A Study of HS-10353 in Adult Participants With Major Depressive Disorder

The 17-item HAM-D is used to rate the severity of depression in participants who were already diagnosed as depressed. The HAM-D total score comprises a sum of the 17 individual item scores. 8 items scored in a range of 0 to 2 include: Insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following 9 items are scored in a range of 0 to 4: Agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. Total HAM-D score can range from 0 to 52, and higher scores indicate severe depression. A negative change from baseline indicates less depression.

HAM-D response is defined as a ≥50% reduction in HAM-D score from baseline. The HAM-D total score comprises a sum of the 17 individual item scores. 8 items scored in a range of 0 to 2 include: Insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following 9 items are scored in a range of 0 to 4: Agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. Total HAM-D score can range from 0 to 52, and higher scores indicate severe depression.

HAM-D remission is defined as HAM-D total score ≤7. The HAM-D total score comprises a sum of the 17 individual item scores. 8 items scored in a range of 0 to 2 include: Insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following 9 items are scored in a range of 0 to 4: Agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. Total HAM-D score can range from 0 to 52, and higher scores indicate severe depression.

The 14-item HAM-A is used to rate the severity of symptoms of anxiety. Each of the 14 items is defined by a series of symptoms and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Scoring for HAM-A is calculated by assigning scores of 0 (not present) to 4 (very severe) to each item. Total HAM-A score is calculated as the sum of the 14 individual item scores with a total score range of 0 to 56, where the score of <17 indicates mild severity, 18 to 24 indicates mild to moderate severity, and 25 to 30 indicates moderate to severe severity. A negative change from baseline indicates less severe symptoms.

The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in participants with mood disorders. Each item is rated on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). Total MADRS score, calculated as the sum of the 10 individual items, ranges from 0 to 60 with a higher score indicating more depression. A negative change from baseline indicates less severe symptoms.

The CGI-S uses a 7-point Likert scale to rate the severity of the participant's illness relative to the clinician's past experience with participants who had the same diagnosis. Considering total clinical experience, a participant was assessed on severity of mental illness at the time of rating as 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; and 7=extremely ill. A higher score indicates extreme illness/more severity. A negative change from baseline indicates less severe illness.

An adverse event (AE) is any untoward medical occurrence in a participant administered with a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an IP whether or not related to the product. An AE can include any undesirable medical condition, even if no study treatment has been administered. A TEAE is defined as an AE with onset after the start of IP, or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study. A serious TEAE is defined as a TEAE that at any dose results in death, is immediately life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or results in a congenital abnormality or birth defect.

Laboratory parameters include serum chemistry- Alanine aminotransferase: >3x upper limit of normal (ULN); Alanine aminotransferase or aspartate aminotransferase: >3x ULN; Bilirubin: >1.5x ULN, >2x ULN; Calcium: <2.0 millimoles per liter (mmol/L); Gamma Glutamyl Transferase [units per liter (U/L)]: >3xULN; Potassium: >5.4 mmol/L; Sodium: >150 mmol/L; Hematology- Hematocrit : Male <0.385 liter/liter (L/L) and Female <0.345 L/L and Male >0.55 L/L and Female >0.49 L/L; Hemoglobin: Male <115 grams/liter (g/L) and Female <100 g/L; Neutrophils: <1.5 10^9/L.

Vital signs include supine and standing systolic blood pressure (SBP) [millimeters of mercury (mmHg)]: <90, >180, increase and decrease from baseline of >=30; Supine and standing diastolic blood pressure (DBP) (mmHg): Increase and decrease from baseline >=20; Standing heart rate (>120 beats per minute); Orthostatic SBP (>=20); Orthostatic DBP (>=10); Orthostatic hypotension (SBP >=20 and DBP >=10, SBP >=20 or DBP >=10).

Supine 12-lead ECGs were performed in triplicate and the standard intervals (heart rate, PR, QRS, QT, and corrected QT interval by Fridericia [QTcF]) as well as any rhythm abnormalities were recorded. Criteria for clinically significant ECG abnormalities included QTcF interval (msec)- >500，or longer than 60 msec from baseline

Suicidality was monitored during the study using the C-SSRS scale. The C-SSRS includes 'yes' or 'no' responses for 5 questions for assessment of suicidal ideation and behavior. Any suicidal behavior: When response is "yes" for any these questions- actual attempt to suicide, engaged in non-suicidal self-injurious behavior, interrupted attempt, aborted attempt, preparatory acts. Any suicidal ideation: When response is "yes" for any of these questions- wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent to suicide.

Sleepiness as measured by the Stanford Sleepiness Scale (SSS) has at least two dimensions: activity and sleepiness. The subjects did not perceive the descriptions to be consistent in each dimension. Participants rated their current sleepiness on a scale from 1 to 7. Scores were assigned as follows: feeling energetic, well energetic but not at their best, awake but somewhat loose, having some degree of grogginess, grogginess, sleepiness, wanting to lie down, not trying to stay awake anymore, falling asleep quickly, feeling dreaming.

The PWC-20 was used to monitor for the presence of potential withdrawal symptoms following discontinuation of HS-10353. The PWC-20 was made up of a list of 20 symptoms (loss of appetite, nausea-vomiting, diarrhea, anxiety-nervousness, irritability, dysphoric mood-depression, insomnia, fatigue-lethargy-lack of energy, poor coordination, restlessness-agitation, diaphoresis, tremor-tremulousness, dizziness-lightheadedness, headaches, muscle aches or stiffness, weakness, increased acuity [sound, smell, touch, pain], paresthesia, difficulty concentrating and remembering, depersonalization-derealization) that were rated on a scale of 0 (not present) to 3 (severe). The PWC-20 total score was derived as the sum of individual item scores, which ranges from 0 (not present) to 60 (severe). Higher scores indicate more severe withdrawal. A negative change from baseline indicates less severe withdrawal.