A Study of HS-10353 in Chinese Participants.

Study Overview
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Brief Summary
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The primary objective of this study is to assess the safety and tolerability of single and multiple oral administered doses of HS-10353 separately in Chinese healthy and major depressive disorder subjects.

Detailed Description
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This is a phase I, randomized, double-blinded, placebo-controlled, both single ascending doses (SAD) study and multiple ascending dose (MAD) clinical trial to assess the safety, tolerability, and pharmacokinetics of HS-10353 tablet(s) separately in Chinese healthy and major depressive disorder (MDD) subjects. Approximately six sequential dose cohorts will be evaluated in SAD study. Sentinel dosing will be employed for the first SAD cohort to protect the subjects' safety. Escalation to the next dose cohort will be undertaken only after safety and PK data are reviewed by the Safety Review Committee (SRC) and agreement reach that it is safe to increase the dose. Each SAD cohort is dosed at approximately weekly intervals to allow adequate time for collection and review of safety and PK data. Approximately three sequential dose cohorts will be evaluated in MAD study. The total daily dose for each MAD cohort will be based on information obtained from the SAD study. Each subject will receive only one dose regimen in this study. Safety data up to Day14 (±1) in SAD and up to Day20 (±1) in MAD will be reviewed prior to the next dose level. The number of Cohorts in SAD and MAD would be adjusted based on the assessment of SRC.

Official Title
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A Phase I Randomized, Double-blinded, Placebo-controlled Dose Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetic of HS-10353 in Chinese Adult Subjects

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: HS-10353
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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SAD Inclusion Criteria Healthy male or female subjects between 18 and 45 years old; Body weight more than 50.0kg (male) or 45.0kg (female), body mass index (BMI) within the range of 19.0 26.0kg/m2; Volunteers agree to refrain from smoking, drinking alcohol. Avoid xanthine or caffeine (including chocolate, tea, coffee, cola, etc.) and avoid strenuous exercise; The male volunteers agreed to refrain from donating sperm from the start of the drug until six months after they stopped the study; The female volunteers agreed to avoid ovum donation from the start of the drug until six months after they stopped the study; Pregnancy test results of female volunteers must be negative within 3 days of administration. SAD 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. Hepatitis B virus surface antigen (HBsAg), hepatitis C virus antibody (HCVAb), human immunodeficiency virus antibody (HIVAb) or syphilis antibody is positive Volunteers had a history of drug dependence or abuse. A heavy smoker or smokers who smoked 5 or more cigarettes per day for 3 months prior to screening or tested positive for nicotine during screening. A history of alcohol abuse or a single consumption of more than 14 units of alcohol (1 unit = 285 mL of beer, 25 mL of spirits, 150 mL of wine) in the nearly two weeks prior to screening or a positive breath test for alcohol at screening. Participate in clinical trials of any drug or medical device within 3 months prior to screening. Any medication taken within 2 weeks of administration, including prescription, over-the-counter, and herbal medicines. Diet or dietary treatment or significant change in dietary habits within 30 days prior to administration for whatever reason. Volunteers who have difficulty swallowing solid tablets or capsule. Volunteers with difficulty in blood collection, unable to tolerate multiple venous blood collection and any blood collection contraindications. MAD Inclusion Criteria Subject has signed an ICF prior to any study-specific procedures being performed. Subject is an ambulatory male or female between 18 and 65 years of age, inclusive. Subject has a diagnosis of MDD that has been present for at least a 4-week period as diagnosed by DSM-5. Subject has a HAM-D17 total score of ≥22 at screening and Day 1 (prior to dosing). Subject is willing to discontinue other antidepressant or anti-anxiety medications （such as benzodiazepines） or antipsychotics during screening and treatment. MAD Exclusion criteria: Subject has a history of suicide attempt. Subject has a recent history or active clinically significant manifestations of metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, dermatological, urogenital, neurological, or eyes, ears, nose, and throat disorders, or any other acute or chronic condition that, in the Investigator's opinion, would limit the subject's ability to complete or participate in this clinical study. Subject has a history of treatment-resistant depression, defined as persistent depressive symptoms despite treatment with adequate doses of antidepressants from two different classes for an adequate amount of time (ie, at least 4 weeks of treatment). Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV), or human immunodeficiency virus (HIV) antibody at screening. Subject has active psychosis per Investigator assessment. Subject has a medical history of seizures. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective disorder. Subject has had exposure to another investigational medication or device within 30 days prior to screening. Subject has had administration of psychotropics that have been initiated within 14 days prior to screening and/or are not being taken at a stable dose. Use of any known strong inhibitors and/or inducers of cytochrome P450 (CYP)3A4 within the 14 days or five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, Seville oranges, or products containing these within 30 days prior to receiving the first dose of study drug.

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: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HS-10353<br>Capsules；Single dose: only one administration; Multiple doses: continuous administration for 7 days | Drug: HS-10353<br>* Single or multiple dose(s) of HS-10353<br>* Other names: HS-10353 capsules;|
| Placebo Comparator: Placebo<br>Capsules；Single dose: only one administration; Multiple doses: continuous administration for 7 days | Drug: Placebo<br>* Single or multiple dose(s) of placebo<br>* Other names: HS-10353 placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endpoints of the trial：AE，SAE | The incidence, severity, and association of AE, SAE and AE leading to withdrawal from the trial | Baseline to end of follow-up (a maximum of 20 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SAD pharmacokinetic endpoints：Cmax | The maximum plasma concentration (Cmax) | Day1-Day6 | 
| SAD pharmacokinetic endpoints：Tmax | Time to Cmax (Tmax) | Day1-Day6 | 
| SAD pharmacokinetic endpoints：AUC0-t | 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 endpoints：AUC0-∞ | The area under the plasma concentration-time curve from time zero to infinite time (AUC0-∞) | Day1-Day6 | 
| SAD pharmacokinetic endpoints：λz | Terminal rate constant (λz) | Day1-Day6 | 
| SAD pharmacokinetic endpoints：t½ | Half-life (t½) | Day1-Day6 | 
| SAD pharmacokinetic endpoints：CL/F | Apparent clearance following oral administration (CL/F) | Day1-Day6 | 
| SAD pharmacokinetic endpoints：Vz/F | Apparent volume of distribution following oral administration (Vz/F) | Day1-Day6 | 
| SAD pharmacokinetic endpoints：MRT | Mean residence time (MRT) | Day1-Day6 | 
| MAD pharmacokinetic endpoints：Css,max | The maximum steady state drug concentration in plasma during dosing interval (Css,max) | Day1-Day12 | 
| MAD pharmacokinetic endpoints：Css,av | Average steady state drug concentration in plasma during dosing interval (Css,av) | Day1-Day12 | 
| MAD pharmacokinetic endpoints：Tss,max | Time to Css, max (Tss,max) | Day1-Day12 | 
| MAD pharmacokinetic endpoints：AUCss, 0-t | The area under the plasma concentration-time curve from time zero to the time of the last measurable concentration over the dosing interval at steady state (AUCss, 0-t) | Day1-Day12 | 
| MAD pharmacokinetic endpoints：DF | Coefficient of fluctuation（DF） | Day1-Day12 | 
| MAD pharmacokinetic endpoints：Rac | Accumulation ratio (Rac) | Day1-Day12 | 
| MAD pharmacokinetic endpoints：Css,min | The minimum steady state drug concentration in plasma during dosing interval (Css,min) | Day1-Day12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase I, major depressive disorder, healthy subject, SAD, MAD