A Study to Evaluate the Efficacy of SAGE-217 in the Treatment of Adult Participants With Major Depressive Disorder

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.

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.

CGI-I response is defined as a CGI-I score of very much improved or much improved. The CGI-I employs a 7-point Likert scale to measure the overall improvement in the participant's condition post-treatment. The Investigator rated the participant's total improvement whether or not it was due entirely to drug treatment. Response choices included: 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse.

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 17-item HAM-D is used to rate the severity of depression in participants who were already diagnosed as depressed. HAM-D subscale scores are calculated as the sum of the items comprising each subscale. The core subscale score is the sum of the following symptom scores, scored in a range of 0 to 4: Depressed mood, feelings of guilt, suicide, work and activities, and retardation. Total HAM-D core subscale scores were transformed to a scale of 0 to 100. Higher scores indicate more severe depression. A negative change from baseline indicates less depression.

The 17-item HAM-D is used to rate the severity of depression in participants who were already diagnosed as depressed. HAM-D subscale scores are calculated as the sum of the items comprising each subscale. The anxiety subscale score is the sum of the following symptom scores: Anxiety (psychic and somatic) [scored in a range of 0 to 4], somatic symptoms (gastrointestinal and general) [scored in a range of 0 to 2], hypochondriasis [scored in a range of 0 to 4], and loss of weight [scored in a range of 0 to 2]. Total HAM-D anxiety subscale scores were transformed to a scale of 0 to 100. Higher scores indicate more severe depression/anxiety. A negative change from baseline indicates less depression.

The 17-item HAM-D is used to rate the severity of depression in participants who were already diagnosed as depressed. HAM-D subscale scores are calculated as the sum of the items comprising each subscale. The Bech-6 subscale score is the sum of the following symptom scores, scored in a range of 0 to 4: Depressed mood, feelings of guilt, work and activities, retardation, anxiety psychic, and somatic symptoms general. Total HAM-D Bech-6 subscale scores were transformed to a scale of 0 to 100. Higher scores indicate more severe depression. A negative change from baseline indicates less depression.

The 17-item HAM-D is used to rate the severity of depression in participants who were already diagnosed as depressed. HAM-D subscale scores are calculated as the sum of the items comprising each subscale. The Maier subscale score is the sum of the following symptom scores, scored in a range of 0 to 4: Depressed mood, feelings of guilt, work and activities, retardation, agitation, and anxiety psychic. Total HAM-D Maier subscale scores were transformed to a scale of 0 to 100. Higher scores indicate more severe depression. A negative change from baseline indicates less depression.

The 17-item HAM-D is used to rate the severity of depression in participants who were already diagnosed as depressed. The HAM-D comprises individual ratings of the following symptoms scored in a range of 0 to 2: Insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight (according to participant), and insight. The following symptoms 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. For each symptom, higher scores indicate more severe depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression.

The ISI is a validated questionnaire designed to assess the nature, severity, and impact of insomnia. The ISI uses a 5-point Likert scale to measure various aspects of insomnia severity (0=none, 1=mild, 2=moderate; 3=severe; 4=very severe), satisfaction with current sleep pattern (0=very satisfied, 1=satisfied, 2=moderately satisfied, 3=dissatisfied, 4=very dissatisfied), and various aspects of the impact of insomnia on daily functioning (0=not at all, 1=a little, 2=somewhat, 3=much, 4=very much). The ISI total score is calculated as the sum of the 7 individual item scores and the possible total score range is from 0 to 28, categorized as follows: 0 to 7=no clinically significant insomnia, 8 to 14=subthreshold insomnia, 15 to 21=clinical insomnia (moderate severity), and 22 to 28=clinical insomnia (severe). Higher scores indicate more severity. A negative change from baseline indicates less severe insomnia.

The Core Consensus Sleep Diary collected subjective responses to a series of questions related to participant's daily sleep pattern (i.e., time to bed, time to fall asleep, time to final awakening, and a question related to quality of sleep) to derive sleep parameters, including sSL, sTST, and sWASO. The take-home participant sleep diary assessment was administered using an eDiary solution. The eDiary was captured using either a provisioned smartphone device or a bring-your-own-device solution, depending on the participant's preference. sTST is a derived parameter calculated as: Time of final awakening - (time when tried to sleep + time taken to fall asleep)-time of being awake after sleep onset. Negative change from baseline in sSL and sWASO indicates improvement. Positive change from baseline in sTST indicates improvement.

The Core Consensus Sleep Diary was used to collect subjective sleep parameter of sNAW. sNAW was calculated from the onset of persistent sleep until lights on. An awakening is defined as at least 2 consecutive epochs of wake. Individual awakenings were separated by at least 1 epoch of Stage N2 (also fairly light, with sudden increases in brain wave frequency known as sleep spindles), N3 (slow wave or deep sleep) or rapid eye movement (REM) sleep. Lower ratings indicate better sleep quality and more refreshing/restorative quality of sleep.

The Core Consensus Sleep Diary collected subjective sleep parameters, including sleep quality (sSQ). The take-home participant sleep diary assessment was administered using an eDiary solution. The eDiary was captured using either a provisioned smartphone device or a bring-your-own-device solution, depending on the participant's preference. sSQ is rated on a 5-point Likert scale ranging from 1 (very poor) to 5 (very good). Higher ratings indicate better sleep quality. sSQ response is defined as having a sSQ score of very good or good.

Participant's health was assessed using Patient-reported outcome (PRO) health related quality of life (HRQOL), SF-36v2 which is a 36-item measure of health status. It covers eight health dimensions including four physical health status domains (physical functioning, role participation with physical health problems, bodily pain, and general health) and four mental health status domains (vitality, social functioning, role participation with emotional health problems, and mental health). Two summary scores, physical component summary (PCS), and mental component summary (MCS) were produced by taking a weighted linear combination of the eight individual domains. The score range for PCS and MCS is 0 to 100 (100=highest level of functioning). Higher scores indicate a better state of health. A negative change from baseline indicates deteriorating health.

The PHQ-9 is a participant-rated depressive symptom severity scale to monitor severity over time for newly diagnosed participants or participants in current treatment for depression. Scoring was based on participants' responses to each of the 9 questions, as follows: 0=not at all; 1=several days; 2=more than half the days; and 3=nearly every day. The PHQ-9 total score was calculated as the sum of the 9 individual item scores. The PHQ-9 total score was categorized as follows: 1 to 4=minimal depression, 5 to 9=mild depression, 10 to 14=moderate depression, 15 to 19=moderately severe depression; and 20 to 27=severe depression. Higher scores indicate more severe depression. A negative change from baseline indicates reduced depression.

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.

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.

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).

Vital signs include supine and standing SBP [mmHg]: <90, >180, increase and decrease from baseline of >=30; Supine and standing 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)- females: >450 to 480, male: >450 to 470, females: >480 to 500, male: >470 to 500 or >500.

Supine 12-lead ECGs were performed in triplicate and the standard intervals (heart rate, PR, QRS, QT, and QTcF) as well as any rhythm abnormalities were recorded. Criteria for clinically significant ECG abnormalities included QTcF interval (msec)- females: >450 to 480, male: >450 to 470, females: >480 to 500, male: >470 to 500 or >500.

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.

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.

The PWC-20 was used to monitor for the presence of potential withdrawal symptoms following discontinuation of SAGE-217. 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.