A Study To Evaluate The Safety, Tolerability And Pharmacokinetics of HS-10345 In Treatment-Resistant Depression

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety, tolerability and pharmacokinetics of intranasal HS-10345 (84mg) compared with placebo in participants with treatment-resistant depression (TRD).

Detailed Description
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This will be a randomized, double-blind, placebo-controlled, multicenter study. Approximately 24 male and female adult participants diagnosed with TRD will participant in this study. There will be 4 study phases: a 4-week screening phase, a 1-day baseline phase, a double-blind treatment phase (Day 1 to Day 15), and a 1-week post-treatment (follow-up) phase. Firstly, 12 patients will be assigned to intranasal placebo or HS-10345 of 84mg. Extra 12 patients may be enrolled depending on the pharmacokinetics analysis of 84mg. Safety assessments will be performed throughout the study. The maximum study duration for a participant will be 7 weeks.

Official Title
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A Phase Ib，Randomized, Double-Blind, Placebo-Controlled Study Evaluating The Safety, Tolerability And Pharmacokinetics of HS-10345 In Chinese Adult Subjects With Treatment Resistant Depression

Conditions
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Treatment Resistant Depressive Disorder

Intervention / Treatment
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* Drug: HS-10345 84mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Each subject must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Participant must meet Diagnostic and Statistical Manual of Mental Disorders -5 Edition -Text Revised (DSM-5) diagnostic criteria for Major Depressive Disorder (MDD), without psychotic features, based upon clinical assessment, and confirmed by the Mini International Neuropsychiatric Interview (MINI). Participant must have had an inadequate response to at least 1 antidepressants in the current episode of depression assessed by the antidepressant treatment response questionnaire (ATRQ), and was taking another oral antidepressant 2 weeks before entering the screening period which will be assessed non-response by Montgomery Asberg Depression Rating Scale (MADRS) during the screening period, defined as MADRS total score reduced ≤25%. Comfortable with self-administration of intranasal medication and able to follow instructions provided. A woman of childbearing potential must have a negative serum (β-human chorionic gonadotropin [β-hCG]) at Screening and a negative urine pregnancy test prior to Period 1 randomization on Day 1. Exclusion Criteria: Subject has a current DSM-5 diagnosis of psychotic disorder, MDD with psychosis, bipolar, obsessive compulsive disorder (OCD), intellectual disability, Autism spectrum Disorder, borderline personality disorder, antisocial personality disorder, histrionic personality disorder, and narcissistic personality disorder. Subject has suicidal ideation with intent to act within the past 6 months based on the Columbia-Suicide Severity Rating Scale (C-SSRS), or has a history of suicidal behavior within the past year as assessed on the C-SSRS. Subject has uncontrolled hypertension (SBP > 140 mmHg or DBP > 90 mmHg) despite diet, exercise or a stable dose of a permitted anti-hypertensive treatment at Screening or Day 1 prior to Period 1 randomization; or any past history of hypertensive crisis. Subject had a history of severe pulmonary insufficiency or SpO2<93% at screening time or prior to dosing. Anatomical or medical conditions that may impede delivery or absorption of study medication. Subject is a woman who is pregnant, breast-feeding, or planning to become pregnant while enrolled in this study or within 12 weeks after the last dose of study drug. Hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCVAb), syphilis antibody and human immunodeficiency virus (HIV) antibody tests positive. Subject has had major surgery, (e.g., requiring general anesthesia) within 12 weeks before screening, or has surgery planned during the time the subject is expected to participate in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HS-10345 84mg<br>Participants will self-administer intranasal HS-10345 84mg on Days 1, 4, 8, and 11 during the double-blind phase | Drug: HS-10345 84mg<br>* 6 sprays of HS-10345 84 mg self-administered as an intranasal formulation for 4 days (Days 1, 4, 8, 11) during the double-blind phase<br>* Other names: HS-10345;|
| Placebo Comparator: Placebo<br>Participants will be self-administered on Days 1, 4, 8, and 11 during the double-blind phase | Drug: Placebo<br>* 6 sprays of placebo self-administered as an intranasal formulation for 4 days (Days 1, 4, 8, 11) during the double-blind phase<br>* Other names: HS-10345 Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs) and Serious Adverse Events (SAEs) | Participants during hospitalization will be closely observed to assure maximal safety and to collect occurrence of all adverse event. To follow-up on the 7th day after discharge, all participants will return to the hospital for information regarding their health condition. All adverse events will be collected with special attention to occurrence of psychotomimetic and dissociative effects after study drug administration. | up to 7 weeks | 
| Change from Baseline (Day -1) in Columbia-Suicide Severity Rating Scale (C-SSRS) Total Score at Day 15 in the Double-Blind Treatment Phase | This scale is intended to be used by individuals who have received training in its administration. The questions contained in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of suicidal ideation or behavior depends on the judgment of the individual administering the scale. A negative change in score indicates improvement. | up to 15 days | 
| Change from Baseline (Day -1) in The Clinician Administered Dissociative States Scale (CADSS) Total Score at 40 minutes and 2 hours after dosing in the Double-Blind Treatment Phase- ANCOVA Analysis on Ranks | This scale is intended to be used to assess the dissociative states of participants. It contains 23 objective items, every item ranges from 0 to 4. A negative change in score indicates improvement. | up to 2 hours | 
| Change From pre-dosing in Modified Observer's Assessment of Alertness and Sedation (MOAA/S) Total Score at 20 minutes、40 minutes and 2 hours after dosing in the Double-Blind Treatment Phase- ANCOVA Analysis on Ranks | The Modified Observer's Assessment of Alertness and Sedation (MOAA/S) scale is frequently used in sedation-related drug and device studies to assess a subject's level of sedation. It ranges from 0 to 5, with a score of 5 defined as awake or minimally sedated, and a score of 0 defined as general anesthesia. This scale is intended to be used by individuals who have received training in its administration. A positive change in score indicates improvement. | up to 2 hours | 
| Change from Baseline (Day -1) in Physician Withdrawal Checklist (PWC-20) Total Score at Day 15 in the Double-Blind Treatment Phase and Day 21 in the Follow-Up Phase- ANCOVA Analysis on Ranks | The PWC-20 was developed to detect any potential BZ-like treatment discontinuation (withdrawal) symptoms caused by experimental anxiolytics of the non-SSRI type. A negative change in score indicates improvement. | up to 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax - maximum HS-10345 plasma concentration | The maximum concentration of the HS-10345 in plasma after drug administration, obtained directly from the measured concentrations. | up to 72 hours after each study drug administration | 
| AUC (0-24) - area under the HS-10345 plasma concentration-time curve from time 0 to 24 hours after study drug administration | The AUC (0-24) is a measure of total plasma exposure to the drug from time point zero to 24 hours after study drug administration. | up to 24 hours after each study drug administration | 
| Tmax - time to reach maximum HS-10345 plasma concentration | The Tmax is time to reach the maximum plasma concentration (Cmax), obtained directly from the actual sampling times. | up to 72 hours after each study drug administration | 
| AUC (0-inf) - area under the HS-10345 plasma concentration-time curve from time 0 to infinity time | The AUC(0-inf) is a measure of total plasma exposure to the drug from time point zero extrapolated to infinity | up to 72 hours after each study drug administration | 
| T1/2 - plasma elimination half-life for HS-10345 | T1/2 will be calculated as 0.693/Kel | up to 72 hours after each study drug administration | 
| Change from Baseline (Day -1) in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at Day 2/8/15- Analysis of Covariance (ANCOVA) Analysis | MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. A negative change in score indicates improvement | up to 15 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment resistant depressive disorder, Intranasal, HS-10345