A Study Evaluating Safety, Pharmacodynamics and Pharmacokinetics of HSK3486 and Etomidate for Induction of Anesthesia in Healthy Male Subjects

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

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).

Study Overview

• Status: Completed
• Conditions: Sedation; General Anesthetic
• Intervention / Treatment: Drug: HSK3486+ etomidate

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 49 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion 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.

Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: HSK3486+etomidate; Cohort 1: HSK3486 0.324 mg/kg + etomidate 0.15 mg/kg Cohort 2: HSK3486 0.216 mg/kg + etomidate 0.2 mg/kg Cohort 3: HSK3486 0.432 mg/kg + etomidate 0.1 mg/kg There were an additional 2 cohorts (Cohorts 4 and 5) planned for dose escalation once the optimal ratio of the drug combination was identified from the first 3 cohorts. However, these 2 cohorts were not done as the results of Cohorts 1 to 3 suggested that dose increases would cause higher occurrence of drug-related adverse events (AEs).

Drug: HSK3486+ etomidate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety by measurement of Adverse Events	on day 1 until 24 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Richmond Agitation Sedation Scale (RASS)	0 Alert and calm; 1 Not fully alert, but has sustained awakening (eyeopening/eye contact) to voice (≥ 10 seconds); 2 Briefly awakens with contact to voice (< 10 seconds); 3 Movement or eye opening to voice (but no eye contact); 4 No response to voice, but movement or eye opening to physical stimulation; 5 No response to voice or physical stimulation	First dose of study drug on day 1
bispectral index (BIS)		First dose of study drug on day 1
subject-rated Quality of Recovery Assessment (QoR-9）		First dose of study drug on day 1
Peak concentration (Cmax)		on day 1 until 24 hours post-dose
Time to plasma peak concentration(Tmax)		on day 1 until 24 hours post-dose
Area Under the Curve		on day 1 until 24 hours post-dose

Collaborators and Investigators

• Sponsor: Sichuan Haisco Pharmaceutical Group Co., Ltd

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2016
• Primary Completion (Actual): December 21, 2016
• Study Completion (Actual): June 28, 2017

Study Registration Dates

• First Submitted: July 4, 2019
• First Submitted That Met QC Criteria: August 11, 2019
• First Posted (Actual): August 13, 2019

Study Record Updates

• Last Update Posted (Actual): August 13, 2019
• Last Update Submitted That Met QC Criteria: August 11, 2019
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Hypnotics and Sedatives; Etomidate
• Other Study ID Numbers: HSK3486-Australian-04

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No