A Phase I, Randomized, Double-blind, Placebo-controlled Dose Escalation Trial to Assess the Safety Tolerability and Pharmacokinetics of Single and Multiple Oral Administration of HS-10356 in Healthy Volunteers
Overview
- Phase
- Phase 1
- Intervention
- HS-10356
- Conditions
- Healthy
- Sponsor
- Jiangsu Hansoh Pharmaceutical Co., Ltd.
- Enrollment
- 76
- Locations
- 1
- Primary Endpoint
- Physical examination:Abdominal
- Last Updated
- 5 years ago
Overview
Brief Summary
The primary objective of this study is to assess the safety and tolerability of single and multiple oral administration of HS-10356 in healthy volunteers.
Detailed Description
This is a phase I, randomized, double-blind, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) clinical trial to assess the safety, tolerability, and pharmacokinetics of HS-10356 oral formulation in Chinese healthy adult volunteers. Approximately five sequential dose panels (single oral doses of 2,6,15,30,45mg HS-10356) will be evaluated in SAD. To protect the safety of volunteers, two sentinel volunteers were first enrolled in the first dose panel (2mg panel) and randomly assigned to HS-10356 or placebo in a 1:1 ratio. After the sentinel volunteers were given the dose for at least 24 hours and confirmed that they were safe, the remaining 6 volunteers were randomly assigned to HS-10356 or placebo in a ratio of 5:1. For the follow-up panels of SAD, volunteers were randomly assigned to either the experimental group or the placebo group (6 cases in HS-10356 and 2 cases in placebo) in a 3:1 ratio using block randomization method. Approximately three sequential dose panels (14 consecutive days for respectively daily oral doses of 6,15,30mg HS-10356, QD) will be evaluated in MAD. Volunteers were randomly assigned to either the experimental group or the placebo group (9 cases in the HS-10356 and 3 cases in the placebo) in a ratio of 3:1 using block randomization method. Each subject will receive only one regimen in this study. Safety data up to Day12 (±2) in SAD and up to Day25 (±2) in MAD will be reviewed prior to dose escalation. Cohorts of SAD and MAD will be added or removed depending on the assessment results of SRC.
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- •Pregnant and breastfeeding female.
- •Volunteers with a history of cardiovascular, respiratory, liver, kidney, digestive tract, mental, neurological, hematological, metabolic and other systemic diseases, who are not suitable to participate in this study as assessed by the investigator.
- •The results of vital signs, physical examination, laboratory examination and 12-lead ECG during screening were abnormal with clinical significance.
- •Major surgery was performed within 3 months prior to the screening or surgery was planned during the study.
- •Severe infections, such as cellulitis, pneumonia, sepsis, have occurred or are present in the 30 days prior to screening.
- •ALT, AST, ALP or bilirubin were higher than the upper limit of normal.
- •Creatinine clearance \< 90mL/min at screening (Cockcroft-Gault method), as follows:
- •(140-age in years)×weight (kg)/72×serum creatinine（mg/dL）×(Female×0.85)；
- •8.Hepatitis B virus surface antigen (HBsAg), hepatitis C virus antibody (HCVAb), human immunodeficiency virus antibody (HIVAb) or syphilis antibody is positive.
- •9.Volunteers had a history of drug dependence or abuse.
Arms & Interventions
HS-10356 single dose
Single oral dose of HS-10356 ascending dose
Intervention: HS-10356
placebo single dose
Single oral dose of placebo ascending doses
Intervention: Placebo
HS-10356 multiple doses
Multiple oral doses of HS-10356 ascending doses
Intervention: HS-10356
Placebo multiple doses
Multiple oral doses of placebo ascending doses
Intervention: Placebo
Outcomes
Primary Outcomes
Physical examination:Abdominal
Time Frame: 24hours after the first and last administration, prior to discharge from hospital in MAD
Laboratory assessment:Haematology
Time Frame: Predose, day4、day7、day10、day14、day19 prior to discharge from hospital in MAD
Laboratory assessment:Clinical Chemistry
Time Frame: Predose, day4、day7、day10、day14、day19 prior to discharge from hospital in MAD
Laboratory assessment:Routine Urinalysis
Time Frame: Predose, day4、day7、day10、day14、day19 prior to discharge from hospital in MAD
Laboratory assessment:Coagulation test
Time Frame: Predose, day4、day7、day10、day14、day19 prior to discharge from hospital in MAD
Vital signs:Blood pressure
Time Frame: Within 1 hour before administration, 1hours, 2hours, 4hours, 12hours on days 1,2,4,6,8,10,12 and 14, once a day on days 15 to 19 in MAD
Vital signs:Pulse rate
Time Frame: Within 1 hour before administration, 1hours, 2hours, 4hours, 12hours on days 1,2,4,6,8,10,12 and 14, once a day on days 15 to 19 in MAD
Vital signs:Respiratory rate
Time Frame: Within 1 hour before administration, 1hours, 2hours, 4hours, 12hours on days 1,2,4,6,8,10,12 and 14, once a day on days 15 to 19 in MAD
Vital signs:Temperature
Time Frame: Within 1 hour before administration, 1hours, 2hours, 4hours, 12hours on days 1,2,4,6,8,10,12 and 14,once a day on days 15 to 19 in MAD
Physical examination:Lymph node
Time Frame: 24hours after the first and last administration, prior to discharge from hospital in MAD
Physical examination:Chest
Time Frame: 24hours after the first and last administration, prior to discharge from hospital in MAD
12-lead electrocardiogram (ECG) parameters ( Heart rate, PR, R-R, QRS and QTcF (average))
Time Frame: Within 1 hour before administration,1hours, 2hours, 3hours, 24hours 120hours after administration in SAD.
Physical examination:General
Time Frame: 24hours after the first and last administration, prior to discharge from hospital in MAD
The incidence, severity, and association of AE, SAE, and adverse events leading to withdrawal from the trial
Time Frame: MAD: Day1~Day25
Secondary Outcomes
- SAD pharmacokinetic endpoint:The maximum plasma concentration (Cmax)(Day1-Day6)
- SAD pharmacokinetic endpoint:Time to Cmax (Tmax)(Day1-Day6)
- SAD pharmacokinetic endpoint:The area under the plasma concentration-time curve from time zero extrapolated to infinite time (AUC0-∞)(Day1-Day6)
- SAD pharmacokinetic endpoint:Terminal rate constant (λz)(Day1-Day6)
- SAD pharmacokinetic endpoint:The area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC0-t)(Day1-Day6)
- SAD pharmacokinetic endpoint:Half life (t½)(Day1-Day6)
- SAD pharmacokinetic endpoint:Apparent clearance following extravascular administration (CL/F)(Day1-Day6)
- SAD pharmacokinetic endpoint:Apparent volume of distribution following extravascular administration (Vd/F)(Day1-Day6)
- SAD pharmacokinetic endpoint:Mean residence time (MRT)(Day1-Day6)
- MAD pharmacokinetic endpoint:The maximum steady state drug concentration in plasma during dosing interval (Css,max)(Day1-Day19)
- MAD pharmacokinetic endpoint:The minimum steady state drug concentration in plasma during dosing interval (Css,min)(Day1-Day19)
- MAD pharmacokinetic endpoint:Average steady state drug concentration in plasma during dosing interval (Css,av)(Day1-Day19)
- MAD pharmacokinetic endpoint:Time to Css, max (Tss,max)(Day1-Day19)
- MAD pharmacokinetic endpoint:The area under the plasma concentration-time curve over the dosing interval at steady state (AUCss)(Day1-Day19)
- MAD pharmacokinetic endpoint:The area under the plasma concentration-time curve from time zero to the time of the last measurable concentration at steady state(AUC0-t)(Day1-Day19)
- MAD pharmacokinetic endpoint:The area under the plasma concentration-time curve from time zero extrapolated to infinite time (AUC0-∞) at steady state(Day1-Day19)
- MAD pharmacokinetic endpoint:Half life (t½)(Day1-Day19)
- MAD pharmacokinetic endpoint:Accumulation ratio (Rac)(Day1-Day19)
- MAD pharmacokinetic endpoint:Apparent clearance at steady state following extravascular administration (CLss/F)(Day1-Day19)
- MAD pharmacokinetic endpoint:Apparent volume of distribution at steady state following extravascular administration (Vd/F)(Day1-Day19)