A Study of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Dosed of HSK36273 in Healthy Volunteers

Study Overview
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Brief Summary
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This is a single-center, Phase 1, placebo and positive-controlled, randomized, partial-blind, integrated, sequential ascending dose / multiple ascending dose study.The safety, tolerability, pharmacokinetics and pharmacodynamics of multiple continuous IV infusion ascending doses of HSK36273 in healthy volunteers will be evaluated.

Official Title
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A Randomized, Partial-Blind, Placebo and Positive-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Ascending Doses of HSK36273 in Healthy Subjects.

Conditions
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Healthy

Intervention / Treatment
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* Drug: HSK36273
* Drug: Placebo
* Drug: Heparin sodium injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult males and females, 18 to 45 years of age (inclusive) at Screening. Body Mass Index (BMI) ≥ 18.0 and ≤ 28.0 kg/m2 and a weight of at least 45 kg for female and 50 kg for male. The subject must be willing and able to provide written informed consent Medically healthy without clinically significant abnormalities at Screening and predose on Day 1, including: Physical examination without any clinically relevant findings. Three conventional 12-ECG recordings (the average of the three measurements will be used to determine eligibility) were consistent with normal cardiac conduction and function. QT interval corrected using the Fridericia method (QTcF) between 350 to 450 msec for male subjects and 350 to 470 msec for female subjects, inclusive. Normal laboratory tests (hematology, biochemistry, urinalysis, coagulation tests (aPTT and PT). No clinically significant findings in serum chemistry, hematology, coagulation, and urinalysis tests as deemed by the Investigator. Must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects. Willing and able to comply with all study evaluations and adhere to protocol schedules and constraints. Exclusion Criteria: History or presence of major diseases of the cardiovascular, respiratory, digestive, urological, hematologic, endocrine, immunologic, skin or nervous system, as well as any acute illness or surgical procedure within the past 3 months as determined by the investigator to be clinically relevant. History of abnormal bleeding episodes, e.g. nosebleeds, or abnormally heavy periods, or extensive bleeding after injury, surgery or dental work within 3 months prior to screening. Any clinically Laboratory tests during the screening period were abnormal and clinically significant as judged by the investigator. Liver function test results (i.e., aspartate aminotransferase [AST], alanine aminotransferase [ALT], and gamma glutamyl transferase[GGT]) and total bilirubin elevated above the ULN. Positive test results for active HIV, hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies (Abs). Hemoglobin or hematocrit clinically significantly less than lower limits of normal at screening. History of drug abuse in the 12 months prior to the first administration of the study drug or alcohol abuse in the 3 months prior. A clinically significant allergic reaction that the investigator believes interferes with the subject's ability to participate in the trial; Known allergies to any of the study drug ingredients, allergy to anticoagulants or antiplatelet drugs or obvious adverse reactions, allergic to two or more drugs or food, allergic to any ingredient in this product and auxiliary materials. Donate blood or plasma within 3 months prior to the first administration of the study drug, or lose more than 400mL of whole blood, or receive blood transfusion within 1 year prior to the first administration of the study drug. History of Participating in another investigational clinical trial within 90 days before the first administration of the study drug. Poor venous access that would hamper a 5-day infusion. Positive pregnancy test at screening or check-in (Day -1). Participation in a clinical trial involving the administration of an investigational or marketed drug within 30 days (90 days for biologics), or five (5) half-lives, whichever is longer, prior to the first dosing or concomitant participation in an investigational study involving no drug administration. Any other factors considered by the investigator to be inappropriate for participation in the trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HSK36273<br>Multiple continuous IV infusion ascending doses in cohort 1-5 | Drug: HSK36273<br>* Multiple continuous IV infusion ascending doses for 5 days<br>|
| Placebo Comparator: Placebo<br>5 cohorts with matching placebo to HSK36273 | Drug: Placebo<br>* Matching placebo<br>|
| Active Comparator: Heparin sodium injection<br>Cohort 1-2 with matching positive control to HSK36273 | Drug: Heparin sodium injection<br>* Matching positive control<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number and severity of treatment emergent adverse events (TEAEs) . | To assess the safety and tolerability of multiple of HSK36273 following 24-hour continuous IV infusions administered over 5 consecutive days with ascending doses in healthy subjects | Day1 to Day8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-24h | Area under the drug concentration-time curve, from time 0h to 24h | within 1 hour before administration until 24 hours after starting administration | 
| AUC0-144h | Area under the drug concentration-time curve, from time 0h to 144h | within 1 hour before administration until 144 hours after administration | 
| Css | Steady-State Concentration with a the Initiation of Continuous IV 5-day Infusion of HSK36273 | within 1 hour before administration until 144 hours after administration | 
| Tss | Time to Reach a Steady-State Concentration Following a the Initiation of Continuous IV 5-day Infusion of HSK36273 | within 1 hour before administration until 144 hours after administration | 
| t1/2 | Apparent terminal half-life | 24 hours after administration | 
| CL | Apparent total clearance of drug | 24 hours after administration | 
| Vd | Apparent volume of distribution | 24 hours after administration | 
| Activated Partial Thromboplastin Time (aPTT) | Clotting Biomarker Activated Partial Thromboplastin Time During the Course of a Continuous IV 5-day Infusion of HSK36273 | within 1 hour before administration until 144 hours after administration | 
| Prothrombin Time (PT) | Clotting Biomarker Prothrombin During the Course of a Continuous IV 5-day Infusion of HSK36273 | within 1 hour before administration until 144 hours after administration | 
| Activated Clotting Time (ACT) | Clotting Biomarker Activated Clotting Time During the Course of a Continuous IV 5-day Infusion of HSK36273 | within 1 hour before administration until 144 hours after administration | 
| FXIa | Change from baseline in factor XI activity | within 1 hour before administration until 144 hours after administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HSK36273, healthy, Phase I, continuous IV