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.
Sichuan Haisco Pharmaceutical Co., Ltd.
48 participants
Apr 7, 2014
Interventional
Conditions
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).
Eligibility
Inclusion Criteria11
- To be enrolled in the study, subjects must meet the following criteria:
- Male, aged 18 - 49 years (inclusive)
- Be in general good health without clinically significant medical history
- American Society of Anesthesiologists (ASA) Physical Status Classification of I or II .
- Body Mass Index (BMI) between 18 and 30 kg/m2 (inclusive)
- 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
- 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)
- 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
- Ability to provide written informed consent
- Willing and able to follow study instructions and likely to complete all study requirements
- Suitable venous and arterial access
Exclusion Criteria20
- Subjects will be ineligible for entry into the study if any of the following apply:
- 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
- History of clinically significant problems with general anesthesia
- 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
- History of excessive alcohol intake (more than four standard drinks daily, on average) or use of recreational drugs within the last 3 months
- Use of prescription or over the counter medications within
- days of Investigational Product administration, with the exception of simple analgesics such as paracetamol and oral non-steroidalanti-inflammatory agents
- Standard donation of blood within 30 days of the study
- Donation of plasma or participation in a plasmapheresis program within 7 days preceding this study
- Receipt of any investigational drug study within 30 days prior to screening
- Unable to fast for the 6 hours prior to Investigational Product administration
- 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
- Anticipated need for surgery or hospitalization during the study
- Anatomical abnormality that would potentially interfere with airway management under unconscious sedation or anesthesia
- History of posture-relatedgastric reflux more than twice weekly
- History of seizures or epilepsy
- History of ischaemic heart disease
- History of brady- or tachy-dysrhythmias requiring medical care
- History of asthma, with bronchospasm requiring treatment in the last 3 months.
- 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.
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Interventions
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.
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ACTRN12614000428662