team, which will use a blindfold and curtain to obscure visible differences 
between treatments for the subject dosed, any blinded study team members, and 
neighboring subjects. In effort to further maintain the blind, within 5 minutes before each 
treatment (test, active control, or placebo; Qualification Phase and Treatment Phase) 
subjects will be administered 2 cc of 1% lidocaine at the injection site in order to block the 
stinging sensation that can occur with propofol injection.
Each treatment administration in the Treatment Phase will be separated by approximately 
24 hours. Serial PD assessments will be performed, including Drug Liking, level of sedation, 
and ability to respond to questions. Subjects will also undergo safety assessments while 
housed in the CRU.
Subjects will be discharged approximately 24 hours following the last dose of study drug in 
Period 4. A telephone follow-up assessment will be performed 3 to 7 days after either last 
drug adminsitration or early withdrawal from the study.  
Assessments for follow-up will be performed as presented in Table 1 or Table 3. 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 47 of 84
3.2
Discussion of Study Design
See Section 3.6.3 for sample size determination.
3.2.1
Subjects and Qualification
This study will be performed in nondependent, recreational CNS depressant users. These 
subjects represent the population most at risk for abusing HSK3486, are familiar with the 
subjective effects of CNS depressants, and are able to tolerate drugs in this class, hence 
provide the most face-valid population for a study of abuse potential. 
The Qualification Phase will ensure that subjects who proceed to the Treatment Phase are 
able to discriminate between propofol and placebo as well as report appropriate responses 
to the drug in a controlled laboratory setting.
A naloxone challenge will ensure subjects are not opioid dependent, which would confound 
study results. 
3.2.2
Propofol as Comparator 
The comparators in an abuse potential study are typically controlled substances from the 
same pharmacologic class as the investigational drug. HSK3486 is a unique chemical 
entity similar to propofol with higher potency but similar efficacy and action. Given 
propofol’s demonstrated abuse potential, it is the appropriate comparator for the study.5
3.2.3
Study Design 
Human abuse potential studies are typically conducted as double-blind crossovers because 
of inter-individual variability in subjective responses. Each subject receives each dose of 
study drug and acts as his/her own control.
3.2.4
Part 1 Stopping Rules for Dose Finding
Dose finding will be halted, pending discussion between sponsor and investigator, in Part 1 
if 1 subject out of 4 demonstrates 1 or more of the below changes in vital signs sustained 
for >2 minutes with verbal stimulation as monitored through the first hour postdose: 
1) Heart rate <40 bpm
2) Systolic BP <80 mmHg 
3) Respiratory rate <6 breaths per minute
4) Pulse oximetry O2 sat <87% with verbal stimulation 
5) Respiratory minute ventilation <60% of baseline
If the sponsor and investigator agree that the vital signs changes noted above were unlikely 
related to study drug and/or that there is no significant safety concern, then dose finding 
may proceed at an increased, decreased, or repeated dose level.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 48 of 84
3.2.5
Part 2 Dose Selection Criteria 
The Investigator and Haisco will determine the doses of HSK3486 and propofol to be used 
in Part 2 of the study using the following criteria as monitored through the first hour postdose:
1) Maximum dose at which subjects are able to adequately complete the battery of human 
abuse potential assessments over most of the 1-hour period
2) Level of consciousness generally 
(Section 3.5.1.2.3)
3) Minute ventilation does not decrease more than 30% for one minute with verbal 
stimulation
4) Oxygen saturation does not fall below 90% for more than 30 sec with verbal stimulation
For both HSK3486 and propofol, the highest doses tested in Part 1 meeting these criteria 
will be used in Part 2, Treatments A and C, respectively. The second dose of HSK3486 to 
be used in Part 2 will be the second highest dose tested in Part 1 (Treatment B) that meets 
these criteria.
3.2.6
Qualification Criteria 
Subjects must meet each of the following criteria at the end of Qualification Phase in order 
to be eligible for participation in the Treatment Phase:
1.
Drug Liking VAS Emax
IV
for active control than for placebo.
2.
Acceptable placebo response based on Drug Liking VAS (score between 40 points and 
60 points, inclusive).
3.
Acceptable overall responses to active control (IV propofol) and placebo on all other 
human abuse potential PD measures, as judged by the Investigator or designee.
4.
Acceptable safety and tolerability after administration of active control (IV propofol).
5.
Oxygen saturation does not fall below 90% for more than 30 sec with verbal stimulation.
3.2.7
Naloxone Challenge 
During the naloxone challenge administered in Parts 1 and 2, all participants will receive IV 
naloxone 0.2 mg dose as an IV bolus, followed by an assessment for signs of opioid 
withdrawal. If there are no signs of opioid withdrawal within 30 seconds after administration, 
a second dose of 0.6 mg IV will be administered within 5 minutes of the first dose, followed 
by another assessment for signs of opioid withdrawal 5 minutes after the second naloxone
dose. Only participants who do not have signs and symptoms of opioid withdrawal, as 
assessed by the Clinical Opioid Withdrawal Scale (COWS score <5), will be eligible to 
proceed with the study (Appendix 8.4). Any participant demonstrating evidence of 
withdrawal (COWS score >5) on any assessment will not be eligible for further participation 
in the trial. The participant will be released from the study center when medically stable, as 
determined by the Investigator. Symptoms reported in the COWS as a consequence of 
opioid withdrawal will not be collected as AEs unless they meet the criteria for a new AE or 
serious adverse event (SAE).

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 49 of 84
3.3
Selection of Study Population
Subjects will be healthy male and female nondependent, nontreatment-seeking recreational 
CNS depressant users.
Part 1
An adequate number of subjects will be screened such that up to 32 subjects (16 subjects 
for HSK3486 dose determination [4 groups of 4 subjects each] and 16 subjects for propofol 
dose determination [4 groups of 4 subjects each]) may be enrolled in Part 1 of the study. Up 
to an additional 16 subjects (2 groups of 4 each for HSK3486 dose determination and 
2 groups of 4 each for propofol dose determination) may be enrolled in Part 1, if necessary.
Part 2
An adequate number of subjects will be screened such that a sufficient number of subjects 
are randomized into the Qualification Phase with the intention of qualifying and randomizing 
approximately 42 subjects into the Treatment Phase, with the intention of completing 
36 subjects. Subjects who participated in Part 1 of the study may be eligible for Part 2 of the 
study at the Investigator’s discretion.
3.3.1
Inclusion Criteria
Note: Restrictions that apply to the period after admission are described in Section 3.4.8, 
except when they concern a statement of willingness.
The following criteria must be met for a subject to be eligible for inclusion in the study:
1) Willing to participate in the study, give written informed consent, and comply with the 
study restrictions.
2) Gender: male or female; females may be of childbearing potential, of nonchildbearing 
potential, or postmenopausal.
3) Age: 18 years to 55 years, inclusive, at Screening.
4) Body mass index (BMI): 18.0 kg/m2 to 30.0 kg/m2, inclusive.
5)
6) Healthy subject, defined by the absence of evidence of any clinically significant, in the 
opinion of the Investigator, active or chronic disease following a detailed medical and 
surgical history, a complete physical examination including vital signs, 12-lead ECG, 
hematology, blood chemistry, serology, and urinalysis.
7) Subject must be a nondependent, nontreatment-seeking recreational CNS depressant 
user, defined as follows:
a.
i.e., for psychoactive effects) with CNS 
depressants 
(e.g., 
benzodiazepines, 
barbiturates, 
zolpidem,
zopiclone, 
propofol/fospropofol, gamma-hydroxybutyrate).
b.
.
c.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 50 of 84
8) Ability and willingness to abstain from alcohol-, caffeine-, and xanthine-containing 
beverages or food (e.g., coffee, tea, cola, chocolate, energy drinks) from 48 hours 
(2 days) prior to first admission to the CRU, throughout the entire study, and until
discharge.
9) All values for hematology and clinical chemistry tests of blood and urine within the 
normal range or show no clinically relevant deviations, as judged by the Investigator.
10) Females of childbearing potential, and males with female partner(s) of childbearing 
potential, as judged by the Investigator, must agree to use 2 forms of contraception, 1 
of which must be a barrier method, during the study and for 90 days after the last drug 
administration. Acceptable barrier forms of contraception are condom, cervical cap, and 
diaphragm. Acceptable non barrier forms of contraception for this study are an 
days prior to dosing any study treatment), and/or spermicide.
11) For females: a negative pregnancy test at Screening and Admission.
12) Postmenopausal females: defined as 12 months with no menses prior to Screening and 
a serum follicle-stimulating hormone (FSH) >40 IU/L at Screening.
13) All nonregular medication (including over-the-counter medication, health supplements, 
and herbal remedies such as St. John’s Wort extract) must have been stopped at least 
14 days prior to (the first) admission to the CRU. An exception is made for 
acetaminophen, which is allowed up to admission to the CRU.
14) All prescribed medication must have been stopped at least 30 days prior to (first) 
admission to the clinical research center. An exception is made for hormonal 
contraceptives, which may be used throughout the study.
15) Able to speak, read, and understand English sufficiently to allow completion of all study 
assessments.
3.3.2
Exclusion Criteria
Note: Restrictions that apply to the period after admission are described in Section 3.4.8, 
except when they concern a statement of willingness.
A subject who meets any of the following criteria will not be eligible for inclusion in the study:
1.
An employee of the Sponsor or research site personnel directly affiliated with this study 
or their immediate family member (defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted).
2.
Drug or alcohol dependence within the 2 years prior to Screening (except nicotine and 
caffeine), as defined by the Diagnostic and Statistical Manual of Mental Disorders, 
fourth edition, text revision (DSM-IV-TR), and/or has ever participated or plans to 
participate in a substance or alcohol rehabilitation program to treat their substance or 
alcohol dependence.
3.
Opioid dependence as judged by the Investigator after a naloxone challenge. 
4.
Women who are pregnant, lactating, or planning to attempt to become pregnant during 
this study or within 90 days of last study drug administration.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 51 of 84
5.
Males with female partners who are pregnant, lactating, or planning to attempt to 
become pregnant during this study or within 90 days of last study drug administration.
6.
Positive drug and alcohol screen (tetrahydrocannabinol [THC], morphine/opiates, 
methadone, oxycodone, phencyclidine, cocaine, amphetamines, methamphetamines, 
ecstasy, barbiturates, benzodiazepines, tricyclic antidepressants, and alcohol) at each 
admission to the CRU. For THC, subjects should ideally test negative. However, 
eligibility decision with regards to THC use will be considered on a case by case basis, 
at the discretion of the Investigator.
7.
Treatment with an investigational drug or device within 5 times the elimination half-life, 
if known (e.g., a marketed product) or within 30 days (if the elimination half-life is 
unknown) prior to first drug administration or is concurrently enrolled in any research 
judged not to be scientifically or medically compatible with this study. An exception may 
be made for subjects who participated in Part 1 of the study.
8.
History or presence of clinically significant abnormality (e.g., obstructive sleep apnea) 
as assessed by physical examination, medical history, ECG, vital signs, or laboratory 
values, which, in the opinion of the Investigator, would jeopardize the safety of the 
subject or the validity of the study results.
9.
Any disease which, in the opinion of the Investigator, poses an unacceptable risk to the 
subjects.
10. Mallampati intubation score >2. 
11. History of clinically significant drug allergy diagnosed by a physician. Confirmatory 
circumstances would include treatment with epinephrine or in an emergency 
department.
12. Any personal or family history of issues with succinylcholine, such as malignant 
hyperthermia or pseudocholinesterase deficiency.
13. History of allergy, adverse reaction (including significant
agitation, etc.), or 
hypersensitivity to propofol, lidocaine, other injected anesthetic agents, or related drugs.
14. History of allergy to eggs, egg products, soybeans or soy products.
15. Heavy smoker (>20 cigarettes per day) and/or is unable to abstain from smoking and/or 
the use of prohibited nicotine-containing products (including e-cigarettes, pipes, cigars, 
chewing tobacco, nicotine topical patches, nicotine gum, or nicotine lozenges) from 
2 hours prior to dosing until at least 4 hours postdose during the in-clinic periods.
16. Routine or chronic use of more than 3000 mg of acetaminophen daily.
17. Strenuous activity (such as exercise), sunbathing, and contact sports within 48 hours 
(2 days) prior to admission to the CRU, during the study, and until after discharge in the 
last study period.
18. History of donation of more than 450 mL of blood within 60 days prior to dosing in the 
CRU or planned donation before 30 days has elapsed since last intake of study drug.
19. Plasma or platelet donation within 7 days of dosing and throughout the entire study.
20. Average intake of more than 14 units of alcohol per week (1 unit of alcohol equals 
approximately 250 mL of beer, 100 mL of wine, or 35 mL of spirits). Alcohol consumption 
will be prohibited 48 hours prior to first admission to the CRU and throughout the entire 
study until the Follow-up visit (including washout period).

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 52 of 84
21. Positive screening test for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus 
(HCV) antibodies, or anti-HIV 1 and 2 antibodies.
22. History of peripheral vasculopathy, including Raynaud’s phenomenon.
23. History of seizures, seizure disorder, or known electroencephalogram (EEG) 
abnormalities.
24. History of mental illness, which, in the opinion of the Investigator, would jeopardize the 
safety of the subject or the validity of the study results.
25. Subject with a history of clinically significant head injury, ongoing seizure disorder, 
chronic tics, or diagnosis or family history of Tourette's syndrome.
26. Subjects with a history of serious structural cardiac abnormalities, cardiomyopathy, 
serious heart rhythm abnormalities, coronary artery disease, advanced arteriosclerosis, 
symptomatic cardiovascular disease, hypertension, or other cardiac problems.
27. Any history of clinically significant suicidality as assessed by the Investigator based 
upon clinical history, source documents, or scores on the Columbia-Suicide Severity 
Rating Scale (C-SSRS).
28. History or presence of clinically significant hepatic or renal disease.
29. History of hyperthyroidism.
30. Difficulty with venous access or unsuitable or unwilling to undergo catheter insertion.
31. Use of a cytochrome p450 (CYP)2D6-inhibiting drug or a serotonergic drug within 
14 days prior to first drug administration in the Qualification Phase.
32. Consumption of any nutrients known to modulate CYP enzymes activity (e.g., grapefruit 
or grapefruit juice, pomelo juice, star fruit, or Seville [blood] orange products) within 
14 days prior to administration of study medication and during the study (including 
washout period) until after discharge in the last study period.
33. A subject who, in the opinion of the Investigator or designee, is considered unsuitable 
or unlikely to comply with the study protocol for any reason.
34. A subject who has pending legal charges or is on probation.
3.3.3
Removal of Subjects from Assessment
Participation in the study is strictly voluntary. A subject has the right to withdraw from the 
study at any time for any reason.
The Investigator has the right to terminate participation of a subject for any of the following 
reasons: difficulties in obtaining blood samples, violation of the protocol, severe AEs or 
SAEs, or for any other reason relating to the subject's safety or integrity of the study data.
If a subject is withdrawn from the study, the Sponsor will be informed immediately. If there 
is a medical reason for withdrawal, the subject will remain under the supervision of the 
Investigator until satisfactory health has returned.
After signing informed consent, subjects who drop out or withdraw for any reason without 
completing all screening evaluations successfully as well as subjects who drop out or 
withdraw prior to the first dose of study drug will be considered screening failures.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 53 of 84
A subject who is withdrawn or voluntarily withdraws from the study for any reason, whether 
related to the study drug or not, after having received the first dose of study drug, will be 
considered an early-termination subject. If a subject is withdrawn for a reason related to the 
study drug, according to the judgment of the Investigator, the early-termination subject will 
not be replaced. If a subject does not complete the study for a reason not related to the 
study drug, the early-termination subject may be replaced after mutual agreement between 
the Sponsor and site. 
The decision regarding the replacement of subjects will be documented.
Every effort will be made to ensure that early-termination subjects who have received study 
drug complete the early-termination assessments/safety follow-up assessments.
3.4
Treatments
3.4.1
Treatments Administered
In Part 1 subjects will be administered either propofol or HSK3486 at a starting dose of 
0.5 mg/kg and 0.1 mg/kg, respectively. In between each group the dose can be increased 
or decreased by no more than 0.125 mg/kg (propofol) or 0.025 mg/kg (HSK3486) relative 
to any previously tested dose. 
In Part 1, subjects will receive a treatment of 2 cc of 1% lidocaine at the injection site to 
minimize pain associated with study drug administration prior to administration of either 
HSK3486 or propofol. 
In the Qualification Phase of Part 2, subjects will undergo a Drug Discrimination Test. Each 
subject will be administered one of the follow treatments: 
Treatment X: IV propofol (dose determined in Part 1)
Treatment Y: Matching placebo
In the Treatment Phase of Part 2, subjects will receive each of the following treatments:
Treatment A: HSK3486 dose 1 (IV bolus over 30 seconds [+5 seconds] from a 
syringe; dose to be determined in Part 1)
Treatment B: HSK3486 dose 2 (IV bolus over 30 seconds [+5 seconds] from a 
syringe; dose to be determined in Part 1)
Treatment C: Propofol (IV bolus over 30 seconds [+5 seconds] from a syringe; dose 
to be determined in Part 1)
Treatment D: Placebo (IV bolus over 30 seconds [+5 seconds] from a syringe)
In order to maintain the blind in Part 2, subjects will be administered 2 cc of 1% lidocaine at 
the injection site within 5 minutes before each treatment (test, active control, or placebo; 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 54 of 84
Qualification Phase and Treatment Phase) in order to block the stinging sensation that can 
occur with propofol injection. Additionally a blindfold and curtain will be used to hide visible 
differences between the separate treatments, and a unblinded dosing team will be used to 
maintain the blind of the site staff performing the study assessments. Further details are
provided in the Pharmacy Manual. 
3.4.2
Identity of Investigational Products 
Test preparation (HSK3486)
Active substance : HSK3486 injectable emulsion 
Activity 
: CNS depression through gamma-aminobutyric acid receptor subtype 
A (GABAA) mediation
In development for: General anesthesia and sedation
Strength 
: 2.5 mg/mL (total dose: 0.05 g in 20 mL) 
Dosage forms 
: Injection
Reference medication (Propofol injectable emulsion)
Active substance : Propofol 
Activity 
: Positive modulation of the inhibitory function of the neurotransmitter 
GABA through the ligand-gated GABAA receptors
Indication 
: General anesthesia and sedation
Strength 
: 10 mg/mL
Dosage form 
: Injection 
Placebo
Substance 
: Intralipid®
Activity 
: Not applicable
Strength 
: Not applicable
Dosage form 
: 20% IV fat emulsion
Masking drug (xylocaine)
Substance 
: Lidocaine HCl
Activity 
: Local anesthetic
Strength 
: 1%
Dosage form 
: Injection
The test preparation will be provided by the Sponsor. The reference medication, placebo, 
and masking drug will be commercially obtained by the Pharmacy. 
For details concerning drug storage and drug accountability see Appendix 8.1. 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 55 of 84
3.4.3
Method of Assigning Subjects to Treatment Groups
Part 1 of the study is non-randomized. 
In Part 2 of the study, subjects enrolled in the Qualification Phase will be randomized to 1 
of 2 treatment sequences (XY or YX) in a 1:1 ratio. Randomization numbers will begin with 
2001. 
Subjects who successfully complete the Qualification Phase and continue to be enrolled in 
the Treatment Phase of Part 2 will be randomized to 1 of 8 treatment sequences (with equal 
allocation) according to two 4×4 William’s design Latin squares. Subject randomization 
numbers for the Treatment Phase will range from 1001 to 10XX with replacement numbers 
ranging from 1101 to 11XX. 
The randomization schedules will be produced by 
 Biostatistics. The study 
biostatistician will create a draft randomization list and a peer biostatistician will review and 
approve that draft list. After the final randomization list has been approved, it will be 
transferred to the pharmacy and kept in a restricted area to which only the pharmacy has 
access. 
3.4.4
Selection of Doses in the Study
To ensure all subjects can complete the necessary assessments in the study a nonsedating 
dose of both HSK3486 and propofol is needed. 
The starting dose of propofol in Part 1 is 0.5 mg/kg, which is similar to a dose of 0.6 mg/kg 
that demonstrated abuse potential in previous work.5 A single-ascending dose study with 
HSK3486 has shown MOAA/S and Richmond agitation-sedation scale scores of 4 and -2, 
respectively, at 0.128 mg/kg,6 which is expected to be slightly too much sedation for the 
assessments in the current study. A dose of 0.1 mg/kg was chosen as an appropriate 
starting dose for HSK3486 in Part 1
The doses used in Part 2 of the study will be determined based on selection criteria outlined 
in Section 3.2.5 from results obtained in Part 1. 
3.4.5
Timing of Doses in the Study
All study treatments will be administered after a minimum of an 8-hour fast. During fasting, 
no fluids are allowed except water, excluding the 2 hours prior to dosing when all fluids 
including water are restricted. Water can be resumed after dosing is complete. 
In Part 2 (Qualification Phase and Treatment Phase), a single treatment will be administered 
each day separated by approximately 24 hours each. 
All study drug will be administered with the subject in the upright position as an IV bolus 
over 30 seconds (+5 seconds). 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 56 of 84
Fasting will continue for a period of at least 4 hours after drug administration. When not 
fasting, noncaffeinated fluids are allowed ad libitum.
3.4.6
Meals During the Study
A fasting period of at least 4 hours is required before obtaining clinical laboratory blood 
samples at all time points (Table 1, Table 2, and Table 3).
With the exception of the restrictions with respect to methylxanthine- and alcohol-containing 
beverages or food as described in Section 3.4.8 and what has been described in 
Section 3.4.5, there are no special requirements related to food and beverage intake. When 
not fasting, meals and snacks (such as decaffeinated coffee, herbal tea, fruit, biscuits) will 
be provided according to site standard operating procedures (SOPs). A standard dinner will 
be provided on the evening before those days where fasting is required until fasting is 
complete. 
3.4.7
Blinding
Part 1 is open-label (not applicable). 
In Part 2, all subjects will be randomized to 1 of 8 treatment sequences according to two 
4×4 William squares. The following controls will be employed to maintain the double-blind 
status of the study:
Due to visible differences between study treatments, a blindfold will be used to hide the 
treatment administered to each subject, and a curtain will be used to hide difference in 
treatment for subjects dosed, any blinded study team members, and neighboring 
subjects. 
An unblinded dosing team will be used to ensure the remainder of the site staff will be 
blinded during study assessments. 
Within 5 minutes before each treatment (test, active control, or placebo; Qualification 
Phase and Treatment Phase) subjects will be administered 2 cc of 1% lidocaine at the 
injection site in order to block the stinging sensation that can occur with propofol 
injection.
The randomization code will be provided to the pharmacist for dispensing purposes and 
kept in the pharmacy, accessible to the pharmacist and the pharmacy technician only.
The laboratory where the PK samples will be analyzed will be provided a copy of the 
randomization code by the pharmacy since only samples of subjects who have received the 
active drug HSK3486 will be analyzed.
3.4.8
Concomitant Medication and Other Restrictions During the Study
Note: Restrictions that apply to the period before admission are described in Section 3.3.1
and Section 3.3.2.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 57 of 84
The use of all prescribed medication is not allowed from at least 30 days prior to admission 
to the clinical research center until follow-up. The use of all over-the-counter medication, 
vitamin preparations and other food supplements, or herbal medications (e.g., St. John’s 
wort) is not allowed from at least 14 days prior to admission to the clinical research center 
until follow-up. An exception is made for:
Acetaminophen: from admission onwards, the Investigator may permit a limited 
amount of acetaminophen for the treatment of headache or any other pain. 
Hormonal contraceptives, which are allowed throughout the study.
Lidocaine.
Intralipid.
Other medication to treat AEs may only be prescribed if deemed necessary by the 
Investigator. If medication is used, the name of the drug, the dose, and dosage regimen will 
be recorded in the electronic case report form (eCRF). All medications (prescription and 
over-the-counter) taken within 30 days of study screening or during the study will be 
recorded in the appropriate section of the eCRF and in the source documents.
The use of methylxanthine-containing beverages or food (coffee, tea, cola, chocolate, 
energy drinks) is not allowed from 48 hour prior to admission until discharge. The use of 
grapefruit (juice) is not allowed from 14 days prior to admission until discharge. Restrictions 
to nicotine-containing products are described in Section 3.3.2.
The use of alcohol is not allowed during the stay in the clinical research center.
Subjects will not be allowed to smoke for 2 hours prior to dosing until at least 4 hours 
postdose during the in-clinic periods.
Strenuous exercise is not allowed within 48 hours (2 days) prior to admission. Strenuous 
exercise is also not allowed during the stay in the clinical research center and until after 
discharge. 
Subjects should not consume any foods containing poppy seeds within 48 hours (2 days) 
prior to admission to the clinical research center as this could cause a false positive drug 
screen result.
Contraceptive requirements for males and females are described in Section 3.3.1. 
3.4.9
Treatment Compliance
Study drug will be administered in the clinical research center by the Investigator or authorized 
designee (Part 1 and Part 2) or an unblinded dosing team (Part 2). Compliance will be further 
confirmed for HSK3486 by bioanalytical assessment in plasma samples (see Section 3.5.4).

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 58 of 84
The exact times of study drug administration and the number of units administered will be 
recorded in the eCRF. 
3.5
Pharmacokinetic, Pharmacodynamic, and Safety Variables
3.5.1
Pharmacokinetic, Pharmacodynamic, and Safety Assessed 
Schedules of assessments are presented in Table 1, Table 2, and Table 3.
3.5.1.1
Pharmacokinetic Measurements
The samples obtained for PK analysis may be used for analysis of metabolites of the study 
drug in the future.
3.5.1.1.1
Blood Sampling
At the time points defined in the schedule of assessments, blood samples of 2 mL each will 
be taken for the analysis of HSK3486 in plasma samples. The blood samples will be taken 
via an indwelling IV catheter or by direct venipuncture. The exact times of blood sampling 
will be recorded in the eCRF. 
Details on sample collection, handling, storage, and shipping will be described in the 
laboratory manual.
3.5.1.2
Pharmacodynamic Measurements
All measures will be taken to prevent missing data due to subjects falling asleep and/or 
impairment of their ability to respond adequately. Missing data will not be imputed for 
statistical summary and analysis.
3.5.1.2.1
Drug Liking (“at this moment”) VAS
Drug Liking assesses the degree that a subject likes a drug effect at the time the question 
is being asked (that is, “at this moment”). Subjects respond to the statement “At this moment, 
my liking for this drug is.” The answer is scored using a 0 to 100-point bipolar VAS anchored 
in the center with a neutral anchor of "neither like nor dislike" (score of 50), on the left with 
"strong disliking" (score of 0) and on the right with "strong liking" (score of 100). 
3.5.1.2.2
Drowsiness/Alertness VAS 
This scale assesses the subject’s mental state at the time the question is being asked (that 
is, at the moment). Subjects respond to the statement “At this moment, my mental state is:” 
The question is scored using a 0 to 100-point bipolar VAS anchored on the left with “very 
drowsy” (score of 0); “neither drowsy nor alert” (score of 50) in the middle; and anchored on 
the right with “very alert” (score of 100).
3.5.1.2.3
MOAA/S Score
The following scale will be used for MOAA/S scoring:
5 = responds readily to name spoken in normal tone

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 59 of 84
4 = lethargic response to name spoken in normal tone
3 = responds only after name is called loudly and/or repeatedly
2 = responds only after mild prodding or shaking
1 = responds only after painful trapezius squeeze
0 = does not respond to painful trapezius squeeze
3.5.1.2.4
Ability to Complete Battery of Abuse Potential Assessment Questions for 1 Hour 
The Investigator will assess if the subject was able to complete the required questions within 
the 1-hour period after study treatment administration. 
3.5.1.2.5
Overall Drug Liking VAS
This scale assesses the subject’s global perception of Drug Liking (i.e., the subjective effects 
over the whole course of the drug experience including any carryover effects). Subjects 
respond to the statement “Overall, my liking for this drug is:” The question is scored using a 
0 to 100-point bipolar VAS anchored on the left with “strong disliking” (score of 0); “neither 
like nor dislike” (score of 50) in the middle; and anchored on the right with “strong liking” 
(score of 100). This scale has the advantage of the subject being relatively less affected or 
unaffected by acute study drug effects (if any) by the time of the assessment.
3.5.1.2.6
Take Drug Again VAS
This test is a subjective assessment of the degree to which a subject would desire to take 
the drug again if given the opportunity. Subjects respond to the statement “Would you want 
to take the drug you just received again, if given the opportunity?” The question is scored 
using a 0 to 100-point bipolar VAS anchored on the left with “definitely would not” (score of 
0); “do not care” (score of 50); and anchored on the right with “definitely would” (score of 
100).
3.5.1.2.7
Drug Effects Questionnaire  
The drug effects questionnaire (DEQ) is a series of scales used to evaluate subjective 
responses at the time the question is being asked to general and specific drug effects 
following acute administration of study treatments. Subjects respond to statements 
assessing the following: any drug effects, good drug effects, and bad drug effects. The 
answer is scored using a 0 to 100-point unipolar VAS anchored on the left by “not at all” 
(score of 0) and on the right by “extremely” (score of 100).
3.5.1.2.8
Relaxation/Agitation VAS 
This scale assesses the subject’s mood at the time the question is being asked (that is, at 
the moment). Subjects respond to the statement “At this moment, my mood is:” The question 
is scored using a 0 to 100-point bipolar VAS anchored on the left with “very relaxed” (score 
of 0); “neither relaxed nor agitated” (score of 50) in the middle; and anchored on the right 
with “very agitated” (score of 100).

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 60 of 84
3.5.1.2.9
Drug Similarity VAS
This scale assesses the subject’s perception of drug similarity (i.e., the subjective opinion 
of whether the drugs are similar). Subjects respond to the statement “[How similar is the 
drug you most recently received [drug 1] to drug you just took [drug 2]?” The question is 
scored using a 0 to 100-point bipolar VAS anchored on the left with “Not at all similar” (score 
of 0) and anchored on the right with “Extremely similar” (score of 100). 
3.5.1.3
Safety and Tolerability Measurements
Safety and tolerability assessments will consist of AEs, clinical laboratory, vital signs, pulse 
oximetry, respiratory volume, 12-lead ECG, continuous cardiac monitoring, physical 
examination, and C-SSRS. Assessments will be performed in accordance with the 
schedules of assessments presented in Table 1, Table 2, and Table 3. 
3.5.1.3.1
Adverse Events
Adverse events will be recorded from signing of the ICF until completion of the follow-up 
visit. Any clinically significant observations, as determined by the Investigator, in results of 
clinical laboratory, 12-lead ECGs, continuous cardiac monitoring, vital signs, pulse oximetry,
physical examinations, or C-SSRS will be recorded as AEs.
A treatment-emergent adverse event (TEAE) is defined as any event not present prior to
the first administration of study drug or any event already present that worsens in either 
severity or frequency following exposure to the study drug. 
At several time points before and after drug administration, subjects will be asked 
nonleading questions to determine the occurrence of AEs. Subjects will be asked in general 
terms about any AEs at regular intervals during the study. In addition, all AEs reported 
spontaneously during the course of the study will be recorded. All answers will be interpreted
by the Investigator using the Medical Dictionary for Regulatory Activities (MedDRA; most 
recent version) for AEs and will be recorded in the eCRF as reported terms. 
The severity of the AEs will be rated as mild, moderate, or severe; the relationship between 
the AEs and the study drug will be indicated as none, unlikely, possibly, likely, or definitely. 
Adverse events assessed as possibly, likely, or definitely will be considered related to the 
study drug; AEs assessed as none or unlikely will be considered not related to the study 
drug. Details on rating the severity of AEs and relationship to study treatment are given in 
Appendix 8.2. 
Pregnancy of female subjects and female partners of male subjects will be monitored along 
with follow-up, if warranted (see Appendix 8.3).

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 61 of 84
3.5.1.3.2
Adverse Events of Special Interest
Part 2 only: AEs of special interest (AESIs) are AEs for a particular product or class of 
products that a Sponsor may wish to monitor carefully. AESIs may be serious or nonserious.
The AESIs due to pharmacological effect of an anesthetic agent include hypoxemia, 
bradycardia, hypotension, allergy/anaphylaxis, and cardiac arrhythmia, 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 1 hour 
postdose. 
Symptomatic bradycardia, where bradycardia
is defined as a heart rate of 
<45 beats/minute that lasts >30 seconds and requiring intervention. Bradycardia is 
evaluated from the initial dose of study drug until 1 hour postdose. 
Severe hypotension defined as an SBP <90 mmHg that lasts >2 minutes and requiring 
treatment. Hypotension is evaluated from the initial dose of study drug until 4 hours
postdose. 
Allergy/anaphylaxis may include angioedema, bronchospasm, erythema, and 
hypotension.  Allery/anaphylaxis is evaluated from the initial dose of study drug until 
4 hours postdose. 
Clinically significant cardiac arrhythmia, as judged by the Investigator. Cardiac arrythmia 
is evaluated from the initial dose of study drug until 4 hours postdose. 
QTc prolongation is a QTc interval of >450 ms in males and >470 ms in females 
occurring within 15 minutes of study drug. 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. 
Start time, end time, and duration should be calculated, and treatment measures (if any) 
should be recorded. Additionally, AESI’s will be categorized as drug related for those 
occurring within 15 minutes from the initial dose of study drug.
3.5.1.3.3
Clinical Laboratory 
Blood and urine samples for clinical laboratory assessments will be collected according to 
site SOPs. All blood and urine specimens will be sent to a local reference laboratory for 
analysis and testing.
The following parameters will be measured:
Hematology: erythrocytes (red blood cells), leukocytes (white blood cells) with 
differential (neutrophils, eosinophils, lymphocytes, monocytes,
and basophils), 
hemoglobin, hematocrit, and platelet count.
Coagulation: prothrombin time/international normalized ratio (PT/INR) will be measured 
at screening only.
Blood chemistry: sodium, potassium, chloride, bicarbonate, creatinine, creatine kinase 
(CK), amylase, lipase, glucose (fasting), urea, albumin, calcium, magnesium, inorganic 
phosphorus, alkaline phosphatase, aspartate aminotransferase
(AST), alanine 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 62 of 84
aminotransferase (ALT), total bilirubin, total protein, total cholesterol, high-density 
lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, and uric acid. Estimated 
creatinine clearance (Cockroft Gault formula) and thyroid stimulating hormone (TSH) 
will be measured at screening only.
Urinalysis: A midstream, clean-catch urine specimen will be collected for dipstick 
analysis of protein, blood, glucose, leukocyte esterase, and pH (to be captured in the 
database). 
The following parameters will also be measured:
Alcohol breath test.
Urine will be collected for the assessment of the following drugs of abuse: THC, 
amphetamines, 
methamphetamines, 
3,4-methylenedioxy-N-methylamphetamine 
(ecstasy), 
opiates/morphine, 
methadone, 
oxycodone, 
phencyclidine, 
cocaine, 
benzodiazepines, tricyclic antidepressants, and barbiturates. Results must be available 
and reviewed before dosing on Day 1.
Serology will be collected for the measurement of HIV-1 and -2 antibodies, HBsAg, , 
and HCV antibody.
For all females, a serum and/or urine pregnancy test will be collected. Results must be 
available and reviewed before dosing.
A FSH and estradiol panel will be performed on all postmenopausal females.
In case of unexplained or unexpected clinical laboratory test values for enrolled subjects, 
the tests will be repeated as soon as possible and followed up until the results are 
considered not clinically significant, as determined by the Investigator and/or an adequate 
explanation for the abnormality is found. The clinical laboratory will clearly mark all 
laboratory test values that are outside the reference range, and the Investigator will indicate 
which of these deviations are clinically significant. These clinically significant laboratory 
result deviations will then be recorded as AEs, and the relationship to the treatment will be 
indicated (see also Appendix 8.2).
The procedures for the collection, handling, and shipping of laboratory samples are 
specified in the laboratory manual(s) provided to the study site.
3.5.1.3.4
Vital Signs
Systolic and diastolic BP and pulse will be recorded after the subject has been resting for at
least 5 minutes in the semirecumbant position; subjects can be moved to an upright position 
temporarily for dosing. These assessments will be made using an automated device
whenever possible. Body temperature and respiratory rate will also be measured.
3.5.1.3.5
Pulse Oximetry 
Pulse oximetry will be assessed using and automated device. 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 63 of 84
3.5.1.3.6
Respiratory Volume 
Respiratory volume and minute ventilation will be measured using the ExSpiron® device.
3.5.1.3.7
Electrocardiogram
A standard 12-lead ECG will be recorded after the subject has been resting for at least 
5 minutes in the semirecumbant position; subjects can be moved to an upright position 
temporarily for dosing. The ECG will be recorded using an ECG machine equipped with 
computer-based interval measurements. The following ECG parameters will be recorded: 
heart rate, PR-interval, QRS-duration, QT-interval, QTc-interval (Fridericia's), and the
interpretation of the ECG profile by the Investigator.
3.5.1.3.8
Continuous Cardiac Monitoring
A 12-lead ECG will be recorded continuously by telemetry from at least 1 hour before to at 
least 4 hours after each drug administration. Subjects will remain quietly semirecumbant
(with minimal disturbance by procedures) for 15 minutes just prior to any PK sampling during 
telemetry and at 3 time points between -1 and -0.25 hours predose (15 minutes each; for 
baseline). Subjects can be moved to an upright position temporarily for dosing. 
All relevant or significant arrhythmic events will be recorded in rhythm strips (10 seconds). 
The ECG will be evaluated by the Investigator for clinically significant events.
During days with telemetry, meals will be standardized. Start and stop time of the (in total) 
15-minute periods will be recorded.
The telemetry will be monitored continuously by a staff member until at least 1 hour 
postdose. 
3.5.1.3.9
Physical Examination
As indicated in the schedules of assessments (Table 1, Table 2, and Table 3), a complete 
physical examination will be performed consisting of all body systems (with the exception of 
genitalia, anus/rectal, and breast examinations, which will only be performed if medically 
indicated). Unscheduled symptom-driven physical examinations may be conducted at any 
time per the Investigator’s discretion.
3.5.1.3.10 Columbia-Suicide Severity Rating Scale 
Suicide-related thoughts and behaviors will be assessed using the C-SSRS. Regulatory 
agencies have been interested in examining suicide-related thoughts and behaviors in 
patients receiving antidepressant and other drugs used in psychiatric illnesses. In Feb 2009, 
the FDA’s Division of Psychiatry Products communicated that information regarding 
suicide-related thoughts and behaviors should be prospectively collected in a standardized 
format (Columbia Classification Algorithm or Suicide Assessment) from all clinical studies,
including Phase 1 studies, for all drugs in development to enable the analysis of 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 64 of 84
suicide-related thoughts and behaviors in an aggregated fashion.7 The tool was developed 
by a National Institute of Mental Health trial group for the purpose of being a counterpart to 
the FDA’s categorization of suicidal events.
The C-SSRS captures the occurrence, severity, and frequency of suicide-related thoughts 
and behaviors during the assessment period.7, 8, 9 The scale includes suggested questions 
to solicit the type of information needed to determine if a suicide-related thought or behavior 
occurred. The C-SSRS will be administered by appropriately trained site personnel. A 
referral to a psychiatrist will be made in case of a significant finding on the C-SSRS.
All AEs obtained through the questionnaire are recorded. The Sponsor or its designee will 
be alerted within 24 hours of the Investigator’s awareness of any SAEs from these 
questionnaires.
3.5.1.3.11 Mallampati Score
The ease of intubation will be assessed using the Mallampati score and the Investigator or 
designee judgement. The Investigator, or designee, will visualize the anatomy of the oral 
cavity, specifically noting whether the base of the uvula, faucial pillars, and soft palate are 
visible. 
1.
Soft palate, uvula, faucial pillars visible
2.
Soft palate, faucial pillars visible but uvula masked by the base of the tongue
3.
Soft palate only visible
3.5.1.4
Total of Blood Volume
Table 4 and Table 5 present the number and volume of blood samples and the total volume 
of blood that will be collected throughout the study per subject.
If deemed necessary by the Investigator or the Sponsor, the number and/or volume of blood 
samples per assessment may be increased, as long as the total volume of blood drawn for 
a subject does not surpass 500 mL (except when extra blood samples need to be taken for 
safety reasons).
Table 4
Number and Volume of Blood Samples and Total Blood Volume Collected 
per Subject - Part 1 
Assessment
Maximum # 
Samples
Volume of Blood per 
Sample (mL)
Total Volume of 
Blood (mL)
Clinical Chemistry
3
8.5 
25.5
Hematology 
3
4 
12
Coagulation 
1
2.7
2.7
Serology
1
8.5
8.5
Total Volume of Blood Drawn
48.7

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 65 of 84
Table 5
Number and Volume of Blood Samples and Total Blood Volume Collected 
per Subject - Part 2
Assessment
Maximum # 
Samples
Volume of Blood per 
Sample (mL)
Total Volume of 
Blood (mL)
Pharmacokinetic
36
2
72
Clinical Chemistry
3
8.5 
25.5
Hematology 
3
4 
12
Coagulation 
1
2.7
2.7
Serology
1
8.5
8.5
Total Volume of Blood Drawn
120.7
3.5.2
Appropriateness of Measurements
The assessments that will be made in this study are standard and generally recognized as 
reliable, accurate, and relevant. 
3.5.2.1
Timing of Assessments
If more than one procedure is required at the same time point, the procedures will be 
conducted as close as possible to the nominal time point, with the order of procedures 
determined at the Investigator’s discretion. Specific sampling windows for individual 
assessments are outlined in the schedule of assessments (Table 1, Table 2, and Table 3).
3.5.3
Pharmacokinetic, Pharmacodynamic, and Safety Variables
3.5.3.1
Pharmacokinetic Variables
PK variables will be the plasma concentrations of HSK3486 and associated PK parameters. 
The PK parameters to be determined or calculated using noncompartmental analysis from 
the plasma concentration-time data for HSK3486 include, but are not limited to, the 
parameters as given in Table 6. A complete list of PK parameters will be provided in the 
statistical analysis plan (SAP).
Table 6
Pharmacokinetic Parameters
Parameter
Description
Cmax
Maximum observed plasma concentration
Tmax
Time to attain maximum observed plasma concentration
Cmax/Tmax
The abuse quotient as a ratio of Cmax over Tmax
AUC0-1
Area under the plasma concentration-time curve from time 0 to 
1 hour postdose 
AUC0-2
Area under the plasma concentration-time curve from time 0 to 
2 hours postdose 
AUC0-4
Area under the plasma concentration-time curve from time 0 to 
4 hours postdose 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 66 of 84
Parameter
Description
AUC0-last
Area under the plasma concentration-time curve up to the last 
point with concentrations above the lower limit of quantification 
(LLOQ) 
AUC0-inf
Area under the plasma concentration-time curve from time 0 to 
infinity calculated as: AUC0-inf=AUC0-t+Clast/kel, 
where Clast is the last measurable plasma concentration 
%AUCextra
Percentage of estimated part for the calculation of AUC0-inf
([AUC0-inf-AUC0-t]/AUC0-inf)*100%
kel
Terminal elimination rate constant
t1/2
Terminal elimination half-life, calculated as 0.693/kel
3.5.3.2
Pharmacodynamic Variables
The PD parameters to be measured include, but are not limited to, the parameters as given 
below. PD parameters are defined in Table 6. A complete list of PD parameters will be 
provided in the SAP.
PD parameters in Part 1 will include:
o
Drug Liking (“at this moment”) VAS Emax
o
Drug Liking (“at this moment, I feel high”) Emax High VAS (secondary endpoint) 
o
Drowsiness/Alertness VAS (Emin [secondary endpoint], TEmin, TA_AUE0-1, and 
TA_AUE0-2) 
o
MOAA/S score
o
Ability to complete battery of abuse potential assessment questions for 1 hour 
PD parameters in Part 2 will include:
o
Drug Liking (“at this moment”) VAS Emax
o
Drug Liking (“at this moment, I feel high”) Emax High VAS 
o
Drowsiness/Alertness VAS (Emin, TEmin, TA_AUE0-1, and TA_AUE0-2) 
o
MOAA/S score 
o
Ability to complete battery of abuse potential assessment questions for 1 hour 
o
Overall Drug Liking VAS – 12- and 24-hour score 
o
Take Drug Again VAS – 12- and 24-hour score
o
Drug Liking VAS (TEmax, TA_AUE, Emin, TEmin, and %reduction)
o
DEQ – Any Drug Effect VAS (Emax, TEmax, and TA_AUE0-1) 
o
DEQ – Good Drug Effects VAS (Emax, TEmax, and TA_AUE0-1) 
o
DEQ – Bad Drug Effects VAS (Emax, TEmax, and TA_AUE0-1) 
o
Relaxation/Agitation VAS (Emax, TEmax, Emin, TEmin, and TA_AUE0-1) 
o
Drug Similarity (“How similar is the drug you most recently received [drug 1] to drug 
you just took [drug 2]?”) VAS

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 67 of 84
Part 2 Endpoints:
The primary endpoint for Part 2 is Drug Liking VAS (Emax).
The secondary endpoints for statistical hypothesis testing are: Take Drug Again VAS
(12- and 24-hour scores); High VAS (Emax); and Overall Drug Liking VAS (12- and 24-hour 
scores).
The secondary endpoints for descriptive analysis are: Good Drug Effects; Bad Drug Effects, 
sick-nausea; Unknown: Any Drug Effects, Drowsiness/Alertness, and Drug Similarity.
Table 7
Pharmacodynamic Parameters
Parameter
Description
Emax
Maximum effect
Emin
Minimum effect
TEmax
Time to maximum effect
TEmin
Time to minimum effect
TA_AUE
Time-averaged area under the effect curve 
TA_AUE0-1 
Time-averaged area under the effect curve from time 0 to 1 hour 
postdose
TA_AUE0-2
Time-averaged area under the effect curve from time 0 to 2 hour 
postdose
%reduction
Percent reduction in Emax
3.5.3.3
Safety Variables
The safety variables to be measured include, but are not limited to, the variables as given 
below. A complete list of safety variables will be provided in the SAP.
AEs
Clinical laboratory
Vital signs
Pulse oximetry
12-lead ECG
Continuous cardiac monitoring
Physical examination
C-SSRS
Respiratory Volume 
3.5.4
Drug Concentration Measurements
The analysis of HSK3486 in plasma samples will be performed with a validated liquid 
chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method. The 
bioanalytical report for the determinations will be included in the clinical study report (CSR). 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 68 of 84
3.5.5
Retention of Blood and Urine Samples
Blood and urine samples remaining after clinical laboratory assessments have been 
performed will not be stored for future use and will be destroyed after analysis as per 
laboratory procedure.
3.6
Statistical Procedures and Determination of Sample Size
3.6.1
Analysis Sets
3.6.1.1
Safety Set
All subjects who have received at least 1 dose of propofol, HSK3486, or placebo.
3.6.1.2
Qualification Safety Set
All subjects who have received at least 1 dose of study drug during the Qualification Phase 
of Part 2. 
3.6.1.3
Pharmacokinetic Set
All subjects who have received at least 1 dose of propofol or HSK3486 in the Treatment 
Phase of Part 2 and provided sufficient bioanalytical assessment results to calculate reliable 
estimates of the PK parameters.
3.6.1.4
Completer Set
All subjects who complete all treatment periods in Part 2 Treatment Phase and have 
sufficient data for evaluation of the primary endpoint, Drug Liking Emax. Subjects who do 
not have at least 1 observation within 2 hours of the median Tmax for each active treatment 
and within 4 hours postdose for placebo for Drug Liking VAS will be excluded. 
3.6.1.5
Modified Completer Set
All subjects in the Completer Set, excluding subjects with unreliable responses based on 
the following prespecified criteria:
1. Similar Drug Liking Emax scores (within 5 point difference) across all study treatments; 
or
2.
Drug Liking Emax for placebo >60 and the difference between Emax (placebo) – Emax
(positive control) > 5. 
This set will be the primary analysis set for all PD endpoints.  
3.6.2
Statistical and Analytical Plan for Pharmacokinetic, Pharmacodynamic, and Safety
Evaluation
A SAP will be generated and finalized prior to database lock (and unblinding of study 
treatment codes). Full details of the analysis to be performed will be included in the SAP.
Any deviation from the SAP will be reported in the section “Changes in Planned Analysis” 
in the CSR. 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 69 of 84
3.6.2.1
Pharmacokinetic Evaluation
The PK parameters and their statistical evaluation will be included in the CSR for this study.
Descriptive statistics will be calculated and presented for each time point by treatment for 
plasma concentrations. 
PK parameters will be calculated and will be summarized by treatment using descriptive
statistics and will be listed and summarized in tabular and/or graphical form.
The natural log transformed PK exposure parameters: Cmax and AUC, will be analyzed using 
a mixed-effect model with treatment, period, and sequence as fixed effects and subject 
nested in sequence as a random effect. The geometric means of each treatment, geometric 
mean ratio of the treatment comparisons, and 90% confidence intervals will be reported. 
The relationship between PK and PD may be evaluated using correlational analysis or 
similar methodology.
3.6.2.2
Pharmacodynamic Evaluation
The PD parameters and their statistical evaluation will be included in the CSR for this study.
PD data and derived PD parameters from Part 1 and Part 2 Treatment Phases will be 
summarized using descriptive statistics by treatment (and by time point as applicable). 
For Part 2, the following sequential hypotheses will be used to evaluate the abuse potential 
of HSK3486 compared to propofol and placebo. 
For study validity, the primary endpoint, Drug Liking Emax, will be compared between propofol 
(Treatment C) and placebo (Treatment D), the following hypothesis will be tested:
Ho
C –
D
a
C –
D > 15 (1)
C
D is mean for placebo. If the treatment difference is 
statistically significant with a margin of 15 points in a 1-sided test at a 5% level of 
significance, validity is established for the study. The 1-sided 95% CIs of the mean 
difference will be calculated. P-values will be provided for the treatment comparisons. And 
the 2-sided 95% CIs will be also derived for the exploratory result.
The treatment comparison for relative abuse potential of HSK3486 will be the comparison 
of Drug Liking Emax between each dose level of HSK3486 (Treatment A and Treatment B) 
and propofol (Treatment C). The following hypothesis will be tested for each comparison:
3.
A: HSK3486 dose 1 vs. C: propofol 
4.
B: HSK3486 dose 2 vs. C: propofol 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 70 of 84
The hypothesis can be expressed as:
Ho
C –
T
2 vs. Ha
C –
T
2,
with 
2 =11,
C is the mean of Drug Liking Emax for propofol (Treatment C),
T is 
mean for Drug Liking Emax for each dose level of HSK3486 (Treatment A and Treatment B). 
If the treatment difference is statistically significant with the 11-point (
2) in a 1-sided test at 
a 5% level of significance, this will demonstrate that the abuse potential of propofol is greater 
than that of HSK3486 by at least 11 points. The 1-sided 95% CIs of the mean difference will 
be calculated. P-values will be provided for the treatment comparisons. And the 2-sided 
95% CIs will be also derived for the exploratory result.
The evaluation of absolute abuse potential of HSK3486 will be the comparison of HSK3486 
versus placebo. The following hypothesis will be tested for each dose level of HSK3486
compared to placebo:
1.
A: HSK3486 dose 1 vs. D: placebo
2.
B: HSK3486 dose 2 vs. D: placebo
The hypothesis can be expressed as:
Ho
T –
D
3 vs. Ha
T –
D <
3,
3 =11 and 
T is the mean of Drug Liking Emax for each dose level of HSK3486 
(Treatments A and B) 
D is the mean of Drug Liking Emax for placebo (Treatment D). 10
If the treatment difference is statistically significantly less than 11-point (
3) in a 1-sided test 
at a 5% level of significance, this will suggest that HSK3486 does not produce a greater 
abuse-related response than placebo. The 1-sided 95% CIs of the mean difference will be 
calculated. P-values will be provided for the treatment comparisons. And the 2-sided 95% 
CIs will be also derived for the exploratory result.
The above hypotheses will be tested sequentially, and no adjustments will be made for 
multiplicity.
A linear mixed-effects model will be fit to each parameter. The model will have treatment, 
period, sequence, and first-order carryover effect (if significant at alpha=0.25) as fixed 
effects, baseline (predose) measurements as a covariate (where applicable), and subject 
as a random effect. If the variance among the treatments is homogeneous, an equal 
variance model will be conducted; if the variance among treatments is heterogeneous, the 
model will be corrected by estimating the variances for treatment separately (an unequal
variance model, using Satterthwaite method and repeated statement heteroscedasticity will 
be adjusted using the repeated statement with subject nested in sequence as a random 
factor with the cross-over design). The residuals from the mixed-effects model will be 
investigated for normality using the Shapiro-Wilk W test. If the normality assumption of the 
model is satisfied (p-
, least square means and 95% confidence intervals for 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 71 of 84
treatment differences will be computed from the linear mixed model, along with the statistical 
significances of all treatment differences.
If the normality assumption of the model is not satisfied, the distribution of the treatment 
differences will be examined for skewness. If the distribution is slightly skewed, a t-test may 
be used for analysis; otherwise, the sign test will be conducted.
Analyses similar to those described for the primary endpoint (Drug Liking Emax) will be 
performed on the secondary endpoints (Take Drug Again VAS 12- and 24-hour scores; High 
VAS Emax; and Overall Drug Liking VAS 12- and 24-hour scores) in the treatment phase. 
The same hypothesis tests and difference margins as noted above for hypotheses will be 
evaluated for the secondary endpoints.
3.6.2.3
Evaluation of Safety and Tolerability
Safety and tolerability will be assessed through AEs, clinical laboratory, vital signs, pulse 
oximetry, respiratory volume, ECGs, continuous cardiac monitoring, physical examination 
findings, C-SSRS, and any other parameter that is relevant for safety assessment.
3.6.2.3.1
Adverse Events
Summary tables of TEAEs will be presented by system organ class based on the MedDRA 
terminology list (preferred terms): a table containing the number of subjects experiencing 
the AE by treatment, a table by treatment and relationship, and a table by treatment and 
severity.
3.6.2.3.2
Clinical Laboratory
Clinical laboratory data will be listed accompanied by an indication if the parameter is 
outside the reference range. A summary of all data outside the reference range of the clinical 
laboratory will be provided. Clinical laboratory data will be presented descriptively, where 
applicable.
3.6.2.3.3
Vital Signs, Pulse Oximetry, Respiratory Volume, and Electrocardiograms
Vital signs, pulse oximetry, respiratory volume, and ECG parameters will be listed, and they 
will be presented descriptively, where applicable.
3.6.2.3.4
Continuous Cardiac Monitoring 
Continuous cardiac monitoring will be performed and monitored in the clinic by the 
Investigator for subject safety. No formal analysis will be performed. All findings will be 
reported as AEs.
3.6.2.3.5
Physical Examination
Changes from baseline for physical examination will be described and listed.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 72 of 84
3.6.2.3.6
Columbia-Suicide Severity Rating Scale 
C-SSRS findings will be listed.
3.6.3
Determination of Sample Size
For assessment of abuse potential, the sample size will be considered the maximum of the 
sample sizes for the validity comparison and primary treatment comparison. Assuming a 
10% dropout rate, approximately 42 subjects will be randomized to the Part 2 Treatment 
Phase, with the intention of completing 36 subjects. 
For the validity comparison, a sample size of 36 subjects will provide 95% power to detect 
a mean difference in the Drug Liking VAS Emax between 0.6 mg/kg propofol and placebo 
that is greater than a margin of 
1=15 in a 1-sided, alpha=0.025 test for study validity. With 
alpha=0.05, a sample size of 36 subjects will provide at least 98% power to detect a mean 
difference in the Drug Liking VAS Emax between 0.6 mg/kg propofol and placebo that is 
greater than a margin of 15-point in a 1-sided test. This assumes Drug Liking Emax mean 
(SD) of 74.4 (14.99) for propofol and 50 (0.33) for placebo, and correlation of 0.5.5
For the primary treatment comparison, evaluating the difference between propofol and 
HSK3486, a sample size of 27 will provide 95% power to reject the null hypothesis that 
HSK3486 has greater abuse potential than propofol, in favor of similarity with less than a 
margin of 
2=11 in a 1-sided alpha=0.025 t-test. With alpha=0.05, a sample size of 27 will 
provide 98% power to reject the null hypothesis that HSK3486 has greater abuse potential 
2=11 in a 1-sided t-test. This 
assumes a mean (SD) of the difference in Drug Liking Emax between HSK3486 and propofol 
of 0 (15).
3.7
Data Quality Assurance
The study may be audited to assess adherence to the clinical study protocol (CSP). During 
the conduct of the study, process-related audits may be performed. An audit certificate will 
be provided in the appendices of the final CSR outlining any audits and other related 
activities performed. 
The clinical research site will be monitored by the study monitor to ensure correct 
performance of the study procedures and assure that the study is conducted according to 
the relevant regulatory requirements. The eCRF entries will be verified with the source
documentation, if applicable (in some cases data are captured directly on the eCRF, 
therefore source data verification is not necessary).
Regulatory authorities, the Institutional Review Board (IRB), and/or the Sponsor’s clinical 
quality assurance group may request access to all source documents, eCRFs, and other 
study documentation for on-site audit or inspection. Direct access to these documents must 
be guaranteed by the Investigator, who must provide support at all times for these activities.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 73 of 84
Quality control principles will be applied throughout the performance of this study. Review 
procedures will be followed for all documents that are generated in relation with the study. 
An explanation will be given for all missing, unused, and spurious data in the relevant 
sections of the CSR.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 74 of 84
4.
ETHICS
4.1
Institutional Review Board
The CSP and the ICFs will be submitted for review and approval by an IRB prior to the 
eligibility screening. The composition of the IRB will be in accordance with the 
recommendations of the International Council for Harmonisation (ICH) E6(R2) Guideline for 
Good Clinical Practice (GCP).10
The contract research organization (CRO) conducting the study will keep the IRB informed 
about the progress of the study. All changes in research activities and all unanticipated 
problems involving risks to human subjects will be immediately reported in accordance with 
IRB requirements. The CRO conducting the study will inform the subjects and the IRB if 
anything occurs on the basis of which it appears that the disadvantages of participation may 
be significantly greater than was foreseen in the research proposal, or if further recruitment 
of subjects in the study has been put on hold for that reason, whichever occurs first. The 
study may be suspended pending further review by the IRB, except insofar as suspension 
would jeopardize the subjects’ health. The CRO conducting the study will take care that all 
subjects are kept informed. 
No changes will be made in the study without IRB approval, except when required to 
eliminate apparent immediate hazards to human subjects.
Notification of the end of the study will be sent to the IRB within 90 days after completion of 
follow-up for the last subject. In case a study is temporarily halted, the site or Sponsor will 
notify the IRB immediately, including the reason for this. In case a study is ended 
prematurely, the IRB will be notified within 15 days, including the reasons for the premature 
termination. The end of the study is defined as the date of receipt of the last data point for 
statistical analysis of the last subject participating in the study.
4.2
Ethical Conduct of the Study
This study will be conducted in accordance with the ethical principles that have their origin 
in the World Medical Association (WMA) Declaration of Helsinki, adopted by the 18th WMA 
General Assembly, Helsinki, Finland, Jun 1964, and subsequent amendments.12
This study is also designed to comply with ICH E6(R2) Guideline for GCP (European 
Medicines 
Agency 
[EMA]/Committee 
for 
Medicinal 
Products 
for 
Human 
Use 
[CHMP]/ICH/135/1995)11 and any applicable national and local laws and regulations (e.g., 
Code of Federal Regulations Title 21, Parts 50, 54, 56, 312, and 314).
Guidelines 
adopted 
by 
the 
ICH 
and 
other 
relevant 
international 
guidelines, 
recommendations, and requirements will be taken into account as comprehensively as 
possible, as long as they do not violate local law.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 75 of 84
Whenever the term “Investigator” is noted in the CSP text, it may refer to either the 
Investigator at the site or an appropriately qualified, trained, and delegated individual of the 
investigational site.
4.3
Subject Information and Consent
All subjects will be informed verbally and in writing regarding the objectives, procedures,
and risks of study participation. The subjects will sign the ICF that contains information about 
the objectives of the study, the procedures followed during the study, and the risks and 
restrictions of the study, with special reference to possible side effects of the study drug and 
potential interactions.
4.4
Privacy
All personal details of subjects will be treated as confidential by the Investigator and staff at 
the CRO conducting the study, and handling of personal data will be in compliance with the 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.13

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 76 of 84
5.
STUDY DOCUMENTATION
5.1
Archiving
The Investigator shall retain essential documents for a period of at least 2 years after the 
last approval of a marketing application in an ICF region and until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of the clinical development of the investigational product. 
These documents will be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the Sponsor. The Sponsor will inform the 
Investigator/institution as to when these documents no longer need to be retained.
5.2
Recording of Data in Source Documents and Electronic Case Report Forms
All data will be collected on source documents and then entered in the eCRFs.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 77 of 84
6.
CONFIDENTIALITY AND PUBLICATION POLICY
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written 
consent is gained from the Sponsor. However, authorized regulatory officials, IRB 
personnel, the Sponsor and its authorized representatives are allowed full access to the 
records.
All study subjects must be informed that their 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, who will be required to give consent for their data to be used as 
described in the ICF. The subjects must be informed that their medical records may be 
examined by auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB members, and by inspectors from regulatory authorities.
Identification of subjects and eCRFs shall be by unique subject numbers only. 
All personal details will be treated as confidential by the Investigator and site staff.
All relevant aspects regarding publication will be part of the contract (or similar document) 
between the Sponsor and CRO conducting the study. 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 78 of 84
7.
REFERENCES
1.
Picard P, Tramèr MR. Prevention of pain on injection with propofol: a quantitative systematic 
review. Anesthesia and analgesia 2000;90(4):963-9.
2.
Vanlersberghe C, Camu F. Propofol. Handbook of experimental pharmacology 2008(182):227-
52.
3.
Devlin JW, Lau AK, Tanios MA. Propofol-associated hypertriglyceridemia and pancreatitis in 
the intensive care unit: an analysis of frequency and risk factors. Pharmacotherapy 
2005;25(10):1348-52.
4.
Investigator's Brochure: HSK2486 Injectable Emulsion 6.0. 10 November 2020. Document 
Control No.
5.
Zacny JP, Lichtor JL, Zaragoza JG, et al. Assessing the behavioral effects and abuse potential 
of propofol bolus injections in healthy volunteers. Drug and alcohol dependence 1993;32(1):45-
57.
6.
A Phase I, placebo and positive-controlled, dose-escalation study to determine the safety, 
pharmacodynamics and pharmacokinetics of a single intravenous injection of HSK3486 in 
healthy subjects (HSK3486 SAD); Clinical Study Report Sichuan Haisco Pharmaceutical Co., 
Ltd; 2015. Document Control No.
7.
Posner K OM, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide 
Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric suicidal risk 
analysis of antidepressants. Am J Psychiatry 2007;164(7):1035-43.
8.
Posner K MG, Stanley B, Oquendo MA, Gould M. Factors in the assessment of suicidality in 
youth. CNS Spectr 2007;12(2):156-62.
9.
K P. State of the Science: Measurement of Suicidal Adverse Events and The Columbia Suicide 
Severity Rating Scale. Presented at NCDEU; Boca Raton, FL.
10.
Chen L, Bonson KR. An Equivalence Test for the Comparison between a Test Drug and 
Placebo in Human Abuse Potential Studies. J of Biopharmaceutical Statistics
Feb 2013;23(2);294-306
11.
International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline, E6(R2): Integrated 
Addendum to ICH E6(R1): Guideline for Good Clinical Practice Guidance for Industry, 
Adopted by the US Department of Health and Human Services, Food and Drug Administration 
(FDA), Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and 
Research (CBER), Mar 2018 
12.
World Medical Association (WMA) Declaration of Helsinki – Ethical Principles for Medical 
Research Involving Human Subjects (18th WMA General Assembly 1964), revised at 64th 
WMA General Assembly, Fortaleza, Brazil, Oct 2013.
13.
Health Insurance Portability and Accountability Act of 1996. Public Law 104 191, 104th 
Congress.
14.
International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline, E2A: Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting Guideline for Industry, 
Adopted by the Food and Drug Administration (FDA), Mar 1995.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 79 of 84
8.
APPENDICES
8.1
Drug Accountability
The Investigator is responsible for the control of drugs under investigation. Adequate records 
of the receipt (e.g., Drug Accountability Forms) and disposition (e.g., Drug Dispensing 
Forms) of the study drug must be maintained. The Drug Dispensing Form(s) must be kept 
current and should contain the following information: 
The identification of the subject to whom the study drug was administered 
The date(s) and quantity of the study drug administered to the subject (when applicable)
The date(s) and quantity of the study drug returned by the subject (when applicable)
All records and drug supplies must be available for inspection by the monitor at every 
monitoring visit. Unused medication will be returned to the Sponsor at the end of the study 
or will be locally destroyed according to study site procedures. The site will retain the original, 
completed Drug Dispensing Form(s) and Drug Accountability Form(s), and copies will be 
returned to the Sponsor upon request. The Investigator’s copy of the Drug Accountability 
Form(s) must accurately document the return of all study drug supplies to the Sponsor if 
applicable.
8.2
Adverse Events and Serious Adverse Events Evaluation and Reporting
8.2.1
Adverse Events
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medical 
treatment or procedure that may or may not be considered related to the medical treatment 
or procedure. AE definitions will be followed as stated in the “Note for Guidance on Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting” (International 
Council of Harmonisation [ICH] topic E2A).13
All AEs reported by the subjects or apparent from their physical appearance during the 
clinical study will be reported on the AE electronic case report form (eCRF) page.
The severity of AEs will be graded using the most current version of the Medical Dictionary 
for Regulatory Activities (MedDRA):
Mild: An AE that is easily tolerated by the subject, causes minimal discomfort, does not 
interfere with everyday activities, and does not require intervention.
Moderate: An AE that is sufficiently discomforting to interfere with normal everyday 
activities; intervention may be needed.
Severe: An AE that prevents normal everyday activities; treatment or other intervention 
usually needed.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 80 of 84
If an AE has multiple aspects, the aspect with the highest severity will be graded.
It is emphasized that the term severe is a measure of severity; thus, a severe AE is not 
necessarily serious. For example, itching for several days may be rated as severe, but may 
not be clinically serious.
In addition, clinically significant changes in physical examination findings and abnormal 
objective test findings (e.g., laboratory, x-ray, electrocardiogram [ECG]) should also be 
recorded as AEs. Test findings and physical examination findings can result in AEs if they: 
Are associated with accompanying symptoms, and/or
Require additional diagnostic testing or medical/surgical intervention, and/or
Lead to a change in study dosing or discontinuation from the study; result in the addition 
of significant additional concomitant drug treatment or other therapy, and/or
Lead to any of the outcomes included in the definition of a serious adverse event (SAE), 
and/or
Are considered to be an AE by the Investigator or Sponsor.
Reporting as an AE should not be triggered by:
Merely repeating an abnormal test, or 
Any abnormal test result that is determined to be an error.
The relationship of any AE to the study drug will be assessed and graded on a 5-point scale: 
none, unlikely, possibly, likely, or definitely. 
Relationship between use of study drug and AE (Causality)
AE (is)
None
Unlikely
Possibly
Likely
Definitely
Clearly the result of an 
external factor
Yes
No
No
No
No
Probably/possibly the result 
of another factor
No
Yes
Yes
No
No
Has a chronological 
relationship with the time of
study drug administration 
and/or represents a known 
reaction to study drug
No
No
Yes
Yes
Yes
Disappears or decreases 
after discontinuation of the 
study drug
NA
NA
NA
Yes
Yes
Recurs on renewed 
administration 
(re-challenge)
No
No
NA
NA
Yes or NA*
AE=adverse event; NA=not applicable
*
A rechallenge is not required; if done, rechallenge would be expected to be positive.

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 81 of 84
8.2.2
Serious Adverse Events
An SAE is any untoward medical occurrence that, on the basis of medical and scientific 
judgment:
Results in death, or
Is life-threatening (this refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe), or  
Requires inpatient hospitalization for a medical reason or prolongation of existing 
hospitalization (this refers to hospital admission required for treatment of the AE). (Note:
this does not include confinement in, for example, a respite unit; a skilled nursing unit; 
rehabilitation facility; the clinical research center; or confinement due to planned or 
unplanned reason unrelated to study), or
Results in persistent or significant disability/incapacity, or
Is a congenital anomaly/birth defect.
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization, but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalization.
SAEs will be collected from the time of informed consent until the final study visit. SAEs 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 until 
stabilized with sequelae. SAEs that begin after the subject’s participation in the study is 
complete, but that the Investigator considers to be related to study drug, may be reported at 
any time. 
The Investigator or clinical site personnel must notify 
of all SAEs, 
regardless of relationship to the investigational drug, within 24 hours of clinical site personnel 
becoming aware of the event. The Investigator will provide the initial notification by sending
a completed “SAE Notification Form,” which must include the Investigator’s assessment of 
the relationship of the event to investigational drug and must be signed by the Investigator. 
In addition, notification is sent to the Institutional Review Board (IRB). 
Follow-up information, or new information regarding an ongoing SAE, must be provided 
promptly to 
. 
All SAE reports should be sent to the contacts provided on Page 4: SAE Contact Information. 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 82 of 84
8.2.3
Suspected Unexpected Serious Adverse Reactions
An SAE that is also an unexpected adverse drug reaction is called a suspected unexpected 
serious adverse reaction (SUSAR). Unexpected adverse reactions are adverse reactions of 
which the nature or severity is not consistent with the applicable product information (e.g.,
IB for an unapproved investigational medicinal product or the Summary of Product 
Characteristics for an authorized medicinal product).
The Sponsor or its representative (e.g., the contract research organization [CRO] conducting 
the study if agreed to before start of the study) will promptly report (expedited reporting) the 
following SUSARs to the IRB:
SUSARs that have arisen in the current clinical study that was assessed by the IRB
SUSARs that have arisen in other clinical studies of the same Sponsor and with the 
same medicinal product, and that could have consequences for the safety of the subjects 
involved in the current clinical study that was assessed by the IRB
Expedited reporting will occur no later than 15 calendar days after the Sponsor or its 
representative has first knowledge of the adverse reactions. For fatal or life-threatening 
cases, the term will be maximally 7 calendar days for a preliminary report with another 
8 days for completion of the report. 
8.2.4
Follow-up of Adverse Events
Follow-up of AEs will continue until resolution, stabilization, or death. In case of ongoing AEs 
at database closure, the data obtained at database closure will be used in the statistical 
analysis. The follow-up of the AE will be documented in the source documents and will be 
described in the final clinical study report (CSR) only if considered relevant by the 
Investigator.
8.3
Pregnancy
A female clinical study subject must be instructed to stop taking the study drug and 
immediately inform the Investigator if she becomes pregnant during the study. Pregnancies 
occurring up to 90 days after the last dose of study drug must also be reported to the 
Investigator. The Investigator will make arrangements for the subject to be counseled by a 
specialist, to discuss the risks of continuing with the pregnancy and the possible effects on 
the fetus. Monitoring of the subject should continue until the outcome of the pregnancy is 
known.
The Investigator should report all pregnancies of female clinical study subjects to the 
Sponsor within 1 working day of becoming aware of them.
If the Investigator becomes aware of a pregnancy occurring in the partner of a male subject 
participating in the study up to 90 days after the last dose of study drug of the male subject, 
the pregnancy should be reported to the Sponsor within 1 working day of obtaining written 

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022
Page 83 of 84
consent from the pregnant partner. The Investigator may make arrangements for the partner 
to be counseled by a specialist, to discuss the risks of continuing with the pregnancy and 
the possible effects on the fetus. Monitoring of the partner should continue until the outcome 
of the pregnancy is known.
8.4
Clinical Opioid Withdrawal Scale
For each item, circle the number that best describes the patient' s signs or symptoms. Rate 
on just the apparent relationship to opiate withdrawal. For example, if pulse rate is increased 
because the patient was jogging just prior to assessment, the increase pulse rate would not 
add to the score.
Subject's Name:
Date and Time:
Reason for this assessment:
Resting Pulse Rate:
beats/minute Measured 
after patient is sitting or lying for one minute
0 pulse rate 80 or below
1 pulse rate 81-100
2 pulse rate 101-120
4 pulse rate greater than 120
GI Upset: over last 1/2 hour
0 no GI symptoms
1 stomach cramps
2 nausea or loose stool
3 vomiting or diarrhea
5 multiple episodes of diarrhea or vomiting
Sweating: over past 1/2 hour not accounted for by
roomtemperature or patient activity
0 no report of chills or flushing
1 participant report of chills or flushing
2 flushed or observable moistness on face
3 beads of sweat on brow or face
4 sweat streaming off face
Tremor observation of outstretched hands
0 no tremor
1 tremor can be felt, but not observed
2 slight tremor observable
4 gross tremor or muscle twitching
Restlessness Observation during assessment
0 able to sit still
1 reports difficulty sitting still, but is able to do so
3 frequent shifting or extraneous movements of 
legs/arms
5 unable to sit still for more than a few seconds
Yawning Observation during assessment
0 no yawning
1 yawning once or twice during assessment 
2 yawning three or more times during assessment
4 yawning several times/minute
Pupil size
0 pupils pinned or normal size for room light
1 pupils possibly larger than normal for room light
2 pupils moderately dilated
5 pupils so dilated that only the rim of the iris is visible
Anxiety or Irritability
0 none
1 patient reports increasing irritability or anxiousness
2 patient obviously irritable or anxious
4 patient so irritable or anxious that participation in 
the assessment is difficult
Bone or Joint aches if patient was having pain
previously, only the additional component attributed
toopiates withdrawal is scored
0 not present
1 mild diffuse discomfort
2 patient reports severe diffuse aching of joints/muscles
4 patient is rubbing joints or muscles and is unable to sit 
still because of discomfort
Gooseflesh skin
0 skin is smooth
3 piloerection of skin can be felt or hairsstanding up
on arms
5 prominent piloerection

CLINICAL STUDY PROTOCOL
HSK3486-110/HCO21333-21333X
VERSION 2.0 04-NOV-2022 
Page 84 of 84
Runny nose or tearing Not accounted for by 
cold - symptoms or allergies
0 not present
1 nasal stuffiness or unusually moist eyes
2 nose running or tearing
4 nose constantly running or tears streaming down 
cheeks
Total Score  
 
The total score is the sum of all 11 items
Initials of person completing assessment:
 
 
 
 
 
 
 
 
 
 
 
 
Score: 5-12 = mild; 13-24 = moderate; 25-36 = moderately severe; more than 36 = severe withdrawal