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Trial registered on ANZCTR


Registration number
ACTRN12614000428662
Ethics application status
Approved
Date submitted
10/04/2014
Date registered
17/04/2014
Date last updated
15/12/2014
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase 1, placebo and positive-controlled, dose-escalation study to determine the safety, pharmacodynamics and pharmacokinetics of a single intravenous injection of
HSK3486 in healthy subjects.
Scientific title
A Phase 1, placebo and positive-controlled, dose-escalation study to determine the safety, pharmacodynamics and pharmacokinetics of a single intravenous injection of
HSK3486 in healthy subjects.
Secondary ID [1] 284422 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
HSK3486 SAD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anesthesia 291624 0
Condition category
Condition code
Anaesthesiology 292002 292002 0 0
Anaesthetics

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
HSK-3486
(single brief IV injection)
Planned dosing schedule change to:
Cohort 1 0.016 mg/kg
Cohort 2 0.064 mg/kg
Cohort 3 0.128 mg/kg
Cohort 4 0.192 mg/kg
Cohort 5 0.288 mg/kg
Cohort 6 0.432 mg/kg
Cohort 7 0.540 mg/kg
Cohort 8 0.648 mg/kg
Cohort 9 0.810 mg/kg

The maximum dose of HSK3486 will be the dose that either produces either

(i) Physiological changes (i.e. vital sign changes) beyond pre-defined ranges or

(ii) A PD effect of unconscious sedation/anesthesia for more than 15 minutes (as measured by a RASS score of - 5).

After the maximum dose has been reached by a subject in a cohort, the data will be reviewed by the DSMB. If the maximum dose is reached in Cohort 1 to 7 the DSMB can decide to either continue with the same dose, or complete cohort dosing at the dose level used in the preceding cohort. If the maximum dose is reached in Cohort 9 dosing of any further subjects will be ceased.

The aim is to have at least five subjects receive the pre-maximal dose, and five subjects receive propofol. Should maximal dosing be reached prior to Cohort 7, a subject will be actively allocated to the positive control.

In Cohorts 3 and 4 a sentinel subject will be enrolled to monitor any possible dose-related adverse effects at the higher doses. In Cohort 3, the dose will be increased by a factor of two. Thereafter, doses in subsequent cohorts will increase by a factor of 1.5, as they approach doses producing a RASS score of -5 for more than 15 minutes, unless the DSMB decides that a lower dose may be required based on findings from the previous cohorts.

The maximum dose of HSK3486 will be that which produces clinically significant hypotension, tachycardia or bradycardia (see below), or that produces a PD effect of anesthesia for more than 15 minutes as measured by RASS score of -5.

Acceptable range of vital signs during drug administration
Blood pressure, Systolic: 80-180 mmHg Blood pressure, Mean: 55-120 mmHg Heart rate: 40-120 bpm
Saturation: >95%

If the maximum dose is reached in Cohort 1 to 8 the DSMB can elect to either continue with the same dose, or complete cohort dosing at the dose level used in the preceding cohort. If the maximum dose is reached in Cohort 9 dosing of any further subjects will be ceased.
Intervention code [1] 289172 0
Treatment: Drugs
Comparator / control treatment
1, Placebo
Cohort 1 and 2
Single brief IV injection of saline.
2, Propofol
Cohort 3 to Cohort 9, 1 propofol
Dose 2.5 mg/kg (single brief IV injection)
Control group
Active

Outcomes
Primary outcome [1] 291894 0
safety
Timepoint [1] 291894 0
1, Vital signs (respiratory rate, sitting radial pulse rate, pulse oximetry, temperature and sitting systolic and diastolic blood pressures (non-invasive) will be measured at the Screening Visit, Day -1, and during the Treatment Visit . Sitting recordings are to be made after the subject
has been sitting up for 3 minutes or more.
2,A 12-lead ECG will be performed at the Screening Visit. At the Treatment Visit, continuous 3-lead ECG will be monitored for 15 minutes prior to dosing and for the first two hours post dosing.
3, Clinical laboratory tests (hematology, chemistry and urinalysis) will be measured at Screening, Day –1, 24 hours
post-dose at the Treatment Visit and at the Follow-up Visit.
4, Subject pain assessment to be monitored every 15 seconds during infusion until loss of response occurs.
5, Concomitant medications
Primary outcome [2] 291924 0
Pharmacodynamics
Timepoint [2] 291924 0
Measured by Richmond Agitation Sedation Scale
1, Prior to Dosing (-15 to 0 minutes) Every 5 minutes
2, 0 to 10 minutes post-dose Every 1 minute
3, 10 to 30 minutes post-dose Every 5 minutes
4, 30 minutes to 2 hours post-dose Every 15 minutes
5, 4, 8, 12 and 24 hours post-dose (+/- 10 minutes)
Primary outcome [3] 291925 0
Tolerability
Timepoint [3] 291925 0
1, Subject pain assessment to be monitored every 15 seconds during infusion until loss of response occurs.
2, Observer pain assessment to be performed at the completion of infusion.
Secondary outcome [1] 307750 0
Pharmacodynamics
Timepoint [1] 307750 0
1. EEG for monitoring BIS with BIS values recorded during the Treatment Visit.
- Prior to Dosing (-15 to 0 minutes) Every 5 minutes.
- 0 to 10 minutes post-dose Every1 minute.
- 10 to 30 minutes post-dose Every 5 minutes.
2, QoR-40 (subject-rated Quality of Recovery Assessment) is to be performed prior to dosing, 10 minutes after a RASS score of 0, and 24 hours post-dose.
Secondary outcome [2] 307848 0
Pharmacokinetics - plasma pharmacokinetics analyses (only to be assessed for subjects who are randomized to HSK3486 in Cohorts 3 to 8.
Timepoint [2] 307848 0
Blood samples for PK assessments will only be obtained for subjects randomized to HSK3486 in Cohorts 3 to 8.
Samples are to be collected as follows: within 30 minutes prior to dosing; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12,
15, 30, 60, 90 minutes and 2, 4, 8 and 24 hours post-dose

Eligibility
Key inclusion criteria
Inclusion Criteria
To be enrolled in the study, subjects must meet the following criteria:
1. Male, aged 18 - 49 years (inclusive)
2. Be in general good health without clinically significant medical history
3. American Society of Anesthesiologists (ASA) Physical Status Classification of I or II .
4. Body Mass Index (BMI) between 18 and 30 kg/m2 (inclusive)
5. Negative screen for drugs of abuse, nicotine, alcohol, hepatitis B surface antigen, hepatitis C and Human Immunodeficiency Virus (HIV) at screening; and drugs of abuse and alcohol pre-dose on Day -1
6. Normal or non-clinically significant findings on a physical examination, 12-lead electrocardiogram (ECG) and vital signs (respiration rate between 12 and 20 breaths per minute, blood pressure between 100-140/60-90 mmHg, heart rate between 50-99 beats per minute, temperature between 35.8 degrees and 37.5 degrees and pulse oximetry values > 95% on room air)
7. Clinical laboratory values within the normal limits as defined by the clinical laboratory, unless the Principal Investigator decides that out-of-range values are not clinically significant
8. Ability to provide written informed consent
9. Willing and able to follow study instructions and likely to complete all study requirements
10. Suitable venous and arterial access

Minimum age
18 Years
Maximum age
49 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion Criteria:
Subjects will be ineligible for entry into the study if any of the following apply:
1. History of allergy or sensitivity to: propofol, components of Fresofol 1% MCT/LCT propofolFresenius MCT/LCT 1%, or HSK3486 (soybean oil, glycerol, egg lecithin, disodium edentate, sodium hydroxide), or plain lignocaine
2. History of clinically significant problems with general anesthesia
3. Urinary cotinine levels indicative of smoking, or a history of regular (more than weekly) use of tobacco- or nicotine-containing products within 2 months prior to screening
4. History of excessive alcohol intake (more than four standard drinks daily, on average) or use of recreational drugs within the last 3 months
5. Use of prescription or over the counter medications within
7 days of Investigational Product administration, with the exception of simple analgesics such as paracetamol and oral non-steroidalanti-inflammatory agents
6. Standard donation of blood within 30 days of the study
7. Donation of plasma or participation in a plasmapheresis program within 7 days preceding this study
8. Receipt of any investigational drug study within 30 days prior to screening
9. Unable to fast for the 6 hours prior to Investigational Product administration
10. Clinically significant (as judged by the Investigator) presence of acute illness (e.g. gastrointestinal illness, infection such as influenza, upper respiratory tract infection) at admission to the clinical study unit
11. Anticipated need for surgery or hospitalization during the study
12. Anatomical abnormality that would potentially interfere with airway management under unconscious sedation or anesthesia
13. History of posture-relatedgastric reflux more than twice weekly
14. History of seizures or epilepsy
15. History of ischaemic heart disease
16. History of brady- or tachy-dysrhythmias requiring medical care
17. History of asthma, with bronchospasm requiring treatment in the last 3 months.
18. Any condition, which in the Investigator’s opinion, puts the subject at significant risk, could confound the study results or may interfere significantly with the subject’s participation in the 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)
Following Screening, subjects who meet the inclusion/exclusion criteria will be assigned a subject number in the order in which they are enrolled in the study. The subject number will determine the allocation of treatment as per the randomization list which will be generated by INCResearch Australia Pty Ltd and provided to the pharmacist. Cohorts 1 and 2 are a placebo controlled design, with open-labelling for the sentinel subjects and double-blind thereafter. Cohorts 3 to 8 are an open-label, positive controlled design.
Paper copies of the blinding envelopes will be produced and checked by internal quality control procedures. Copies will be given to the Pharmacist(s) for dispensing of study medication. One paper copy will be placed in a sealed envelope and retained in a secure restricted access area at the Study Site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
7/04/2014
Actual
7/04/2014
Date of last participant enrolment
Anticipated
20/10/2014
Actual
29/10/2014
Date of last data collection
Anticipated
Actual
Sample size
Target
48
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 2307 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 7984 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 289071 0
Commercial sector/Industry
Name [1] 289071 0
Sichuan Haisco Pharmaceutical Co., Ltd.
Country [1] 289071 0
China
Primary sponsor type
Commercial sector/Industry
Name
Sichuan Haisco Pharmaceutical Co., Ltd.
Address
Sichuan Haisco Pharmaceutical Co., Ltd.
136 Baili Road
Chengdu Cross-Straits IT Industry Development Zone
Wenjiang District, Chengdu, Sichuan Province
611130P. R. China
Country
China
Secondary sponsor category [1] 287733 0
None
Name [1] 287733 0
None
Address [1] 287733 0
None
Country [1] 287733 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290864 0
Royal Adelaide Hospital Human Research Ethics Committee
Ethics committee address [1] 290864 0
Level 3, Hanson Institute, IMVS Building
Royal Adelaide Hospital
North Terrace
Adelaide , South Australia, 5000
Ethics committee country [1] 290864 0
Australia
Date submitted for ethics approval [1] 290864 0
05/02/2014
Approval date [1] 290864 0
07/03/2014
Ethics approval number [1] 290864 0
HREC/14IRAH/45

Summary
Brief summary
This is the first clinical trial of HSK3486 and will be conducted in healthy volunteers to determine the safety, tolerability (including pain on injection), and PK(only to be assessed for subjects who are randomized to HSK3486 in Cohorts 3 to 8)and PD and profiles of HSK3486 administered as a single IV injection.
Results from this study will supports further clinical development of HSK3486. This study will be performed in compliance with the protocol, International Conference on Harmonization Good Clinical Practice (ICH GCP) and local regulatory requirements. Aspects of the study concerned with the investigational product will meet the requirements of Good Manufacturing Practice (GMP).
Trial website
None
Trial related presentations / publications
None
Public notes
Nil
Attachments [1] 29 29 0 0
/AnzctrAttachments/366149-HSK3486 HREC Approval.pdf

Contacts
Principal investigator
Name 47654 0
Prof Guy Ludbrook
Address 47654 0
Royal Adelaide Hospital
North Terrace
Adelaide SA5000
AUSTRALIA
Country 47654 0
Australia
Phone 47654 0
+61 (0)8 8222 2712
Fax 47654 0
Email 47654 0
[email protected]
Contact person for public queries
Name 47655 0
Yan Zhang
Address 47655 0
Yan Zhang
Sichuan Haisco Pharmaceutical Co., Ltd.
136 Baili Road
Chengdu Cross-Straits IT Industry
Development Zone
Wenjiang District, Chengdu, Sichuan Province
611130 P. R. China
Country 47655 0
China
Phone 47655 0
+86-28-67250476
Fax 47655 0
Email 47655 0
[email protected]
Contact person for scientific queries
Name 47656 0
Seymour Mong
Address 47656 0
Seymour Mong
Sichuan Haisco Pharmaceutical Co., Ltd.
136 Baili Road
Chengdu Cross-Straits IT Industry
Development Zone
Wenjiang District, Chengdu, Sichuan Province
611130 P. R. China
Country 47656 0
China
Phone 47656 0
+86-28-67250476
Fax 47656 0
Email 47656 0
[email protected]

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