A Study to Evaluate the Efficacy of Sage-217 in the Treatment of Adult Participants With Major Depressive Disorder (MDD)

The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to the following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either a 3-point (0 to 2) or a 5-point scale (0 to 4), with 0=none/absent and 4=most severe. The total HAM-D score is the sum of individual items, ranging from 0 to 52; where a higher score indicates more depression. A negative change indicates improvement. A mixed Model for Repeated Measures (MMRM)was used for the analysis.

Time frame: Baseline, Day 15

Population: The FAS included all randomized participants who were administered IP with valid baseline HAM-D total score and had at least 1 valid post-baseline HAM-D total score. Overall number of participants analyzed are the number of participants with data available for analysis.

The 14-item HAM-A is comprised of a series of symptoms, and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). The HAM-A total score was calculated as the sum of the 14 individual item scores. The scoring for HAM-A is calculated by assigning scores of 0 (not present) to 4 (very severe) to each item, with a total HAM-A score range of 0 to 56, where \<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 improvement. MMRM was used for the analysis.

Time frame: Baseline, Day 15

Population: FAS included all randomized participants who were administered IP with valid baseline HAM-D total score and had at least 1 valid post-baseline HAM-D total score. Overall number of participants analyzed is the number of participants with data available for analysis.

The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in participants with mood disorders. The MADRS total score was calculated as the sum of the 10 individual item scores and each item yields a score of 0 to 6. The overall MADRS score ranges from 0 to 60 where higher MADRS scores indicate more severe depression. A negative change indicates improvement. MMRM was used analysis.

Time frame: Baseline, Day 15

Population: FAS included all randomized participants who were administered IP with valid baseline HAM-D total score and had at least 1 valid post-baseline HAM-D total score. Overall number of participants analyzed is the number of participants with data available for analysis.

Participant's health was assessed using PRO health related quality of life (HRQOL) SF-36 V2. SF-36v2 covers 8 health dimensions, including 4 physical health status domains (physical functioning, role participation with physical health problems \[role-physical\], bodily pain, and general health) and 4 mental health status domains (vitality, social functioning, role participation with emotional health problems \[role-emotional\], and mental health). Physical Component Summary and the Mental Component Summary are derived from the 8 domains. Each domain is scored by summing the individual items, scores varying between 0 and 100. Both the domain scores and the component summary scores are norm-based. A higher score indicates a better state of health. Positive change indicates improvement. MMRM was used for the analysis.

Time frame: Baseline, Days 8, 15, 28 and 42

Population: FAS included all randomized participants who were administered IP with valid baseline HAM-D total score and had at least 1 valid post-baseline HAM-D total score. Number analyzed is the number of participants with data available for analysis at the given timepoints.

The PHQ-9 is a participant-rated depressive symptom severity scale where scoring is based on responses to specific questions. The score was calculated as the sum of the 9 individual item scores. The PHQ-9 total score ranges from 0 to 27 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 with a higher score indicating more depression. A negative change indicates improvements. MMRM was used for analysis.

Time frame: Baseline, Days 8, 15, 28 and 42

Population: FAS included all randomized participants who were administered IP with valid baseline HAM-D total score and had at least 1 valid post-baseline HAM-D total score. Number analyzed is the number of participants with data available for analysis at the given timepoints.

The CGI-S is a 7-point Likert scale to rate the severity of the participant's illness at the time of assessment, relative to the clinician's past experience with participants who have the same diagnosis. A participant is assessed on severity of mental illness at the time of rating as 1=normal, not at all ill; 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; and 7= among the most extremely ill participants. A negative change from baseline indicates improvement. MMRM was used for the analysis. A negative change from baseline indicates improvement. MMRM was used for the analysis.

Time frame: Baseline, Day 15

Population: FAS included all randomized participants who were administered IP with valid baseline HAM-D total score and had at least 1 valid post-baseline HAM-D total score. Overall number of participants analyzed are the number of participants with data available for analysis.

The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to the following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either a 3-point (0 to 2) or a 5-point scale (0 to 4), with 0=none/absent and 4=most severe. The total HAM-D score is the sum of individual items, ranging from 0 to 52; where a higher score indicates more depression. A negative change from baseline indicates improvement. MMRM was used for the analysis.

Time frame: Baseline, Days 3, 8, and 42

Population: FAS included all randomized participants who were administered IP with valid baseline HAM-D total score and had at least 1 valid post-baseline HAM-D total score. Number analyzed is the number of participants with data available for analysis at the given timepoints.

The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to the following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either a 3-point (0 to 2) or a 5-point scale (0 to 4), with 0=none/absent and 4=most severe. The total HAM-D score is the sum of individual items, ranging from 0 to 52; where a higher score indicates more depression. HAM-D remission is defined as HAM-D total score less than or equal to (≤) 7. GEE model was used for the analysis.

Time frame: Days 15 and 42

Population: FAS included all randomized participants who were administered IP with valid baseline HAM-D total score and had at least 1 valid post-baseline HAM-D total score. Number analyzed is the number of participants with data available for analysis at the given timepoints.

The 17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to the following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either a 3-point (0 to 2) or a 5-point scale (0 to 4), with 0=none/absent and 4=most severe. The total HAM-D score is the sum of individual items, ranging from 0 to 52; where a higher score indicates more depression. HAM-D response is defined as having a greater than or equal to (≥) 50% reduction in HAM-D score from baseline. Generalized Estimating Equation (GEE) method was used for the analysis.

Time frame: Days 15 and 42

Population: FAS included all randomized participants who were administered IP with valid baseline HAM-D total score and had at least 1 valid post-baseline HAM-D total score. Number analyzed is the number of participants with data available for analysis at the given timepoints.

CGI-I response is defined as having a CGI-I score of very much improved (score of 1) or much improved (score of 2). The CGI-I employs a 7-point Likert scale to measure the overall improvement in the participant's condition posttreatment. Response choices include 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse. GEE model was used for the analysis.

Time frame: Day 15

Population: FAS included all randomized participants who were administered IP with valid baseline HAM-D total score and had at least 1 valid post-baseline HAM-D total score. Overall number of participants is the participants with response.

17-item HAM-D scale is used to assess the severity of depression. It is comprised of individual ratings related to following symptoms: depressed mood, feelings of guilt, suicide, insomnia, work and activities, retardation, agitation, anxiety, somatic symptoms, genital symptoms, hypochondriasis, loss of weight, and insight. Individual items are scored on either a 3-point (0 to 2) or a 5-point scale (0 to 4), with 0=none/absent and 4=most severe. Total HAM-D score is sum of individual items, ranging from 0 to 52; where higher score indicates more depression. Time to first HAM-D response is defined as time from first administration of the study drug to first time when ≥50% reduction in HAM-D score from baseline is achieved.

Time frame: Up to Day 57

Population: FAS included all randomized participants who were administered IP with valid baseline HAM-D total score and had at least 1 valid post-baseline HAM-D total score. Overall number of participants analyzed is the number of participants with response.