Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001620415
Ethics application status
Approved
Date submitted
19/11/2016
Date registered
23/11/2016
Date last updated
23/11/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
An Open Label, Single-Center, Single Dose Combination of HSK3486 and Etomidate Intravenous Bolus Injection to Determine the Safety, Pharmacodynamics and Pharmacokinetics for Induction of Anesthesia in Healthy Male Subjects
Scientific title
An Open Label, Single-Center, Single Dose Combination of HSK3486 and Etomidate Intravenous Bolus Injection to Determine the Safety, Pharmacodynamics and Pharmacokinetics for Induction of Anesthesia in Healthy Male Subjects
Secondary ID [1] 290286 0
None
Universal Trial Number (UTN)
None
Trial acronym
HSK3486 SAD_04
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anesthesia 300524 0
Condition category
Condition code
Anaesthesiology 300388 300388 0 0
Anaesthetics

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All subjects will receive a combined dose of HSK3486 and etomidate administered as a single bolus IV injection (a prepared pre-mixed formulation containing HSK3486 and etomidate micro-emulsion formulations) via infusion pump over 60 seconds into the antecubital fossa of the hand.
There are a total of 5 cohorts, of 5 subjects planned for the study. The doses for Cohorts 1 to 3 have been selected based on reductions to the individual recommended clinical doses for each of HSK3486 and etomidate to make a total anesthetic dose similar to a standard dose of propofol of 2.5 mg/kg.
The doses for Cohorts 4 and 5 will be determined following an interim review by the SRC of the safety and PD results for the completed Cohorts 1 to 3 (up to Day 7).
The proposed doses for each of the cohorts are as follows:
Cohort 1: 0.324 mg/kg HSK3486 plus 0.15 mg/kg etomidate
Cohort 2: 0.216 mg/kg HSK3486 plus 0.2 mg/kg etomidate
Cohort 3: 0.432 mg/kg HSK3486 plus 0.1 mg/kg etomidate
Cohort 4: Dose for HSK3486 and etomidate to be confirmed
Cohort 5: Dose for HSK3486 and etomidate to be confirmed
Dosing of subjects will occur at intervals of no less than 2 hours, to assess short-term safety between subjects.
On the evening of check-in subjects may be given dinner or snacks but must fast from 11:00 pm through at least 6 hours from the start of investigational product administration. During this time water is permitted but must be ceased at least 2 hours prior to the schedule dose time.
Intervention code [1] 296090 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 299834 0
Assess the safety & tolerability of a single bolus intravenous (IV) injection of combinations of HSK3486 and etomidate for induction of anesthesia in healthy adult male subjects.
Timepoint [1] 299834 0
A complete physical examination will be conducted at the Screening. At Day 1 a brief exam will be performed to confirm no changes from screening.
Vital signs (respiratory rate, heart rate, pulse oximetry, temperature, non-invasive BP [systolic and diastolic BP and MAP]) will be measured at the Screening visit, Day -1, and during the Treatment Visit( every 1 min during 0 min to 30 min, every 5 min during 30 min to 60 min, 2 hours (+/- 10 minute), 4 hours (+/- 10 minutes), 8 hours (+/- 10 minutes) , 12 hours (+/- 10 minutes) and 24 hours post dose (+/- 30 minutes) ) and at the Follow up visit.
The laboratory tests are to be performed at Screening, Day -1, 24 hours post-dose at the Treatment Visit and the Follow-Up Visit.
Computerized 12-lead ECG will be performed at the Screening visit. At the treatment visit, a continuous 3-lead ECG will be performed for 30 minutes (+/- 1 minute) prior to dosing and for the first 2 hours (+/- 1 minute) post dosing. Also a 12-lead ECG will be performed at 30 minutes (+/- 1 minute) prior to dosing, then at 0, 10, 15, 30 minutes (+/- 1 minute) and 1 hour (+/- 1 minute) post dose.
The presence of involuntary movements will be recorded from the onset of drug administration until RASS has returned to baseline.
Neurovascular assessments of the hand distal to the placement of the arterial line are to be performed every 30 minutes (+/- 1 minute) from the time of arterial line insertion until removal. Following removal of the line, the assessments will be performed every 4 hours (+/- 10 minutes) for 8 hours and at 24 hours post dose.
Primary outcome [2] 300259 0
Assess the pharmacodynamics (PD) of a single bolus intravenous (IV) injection of combinations of HSK3486 and etomidate for induction of anesthesia in healthy adult male subjects.
Timepoint [2] 300259 0
Onset of sedation/anesthesia will be defined as the time to loss of response to oral command and time to loss of eyelash reflex. Loss of response to oral command is captured under RASS, and eyelash reflex will be sought every 15 seconds after dosing until absent.
The RASS will be measured during the Treatment Visit evaluated and recorded at every minute post dose until the RASS score recovers to 0 for consecutive 3 minutes.
The EEG (raw EEG) and the processed parameter BIS will be recorded during the Treatment Visit with BIS values evaluated and recorded at every minute post dose until the RASS score recovers to 0 for consecutive 3 minutes using a fronto-parietal montage.
A subject assessment of the quality of recovery after anesthesia will be conducted using the QoR-9 which is to be performed prior to dosing, 10 minutes after a RASS score of 0, and 24 hours post-dose during the Treatment Visit.
Secondary outcome [1] 328250 0
Assess the pharmacokinetics (PK) of IV injected HSK3486, in the presence of etomidate, in healthy subjects.
The plasma concentration of HSK3486 will be analyzed using non-compartmental analytical procedures and validated software to estimate the following PK parameters:
Maximum observed plasma concentration (Cmax)
Time to maximum plasma concentration (tmax)
Area under the plasma concentration-time curve from time zero to the time of the last measurable concentration and time zero to infinity (AUC0-last and AUC0-inf)
Apparent terminal elimination rate constant (kel)
Apparent terminal elimination half-life (t1/2)
Clearance (CL)
Volume of distribution (Vd)
Mean residence time from time zero to infinity (MRT0-inf)
Timepoint [1] 328250 0
Samples for PK are to be collected as follows: within 30 minutes prior to dosing; 0.5 minutes, 1 minute, 1.5 minutes, 2 minutes, 4 minutes, 5 minutes, 8 minutes, 12 minutes, 15 minutes, 30 minutes, 1 hour (+/- 1 minute), 1.5 hours (+/- 1 minute), 2 hours (+/- 2 minute), 4 hours (+/- 2 minutes), 8 hours (+/- 2 minutes) and 24 hours post dose (+/- 2 minutes).

Eligibility
Key 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, as determined by the investigator
3.American Society of Anesthesiologists 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, alcohol, hepatitis B surface antigen, hepatitis C and Human Immunodeficiency Virus (HIV) at screening; and drugs of abuse, alcohol pre dose on Day -1
6.Normal or non-clinically significant findings on a physical examination, 12-lead ECG and vital signs (respiration rate between 12 and 20 breaths per minute, BP between 100-140/50-90 mmHg, heart rate between 45-99 beats per minute, temperature between 35.8 degrees and 37.5 degrees). Pulse oximetry values >95% on room air.
7.Clinical laboratory values within the normal limits as defined by the clinical laboratory, unless the 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
Subjects will be ineligible for entry into the study if any of the following apply:
1.History of allergy or sensitivity to: propofol, etomidate or components of HSK3486 (excipients soy bean oil, glycerine, triglycerides, purified egg phospholipids, sodium oleate and sodium hydroxide), or plain lignocaine
2.History of clinically significant problems with anesthesia induction
3.Current smoker, 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 4 standard drinks daily, on average) or use of recreational drugs within the last 3 months prior to screening
5.Intake of > 8 caffeine-containing drinks per day, on average, or approximately 800mg of caffenine daily on average; history of intolerance of abstinencce from caffeine for 3 days
6.Use of prescription or over the counter medications within 7 days of investigational product administration, with the exception of paracetamol, oral non-steroidal anti-inflammatory agents, topical over the counter preparations and routine vitamins (if they do not exceed the recommended daily dose), unless agreed as non-clinically relevant by the investigator and sponsor.
7.Standard donation of blood within 30 days of the study
8.Donation of plasma or participation in a plasmapheresis program within 7 days of investigational product administration
9.Receipt of any investigational study drug within 30 days prior to screening
10.Unable to fast for the 6 hours prior to investigational product administration
11.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
12.Anticipated need for surgery or hospitalization during the study
13.Craniofacial abnormality that would potentially interfere with airway management under unconscious sedation or anesthesia
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
19.Receipt of HSK3486 less than 4 weeks prior to the start of the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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
Other
Other design features
There are a total of 5 cohorts of 5 subjects planned for the study. The doses for Cohorts 1 to 3 have been selected based on reductions to the recommended clinical doses for each of HSK3486 and etomidate.
The doses for Cohorts 4 and 5 will be determined following an interim review by the Safety Review Committee of the safety and PD results for the completed Cohorts 1 to 3 (up to Day 7).
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
In general, all data will be summarized using descriptive statistics. Summaries of continuous variables will present mean, median, standard deviation, minimum, and maximum; summaries of categorical variables will present frequencies and percentages. All data will be presented in subject data listings.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
5/12/2016
Actual
Date of last participant enrolment
Anticipated
31/01/2017
Actual
Date of last data collection
Anticipated
9/02/2017
Actual
Sample size
Target
25
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA

Funding & Sponsors
Funding source category [1] 294669 0
Commercial sector/Industry
Name [1] 294669 0
Sichuan Haisco Pharmaceutical Co., Ltd
Country [1] 294669 0
China
Primary sponsor type
Commercial sector/Industry
Name
Sichuan Haisco Pharmaceutical Co., Ltd
Address
136 Baili Road, Chengdu Cross-Straits IT Industry, Development Zone, Wenjiang District, Chengdu, Sichuan Province 611130, P.R. China
Country
China
Secondary sponsor category [1] 293520 0
None
Name [1] 293520 0
Address [1] 293520 0
Country [1] 293520 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296100 0
Royal Adelaide Hospital Human Research Ethics Committee
Ethics committee address [1] 296100 0
Level 4, Women's Health Centre
Royal Adelaide Hospital
North Terrace
Adelaide, South Australia, 5000
Ethics committee country [1] 296100 0
Australia
Date submitted for ethics approval [1] 296100 0
05/10/2016
Approval date [1] 296100 0
08/11/2016
Ethics approval number [1] 296100 0
HREC/16/RAH/404

Summary
Brief summary
This study is designed as an open label, single dose combination of HSK3486 and etomidate in healthy adult male subjects. The study will evaluate the anesthetic/sedation effect of the combination of the 2 drugs and the safety profile including pain on injection, hypotension, tachycardia or bradycardia effects (HSK3486), and involuntary muscle movements, nausea and vomiting potential and adrenal suppression (etomidate).
All subjects will be administered HSK3486 plus etomidate. Subjects will be confined to the study unit from the evening of Day -1 until the morning of Day 2, then will be required to return for a follow up visit on Day 7.
Intensive PD, PK, safety and tolerability and assessments will be performed prior to dosing on Day 1 until 24 hours post-dose (Day 2).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 69522 0
Prof Guy Ludbrook
Address 69522 0
Royal Adelaide Hospital
North Terrace
Adelaide SA, 5000
Country 69522 0
Australia
Phone 69522 0
+61(0)882222712
Fax 69522 0
Email 69522 0
[email protected]
Contact person for public queries
Name 69523 0
Ms Yan Xu
Address 69523 0
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 69523 0
China
Phone 69523 0
+86-21-50799069
Fax 69523 0
Email 69523 0
[email protected]
Contact person for scientific queries
Name 69524 0
Prof Seymour Mong
Address 69524 0
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 69524 0
China
Phone 69524 0
+86-28-67250476
Fax 69524 0
Email 69524 0
[email protected]

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No Supporting Document Provided



Results publications and other study-related documents

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