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Trial registered on ANZCTR


Registration number
ACTRN12619001739101
Ethics application status
Approved
Date submitted
26/11/2019
Date registered
9/12/2019
Date last updated
15/09/2020
Date data sharing statement initially provided
9/12/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase I Clinical Study Evaluating the Safety, Tolerability and Pharmacokinetics of HSK21542 in Healthy Volunteers
Scientific title
A Phase I Clinical Study Evaluating the Safety, Tolerability and Pharmacokinetics of HSK21542 in Healthy Volunteers
Secondary ID [1] 299833 0
HSK21542-101
Universal Trial Number (UTN)
U1111-1244-5867
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute and Chronic Pain 315214 0
Condition category
Condition code
Anaesthesiology 313717 313717 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a double-blinded, placebo controlled, single ascending dose (SAD), multi-cohort trial.
concentrations, HSK21542 concentration, pharmacokinetics parameters and identification of HSK21542 metabolites in urine. Also faeces samples will be collected, and faecal weight recorded pre-dose and at specified time intervals up to 48 h post dose for determination of HSK21542 concentration and identification of HSK21542 metabolites in feces.

The study will consist of a total of 72 participants are planned to be enrolled and allocated into 9 dose cohorts at the following dose levels: 0.2, 0.5, 1, 1.5 , 0.02, 0.05 and 1 µg/kg by intravenous injection at 40 mL/h over a period of 15 minutes using an intravenous pump.

Each dose cohort will include 8 participants (active:placebo = 6:2). Each participant can only be involved in one dose cohort. Participants receiving HSK21542 will be given a single dose of HSK21542 via intravenous injection on Day 1, and participants receiving placebo will be given a single dose of matched placebo via intravenous injection on Day 1 with same administration as active drug. Participants will be confined at the clinical facility from Day -1 through to Day 3, when they will be discharged following completion of all assessments. Participants will return to the clinical facility for final safety assessments at an End of Study (EOS) visit on Day 8 ± 1 day.


Dosing in each dose cohort will start with two sentinel participants with one of the two sentinels randomized to receive HSK21542 and the other randomized to receive placebo. The safety and tolerability of each sentinel will be monitored until Day 3 and will be reviewed prior to dosing the remainder of participants in each cohort. The study principal investigator (PI) will review safety/tolerability information available on the sentinel participants on Day 3 and will make the decision to dose the remaining 6 participants in the cohort.

Cohorts will be dosed in an escalating order, each dose level increased by no more than 2.5-fold over the previous dose level. The dose of a cohort may be appropriately adjusted according to the results of the previous dose cohort. The decision to escalate between dose levels will be based upon review of blinded safety data (ie, haematology, biochemistry, coagulation, thyroid function, blood electrolytes, ECG, vital signs and AE data) through to Day 8 and available blinded PK data by the Safety Monitoring Group (SMG).
The SMG will consist of the PI, an independent Medical Monitor and a sponsor medical representative. The SMG will review the data, discuss the findings, and decide to:
a) enrol the next dose group at the protocol-defined higher dose level;
b) enrol the next dose group at an intermediate higher dose level;
c) enrol the next dose group at a lower dose level than the current dose level; or
d) terminate enrollment in the study.
If the dose level is determined not to be safe and tolerated, the study drug assignment for those participants with a safety concern may be unblinded.

Dosing will proceed to the next dose level until evaluation of the maximum dose specified in the protocol (20 µg/kg) or the trial is stopped by the SMG. The trial can be terminated at any stage during escalation when any of the criteria for termination are met, even if the maximum dose is not reached.

For Cohort 4 (1,5µg/kg dose) only:
Urine samples will be collected pre-dose and at specified time intervals up to 48 h post dose for determination of electrolyte (sodium, potassium, calcium, magnesium, and chlorine) concentrations, HSK21542 concentration, pharmacokinetics parameters and identification of HSK21542 metabolites in urine. Also faeces samples will be collected, and faecal weight recorded pre-dose and at specified time intervals up to 48 h post dose for determination of HSK21542 concentration and identification of HSK21542 metabolites in feces.
Intervention code [1] 316154 0
Treatment: Drugs
Comparator / control treatment
Placebo composition:
Glacial Acetic Acid
Sodium Acetic (NaC2H3O2) anhydrous
Water for Injection as solvent
Control group
Placebo

Outcomes
Primary outcome [1] 322056 0
To evaluate the safety and tolerability of a single HSK21542 injection administered intravenous in healthy volunteers by clinical observations, safety laboratories tests, cardiac monitoring, vital sign and SpO2 measurements and adverse event assessment.
Timepoint [1] 322056 0
Physical examination will be conducted at Screening, Day -1, Day 1 pre-dose, Day 3, Day 8 and and additional focused assessments suggested by the presence of specific symptoms. Also Ramsay sedation scale and drug-liking visual analog scale (VAS) Day -1 (Ramsay sedation scale only), pre-dose on Day 1, and then 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h post-dose to evaluate the neurological status post-dose. Vital signs: systolic and diastolic blood pressure, respiratory rate, body temperature, and heart rate and SpO2 will be measured at screening, Day -1, pre-dose on Day 1, and then 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h post-dose, and on Day 8. Cardiac monitoring: Continuous ECG monitoring (telemetry) will be conducted from 30 min pre-dose to 24 h post-dose and 12-lead ECG will be performed at screening, pre-dose on Day 1, and then 15 min, 30 min, 1 h, 3 h, 8 h, 12 h, 24 h, 48 h post-dose and on Day 8. Safety laboratory testing for Serum Chemistry, Haematology, Coagulation, Thyroid function and Urinalysis will be completed at the following time points: Screening, Day-1, Day 2 and Day 8, addition of cardiac troponin 1 test for any subject who develops signs or symptoms consistent with cardiac impairment.
Secondary outcome [1] 377195 0
To assess the pharmacokinetics (PK) of HSK21542 following administration of a single intravenous injection in healthy volunteers.
Timepoint [1] 377195 0
Drug detection assay using a volunteer plasma.
Main plasma PK parameters will include: AUC0-t, AUC0-8, Tmax, Cmax, t1/2, CL, and Vss.
The following pharmacokinetics parameters will be determined:
- Plasma concentration data will be analyzed based on the pharmacokinetics- concentration set
- Analysis of HSK21542 plasma concentration data for each dose group.
- Analysis of plasma PK parameter for the 0.2 µg/kg dose group will be performed first.
Samples will be collected at the following sampling time points: pre-dose and then 10 min, 15 min, 17 min, 20 min, 25 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h and 24 h post-dose (based on the start of the intravenous injection). At each time point, 3 mL of whole blood will be collected.
The PK blood sampling time points of the other dose groups can be adjusted on the basis of the PK results arising during the conduct of this study.
Secondary outcome [2] 377200 0
Exploratory objective:

To identify and assess any potential metabolites of HSK21542 and their pharmacokinetics following the administration of a single intravenous injection in healthy volunteers.
Timepoint [2] 377200 0
Analysis of plasma for potential metabolites of HSK21542, if any found, at specific time points.
Samples will be collected at the following sampling time points: pre-dose and then 10 min, 15 min, 17 min, 20 min, 25 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h and 24 h post-dose (based on the start of the intravenous injection). At each time point, 3 mL of whole blood will be collected.
Main plasma PK parameters for metabolites will include: AUC0-t, AUC0-8, Tmax, Cmax, t1/2, CL, and Vss.
Secondary outcome [3] 377220 0
Exploratory objective:

To evaluate the effects of HSK21542 injection on corrected QT interval using Fridericia’s formula (QTcF) prolongation in healthy volunteers for all cohorts.
Timepoint [3] 377220 0
Continuous cardiac monitoring (telemetry) 12-lead ECG: including but not limited to the measurements of heart rate, PR, RR, QRS, QT and QTcF intervals will be performed at screening, pre-dose on Day 1, and then 10 min, 15 min, 30 min, 1 h, 3 h, 8 h, 12 h, 24 h, 48 h post-dose, and on Day 8 ± 1 day. Triplicate ECG recording 3 times within 2 minutes (with an allowable window of 1 min if required), with each recording continuously running = 10 seconds, pertaining at least 5 cardiac cycles. To ensure the safety of participants, each ECG result should be compared to baseline measurements. For any scheduled ECG, if an increase by >45 msec from baseline (QTcF value at the last pre-dose timepoint) in QTcF interval, or an absolute QTcF value >500 msec is present, the ECG measurement must be repeated every 15 min until 2 consecutive ECGs show QTcF values falling below the threshold that indicates repeated measurements, and will be overseen by a cardiologist to establish the course of further assessments.
Secondary outcome [4] 377221 0
Exploratory objective:

To explore the relationship of drug exposure with urine output.
Timepoint [4] 377221 0
Urine will be collected during the periods of 12 h pre-dose to 0 h, and then 0-2 h, 2-4 h, 4-8 h, 8-12 h, 12-24 h, and 24-48 h post-dose, to assess the urine output following the administration of a single intravenous injection in healthy volunteers.
Secondary outcome [5] 377222 0
Exploratory objective: To measure the amount of HSK21542 in relation with urine electrolytes excreted in the urine of healthy volunteers, only for cohort 4 ( dose level 1.5 µg/kg).
Timepoint [5] 377222 0
Urine will be collected during the periods of 12 h pre-dose to 0 h, and then 0-2 h, 2-4 h, 4-8 h, 8-12 h, 12-24 h, and 24-48 h post-dose, and a 20 ml urine sample from each time period will be retained for the determination of urine electrolytes (1.5 µg/kg dose group only)
Secondary outcome [6] 377501 0
Exploratory objective:

To explore the relationship of drug exposure with prolactin assessment.
Timepoint [6] 377501 0
Prolactin level will be assessed by serum assay and will be performed at screening, pre-dose on Day 1, and then 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h post-dose time points for all cohorts.
Secondary outcome [7] 377502 0
Exploratory objective: To measure the amount of HSK21542 excreted in the feces of healthy volunteers, only for cohort 4 (dose level 1.5 µg/kg).
Timepoint [7] 377502 0
The amount of Hsk21542 will be assessed from fecal samples which will be collected from Day -1 to pre-dose Day 1, and the 0 to 48 h post-dose for the determination of fecal drug concentration and metabolite identification. The fecal weight will be recorded.
Secondary outcome [8] 377745 0
Exploratory objective: To identify and assess any potential metabolites of HSK21542 excreted in the feces of healthy volunteers, only for cohort 4 (dose level 1.5 µg/kg).
Timepoint [8] 377745 0
The amount of possible metabolites of HSK21542 will be assessed from fecal samples which will be collected from Day -1 to pre-dose Day 1, and the 0 to 48 h post-dose for the determination of fecal drug concentration and metabolite identification. The fecal weight will be recorded.
Secondary outcome [9] 377748 0
Exploratory objective: To identify and assess any potential metabolites of HSK21542 excreted in the urine of healthy volunteers, only for cohort 4 (dose level 1.5 µg/kg).
Timepoint [9] 377748 0
The amount of possible metabolites of HSK21542 will be assessed from the urine, which will be collected during the periods of 12 h pre-dose to 0 h, and then 0-2 h, 2-4 h, 4-8 h, 8-12 h, 12-24 h, and 24-48 h post-dose, and a 20 ml urine sample from each time period will be retained.

Eligibility
Key inclusion criteria
Healthy Volunteers:

1. Males and females aged 18–45 years old (inclusive) at screening;
2. Male volunteers no less than 50 kg, or female volunteers no less than 45 kg, with body mass index [BMI] in the range of 18.0–30.0 kg/m2 (inclusive) at screening;
3. Healthy volunteers, as assessed by the investigator based on past medical history, comprehensive physical examination, vital signs, and specified tests and examinations.
4. Female volunteers must:
a. Be of nonchildbearing potential ie, surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before screening) or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause), or
b. If of childbearing potential, must have a negative pregnancy test at screening (serum test) and before study drug administration (Day -1 urine test). They must agree not to attempt to become pregnant, must not donate ova, and must use a highly effective contraceptive method from signing the consent form until at least 90 days after the last dose of study drug.
5 .Be non-smokers (including tobacco and e-cigarettes) for at least 1 month prior to participation in the study.
6. Male volunteers, if not surgically sterilized, must be willing not to donate sperm and, if engaging in sexual intercourse with a female partner who could become pregnant, must be willing to use a condom in addition to having the female partner use a highly effective contraceptive method from signing the consent form until at least 90 days after the last dose of study drug.
7. Fully understand the nature, purpose, and potential benefits, inconveniences and risks of the trial. Understand the study procedure and voluntarily provide written informed consent.
8. Able to communicate with the investigator and to follow all requirements of the study, and willing to be admitted into the phase I clinical facility.
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Any previous serious clinical conditions of the circulatory system, endocrine system, nervous system, digestive system, respiratory system, and hematological, immunological, psychiatric and metabolic abnormalities, or any disease or physiological condition that may interfere with the results of this trial;
2. Clinically significant abnormalities upon physical examination, vital signs monitoring, ECG, and laboratory tests (including hematology, urinalysis, biochemistry, coagulation, thyroid function), as assessed by the investigator at screening;
3. Volunteers with positive hepatitis B surface antigen, positive hepatitis C antibody, positive Treponema pallidum antibody, or positive human immunodeficiency virus (HIV) antibody test results;
4. QTcF > 450 msec upon ECG;
5. Volunteers who have a history of a severe drug hypersensitivity/anaphylaxis or who are allergic to two or more drugs and foods or who are allergic to any of the ingredients in the study drug including its excipients;
6. Volunteers who cannot tolerate venipuncture and/or have a history of hemophobia or fear of needles;
7. History of long-term excessive intake (more than 8 cups per day, one cup = 250 mL) of tea, grapefruit, coffee, or caffeinated or grapefruit-based beverages;
8. Volunteers with a history of alcohol abuse within 3 months prior to screening, that is, more than 14 units of alcohol per week (1 unit = 285 mL of full strength beer (4.8% alcohol), 375 mL of mid strength beer (3.5% alcohol), 425 mL of low strength beer (2.7% alcohol), 30 mL of 40% hard liquor, 100 mL of wine);
9. Volunteers with a positive alcohol breath test;
10. Volunteers with a positive urine nicotine test;
11. Volunteers with drug abuse or dependence, or with a positive urine drugs of abuse test;
12. Use of any prescription medications or over-the-counter medications (including herbal medicines, diet aids, vitamins, or hormone supplements) within 14 days or 5 half-lives of the medication (whichever is longer) prior to dose administration, except occasional use of paracetamol;
13. Blood donation or loss of blood > 450 mL within the past 3 months;
14. Participation in any clinical trials within the past 3 months;
15. For females of childbearing potential, a positive serum pregnancy test at screening or a positive urine pregnancy test with confirmatory serum pregnancy test on Day -1;
16. Volunteers who plan to become pregnant within the next 6 months;
17. Any other factors judged by the investigator to be unsuitable for participating in this study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation occur at Cmax (central randomisation)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
6(active): 2(placebo) per cohort

Simple randomisation table created by computer software.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other
Other design features
Multiple cohort trial, 9 cohorts in total.
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
Statistical analysis sets:
1. Full analysis set (FAS): All randomized participants who have received the study drugs and have at least one post-dose assessment.
2. Safety set (SS): All participants who have received the study drugs and have documented safety measures.
3. Pharmacokinetics-concentration set (PKCS): All eligible participants who have received at least one dose of study drug and have at least one effective post-dose HSK21542 concentration measure.
4. Pharmacokinetics-parameters set (PKPS): All eligible participants who have received at least one dose of study drug and have at least one effective post-dose HSK21542 PK parameter.
5. Pharmacokinetics -mass balance set (PKMS): All eligible participants who received the full 1.5 µg/kg dose of study drug and were able to provide urine/feces samples over the 48-hour post-dose period,
6. Concentration-QTc set (CQS): All eligible participants who have received at least one dose of study drug and have at least one evaluable concentration-QTc assessment.

Sample size consideration
This study is the first in human study with HSK21542 and such no formal sample size calculation was performed. Results from this study will be utilized for sample size calculations of subsequent studies.

Demographic Data
1. Analyzed based on the FAS.
2. Demographics and other baseline characteristics will be summarized using descriptive statistics.
3. For continuous variables, the number of cases, mean, standard deviation, median, quartile, minimum, and maximum will be calculated.
4. The frequency and percentage will be calculated for count and ranked data.

Analysis of drug compliance and concomitant medication
1. Analyzed based on the FAS.
2. Analysis of drug compliance: Whether the investigational product was taken on time and at the correct dose.
3. A detailed description of concomitant medications will be listed.

Safety analysis
1. Analyzed based on the SS.
2. AEs will be coded using MedDRA (version 20.0 or above) by system organ class (SOC) and preferred term. The number of TEAEs and serious TEAEs as well as the number and percentage of participants with TEAEs and serious TEAEs, will be summarized by SOC and preferred term and tabulated for each dose group. Summaries by severity and relationship will also be presented. The percentage of participants who discontinued the study due to a TEAE will be summarized and tabulated for each dose group.
3. The measured values and changes from baseline in the following items over time will be listed in three-line tables: SpO2, Ramsay sedation scale, drug-liking VAS, blood sodium, blood potassium, blood calcium, blood chlorine, blood magnesium and hematocrit.
4. Laboratory tests: measured values and change from baseline as well as pre- and post-dose clinical assessment will be listed for each participant and summarized by treatment and sampling time point.
5. ECG: measured values and change from baseline as well as pre- and post-dose clinical assessment will be listed for each participant and summarized by treatment and assessment time point.
6. Physical examination: examination findings and clinical assessment will be listed for each participant.
7. Vital signs: measured values and change from baseline values will be listed for each participant and summarized by treatment and assessment time point.
8. Fluid consumption: volume of fluid consumed within each observation window will be listed for each participant and summarized by treatment and observation window.

Pharmaceutical analysis
1. Plasma concentration data will be analyzed based on the PKCS and PK parameters will be analyzed based on the PKPS.
2. Analysis of HSK21542 plasma concentration data: Individual and mean HSK21542 plasma concentrations at each timepoint will be presented graphically for each dose group with concentration displayed on a linear and logarithmic scale and standard deviation for the mean values. The HSK21542 plasma concentration data at each timepoint will also be tabulated and summarized using descriptive statistics (the number of cases, arithmetic mean, standard deviation, coefficient of variation, minimum, and maximum) for each dose group.
3. Analysis of plasma PK parameters: The PK parameters for each participant will be calculated using a non-compartmental analysis method and tabulated for each dose group. The number of cases, arithmetic mean, standard deviation, coefficient of variation, minimum, maximum, and geometric mean for each parameter will be calculated and presented. Dose proportionality will be assessed using the power model.
4. The above PK analyses may also be performed for metabolite(s) if metabolite data are available.

Concentration-QTcF Analysis
1. Analyzed based on the CQS.
2. The HSK21542 plasma concentration data obtained in this study will be integrated with the ECG data to carry out exploratory analysis of the relationship between HSK21542 plasma concentration and QTcF using a PK/pharmacodynamic modeling method (for example, nonlinear mixed effect model). The results of such analysis will be reported separately.

Relationship to drug exposure analysis
1. Analyzed based on the PKCS
2. The study will analyze the relationship of prolactin level and urine output with HSK21542 injection exposure based on the results of the prolactin and urine samples assayed at different time points.

Mass balance analysis (1.5 µg/kg group only)
1. Analyzed based on the PKMS
2. Total amount excreted in urine and dose amount recovered (as a percentage of total dose) for the primary compound, metabolite(s) and overall will be determined from urine and fecal samples collected and amounts listed for each participant and summarized for the treatment group.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
19/12/2019
Actual
4/12/2019
Date of last participant enrolment
Anticipated
30/04/2020
Actual
21/04/2020
Date of last data collection
Anticipated
4/06/2020
Actual
28/04/2020
Sample size
Target
72
Accrual to date
Final
40
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 15307 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 28618 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 304293 0
Commercial sector/Industry
Name [1] 304293 0
Haisco Pharmaceutical (Australia) Pty Ltd
Country [1] 304293 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Avance Clinical
Address
Level 1/2 Ann Nelson Drive, Thebarton, SA, 5031
Country
Australia
Secondary sponsor category [1] 304620 0
None
Name [1] 304620 0
Address [1] 304620 0
Country [1] 304620 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304749 0
Bellberry HREC
Ethics committee address [1] 304749 0
Ethics committee country [1] 304749 0
Australia
Date submitted for ethics approval [1] 304749 0
23/10/2019
Approval date [1] 304749 0
22/11/2019
Ethics approval number [1] 304749 0
2019-10-901-A-6

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 98074 0
Dr Paul Wabnitz
Address 98074 0
CMAX Clinical Research, Level 5, 18a North Terrace, Adelaide, SA, 5000
Country 98074 0
Australia
Phone 98074 0
+61 870887900
Fax 98074 0
+61 870887999
Email 98074 0
[email protected]
Contact person for public queries
Name 98075 0
Katherine Mudge
Address 98075 0
CMAX Clinical Research, Level 5, 18a North Terrace, Adelaide, SA, 5000
Country 98075 0
Australia
Phone 98075 0
+61 870887900
Fax 98075 0
+61 870887999
Email 98075 0
[email protected]
Contact person for scientific queries
Name 98076 0
Li Chen
Address 98076 0
Haisco Pharmaceutical, 136 Baili Road Chengdu Cross-Straits IT Industry
Development Zone, Wenjiang District, Chengdu,
Sichuan province 611130, P.R. China
Country 98076 0
China
Phone 98076 0
+11 86 10 13699296464
Fax 98076 0
Email 98076 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



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