A Study to Evaluate SAGE-217 in Participants With Severe Postpartum Depression

• Sponsor: Sage Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02978326
• Collaborator: (none)
• Enrollment: 276
• Locations: 27
• Arms: 3
• Actual Duration (Months): 23.2
• Patients Per Site: 10.2
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The primary purpose of this study was to determine if treatment with SAGE-217 reduces depressive symptoms in participants with severe postpartum depression (PPD) compared to placebo as assessed by the change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) total score at Day 15 and to evaluate the safety and tolerability of SAGE-217 compared to placebo as assessed by the incidence of adverse events, vital sign measurements, clinical laboratory evaluations, electrocardiogram (ECG) parameters, and the Columbia Suicide Severity Rating Scale (C-SSRS).

Condition or Disease	Intervention/Treatment	Phase
Postpartum Depression	Drug: SAGE-217 15/20 mg Oral Solution; Drug: Placebo; Drug: SAGE 217 30 mg Capsules	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 276 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study Evaluating the Efficacy, Safety, and Pharmacokinetics of SAGE-217 in the Treatment of Adult Female Subjects With Severe Postpartum Depression
• Actual Study Start Date: Jan 4, 2017
• Actual Primary Completion Date: Nov 15, 2018
• Actual Study Completion Date: Dec 11, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part A: SAGE-217 15/20 mg Oral Solution Participants received SAGE-217, 15 milligrams (mg), oral solution, twice daily (BID) for first 2 days followed by SAGE-217, 15 or 20 mg, oral solution, BID, starting on Day 3 for up to 14 days as tolerated.	Drug: SAGE-217 15/20 mg Oral Solution; SAGE-217, 15 mg oral solution, BID for Days 1 to 2 followed by 20 mg oral solution BID for Days 3 to 14. If not tolerated, 15 mg for the rest of study (Days 3 to 14).
Placebo Comparator: Part B: Placebo Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Drug: Placebo; SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.
Experimental: Part B: SAGE 217 30 mg Capsules Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.	Drug: SAGE 217 30 mg Capsules; SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.

Outcome Measures

Primary Outcome Measures

1. Parts A and B: Change From Baseline in the 17-Item Hamilton Rating Scale for Depression (HAM-D) Total Score at Day 15 [Parts A and B: Baseline, Day 15]

   The 17-item HAM-D is used to rate the severity of depression in participants who are already diagnosed as depressed. 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 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. The HAM-D total score was calculated as the sum of the 17 individual item scores and could range from 0 to 52. Higher scores indicated more severe depression. A negative change from Baseline indicates less depression.

Secondary Outcome Measures

1. Parts A and B: Change From Baseline in the HAM-D Total Score at Days 3, 8, 21 and 45 [Part B: Baseline, Days 3, 8, 21 and 45]

   The 17-item HAM-D is used to rate the severity of depression in participants who are already diagnosed as depressed. 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 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. The HAM-D total score was calculated as the sum of the 17 individual item scores and could range from 0 to 52. Higher scores indicated more severe depression. A negative change from Baseline indicates less depression.

2. Parts A and B: Percentage of Participants With HAM-D Response [Part B: Days 3, 8, 15, 21 and 45]

   HAM-D Response was defined as having a 50 percent (%) or greater reduction from Baseline in HAM-D total score. The HAM-D total score was calculated as the sum of the 17 individual item scores and could range from 0 to 52. The items on HAM-D included: depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, insomnia (early night, middle night, early hours [morning]), work and activities, retardation (slowness of thought and speech; impaired ability to concentrate; decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms (gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and insight. Higher scores indicated more depression.

3. Parts A and B: Percentage of Participants With HAM-D Remission [Part B: Days 3, 8, 15, 21 and 45]

   HAM-D Remission was defined as a HAM-D total score of less than or equal to (<=)7. The HAM-D total score was calculated as the sum of the 17 individual item scores and could range from 0 to 52. The items on HAM-D included: depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, insomnia (early night, middle night, early hours [morning]), work and activities, retardation (slowness of thought and speech; impaired ability to concentrate; decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms (gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and insight. Higher scores indicated more depression.

4. Parts A and B: Change From Baseline in HAM-D Subscales Scores [Part B: Baseline, Days 3, 8, 15, 21 and 45]

   HAM-D is used to rate the severity of depression in participants who are already diagnosed as depressed. HAM-D subscales: Core subscale (symptoms-depressed mood, feelings of guilt, suicide, work and activities, and retardation ); Anxiety subscale (symptoms-anxiety [psychic and somatic], somatic symptoms [gastrointestinal and general], hypochondriasis, loss of weight); Bech-6 subscale (symptoms-depressed mood, feelings of guilt, work and activities, retardation, anxiety psychic, and somatic symptoms general); Meier subscale (symptoms-depressed mood, feelings of guilt, work and activities, retardation, agitation, and anxiety psychic). Each item was scored in a range of 0 to 2 or 0 to 4, higher scores=greater degree of depression. Subscale scores were calculated as the sum of the individual item scores comprising each subscale. Scores were transformed to a scale of 0 to 100, with higher scores indicated more severe depression. A negative change from Baseline indicates less depression.

5. Parts A and B: Change From Baseline in HAM-D Individual Item Scores [Part B: Baseline, Days 3, 8, 15, 21 and 45]

   The 17-item HAM-D is used to rate the severity of depression in participants who are already diagnosed as depressed. Individual items on the scale were scored in a range of 0 to 2 or 0 to 4. Symptoms scored in a range of 0 to 2: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following symptoms were 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. Higher scores indicated a greater degree of depression. A negative change from Baseline indicates less depression.

6. Parts A and B: Change From Baseline in Montgomery and Åsberg Depression Rating Scale (MADRS) Total Score [Part B: Baseline, Days 3, 8, 15, 21 and 45]

   The MADRS is a 10-item questionnaire used to measure the severity of depressive episodes in participants with mood disorders. It includes questions on the following symptoms: apparent sadness; reported sadness; inner tension; reduced sleep; reduced appetite; concentration difficulties; lassitude; inability to feel; pessimistic thoughts; and suicidal thoughts. Each item was scored in a range of 0 (no symptoms) to 6 (symptoms of maximum severity). The MADRS total score was calculated as the sum of the 10 individual item scores and could range from 0 to 60. Higher scores indicated more severe depression. A negative change from Baseline indicates less depression.

7. Parts A and B: Percentage of Participants With Clinical Global Impression - Improvement (CGI-I) Response [Part B: Days 3, 8, 15, 21 and 45]

   The Clinical Global Impression - Improvement (CGI-I) item of the CGI scale uses a 7-point Likert scale to measure the overall improvement in the participant's condition posttreatment. The investigator rated the participant's total improvement whether or not it was due entirely to drug treatment. Response choices included: 0=not assessed, 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse. CGI response was defined as a CGI-I score of 1 (very much improved) or 2 (much improved). The percentage of participants with overall improvement in post-treatment condition, rated by investigator as very much improved (CGI-I score of 1) or much improved (CGI-I score of 2) is reported.

8. Parts A and B: Change From Baseline in Hamilton Anxiety Rating Scale (HAM-A) Total Score [Part B: Baseline, Days 3, 8, 15, 21 and 45]

   The 14-item HAM-A was used to rate the severity of symptoms of anxiety. Each of the 14 items was defined by a series of symptoms and measured both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). The individual items were scored in a range of 0 (not present) to 4 (very severe). The HAM-A total score was calculated as the sum of the 14 individual item scores and could range from 0 to 56 where a score of <17=mild severity; 18-24= mild to moderate severity and 25-30=moderate to severe severity. A negative change from Baseline indicates less anxiety.

9. Parts A and B: Percentage of Participants With MADRS Response [Part B: Days 3, 8, 15, 21 and 45]

   MADRS response was defined as having a 50% or greater reduction from Baseline in MADRS total score. The MADRS is a 10-item questionnaire used to measure the severity of depressive episodes in participants with mood disorders. It includes questions on the following symptoms: apparent sadness; reported sadness; inner tension; reduced sleep; reduced appetite; concentration difficulties; lassitude; inability to feel; pessimistic thoughts; and suicidal thoughts. Each item was scored in a range of 0 (no symptoms) to 6 (symptoms of maximum severity). The MADRS total score was calculated as the sum of the 10 individual item scores and could range from 0 to 60. Higher scores indicated more depression.

10. Parts A and B: Percentage of Participants With MADRS Remission [Part B: Days 3, 8, 15, 21 and 45]

    MADRS Remission was defined as a MADRS total score of <=10. The MADRS is a 10-item questionnaire used to measure the severity of depressive episodes in participants with mood disorders. It includes questions on the following symptoms: apparent sadness; reported sadness; inner tension; reduced sleep; reduced appetite; concentration difficulties; lassitude; inability to feel; pessimistic thoughts; and suicidal thoughts. Each item was scored in a range of 0 (no symptoms) to 6 (symptoms of maximum severity). The MADRS total score was calculated as the sum of the 10 individual item scores and could range from 0 to 60. Higher scores indicated more depression.

11. Parts A and B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [Part A: Up to Day 75; Part B: Up to Day 45]

    An Adverse Event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE was defined as an AE with an onset that occurs after receiving study drug.

12. Part B: Number of Participants With Potentially Clinically Significant Vital Sign Measurements [Part B: From first dose of study drug up to 45 days]

    Vital signs included assessments of supine and standing systolic blood pressure (SBP), supine and standing diastolic blood pressure (DBP), and heart rate.

13. Part B: Number of Participants With Potentially Clinically Significant Laboratory Evaluations [Part B: From first dose of study drug up to 45 days]

    Laboratory tests included tests of Hematology, Chemistry, and Urinalysis.

14. Part B: Change From Baseline in Electrocardiogram (ECG) Parameter Heart Rate [Part B: Baseline, Days 8, 15, and 21]

    ECG parameters included assessment of the standard 12-lead ECG intervals: QT, QTcF, PR, RR, QRS, and heart rate. Heart rate was measured in terms of beats per minute. Change from Baseline in heart rate at specified time points were reported.

15. Part B: Change From Baseline in ECG Parameters-PR Interval, RR Interval, QRS Duration, QT Interval, QTcF Interval [Part B: Baseline, Days 8, 15, and 21]

    ECG parameters included assessment of the standard 12-lead ECG intervals: QT, QTcF, PR, RR, QRS, and heart rate. Change from Baseline in PR Interval, RR Interval, QRS Duration, QT Interval, QTcF Interval is reported.

16. Part B: Number of Participants With a Response of "Yes" to Any Suicidal Ideation or Suicidal Behaviors Item Using the Columbia Suicide Severity Rating Scale (C-SSRS) [Part B: Up to Day 45]

    C-SSRS was used to assess the suicidality of participants during the study. The assessment included "yes" or "no" responses for 5 questions, each related to suicidal ideation (wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods, active suicidal ideation with some intent, active suicidal ideation with specific plan) and suicidal behavior (preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, suicide). Numeric ratings were provided for severity of ideation (if present), from 1 to 5, with 5 being the most severe. Number of participants with a response of 'yes' to any suicidal ideation or suicidal behavior item as measured by C-SSRS is reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Participant either must have ceased lactating at screening or, if still lactating or actively breastfeeding at screening, must agree to temporarily cease giving breast milk to her infant(s)

• Participant has had a Major Depressive Episode that began no earlier than the third trimester and no later than the first 4 weeks following delivery, as diagnosed by the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 Axis I Disorders (SCID-I)

• Participant was <=six months postpartum.

Key Exclusion Criteria:

• Active psychosis

• Attempted suicide associated with current episode of postpartum depression

• Medical history of seizures

• Medical history of bipolar disorder, schizophrenia, and/or schizoaffective disorder.

Note: suicidal ideation was not an exclusion. Other protocol-defined inclusion/exclusion criteria might apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sage Investigational Site	Little Rock	Arkansas	United States	72209
2	Sage Investigational Site	Beverly Hills	California	United States	90212
3	Sage Investigational Site	Oceanside	California	United States	92056
4	Sage Investigational Site	Wildomar	California	United States	92595
5	Sage Investigational Site	Washington	District of Columbia	United States	20011
6	Sage Investigational Site	Aventura	Florida	United States	33027
7	Sage Investigational Site	Miami	Florida	United States	33173
8	Sage Investigational Site	Orlando	Florida	United States	32807
9	Sage Investigational Site	Pensacola	Florida	United States	32502
10	Sage Investigational SIte	Pinellas Park	Florida	United States	33782
11	Sage Investigational Site	Atlanta	Georgia	United States	30331
12	Sage Investigational Site	Decatur	Georgia	United States	30030
13	Sage Investigational Site	Hoffman Estates	Illinois	United States	60169
14	Sage Investigational Site	Owensboro	Kentucky	United States	42303
15	Sage Investigational Site	Lake Charles	Louisiana	United States	70629
16	Sage Investigational Site	New Orleans	Louisiana	United States	70115
17	Sage Investigational Site	Saint Charles	Missouri	United States	63304
18	Sage Investigational Site	Las Vegas	Nevada	United States	89102
19	Sage Investigational Site	Manhasset	New York	United States	11030
20	Sage Investigational Site	New York	New York	United States	10036
21	Sage Investigational Site	Chapel Hill	North Carolina	United States	27599
22	Sage Investigational Site	Raleigh	North Carolina	United States	27612
23	Sage Investigational Site	Providence	Rhode Island	United States	02904
24	Sage Investigational Site	Fort Worth	Texas	United States	76060
25	Sage Investigational Site	Houston	Texas	United States	77058
26	Sage Investigational Site	Richardson	Texas	United States	75080
27	Sage Investigational Site	Orem	Utah	United States	84058

Sponsors and Collaborators

• Sage Therapeutics

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jul 2, 2018
• Statistical Analysis Plan - Dec 11, 2018

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Sage Therapeutics
• ClinicalTrials.gov Identifier: NCT02978326
• Other Study ID Numbers: 217-PPD-201
• First Posted: Nov 30, 2016
• Last Update Posted: Feb 10, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Sage Therapeutics: Postpartum Care
• Additional relevant MeSH terms: Depression, Postpartum; Depression; Depressive Disorder

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 27 investigative centers in the United States of America from 04 January 2017 to 11 December 2018. Study was conducted in 2 parts. In Part A, only 1 participant was enrolled and thus no analysis was performed for Part A. All analysis sets were defined only for Part B. For Part A, only adverse events incidence were captured.
Pre-assignment Detail	A total of 276 participants were enrolled and consented of which 154 eligible participants were randomized and thus presented in participant flow. Rest of the 123 participants were not randomized and not part of any analyses. 152 randomized participants received study drug and 143 completed the study.

Arm/Group Title	Part A: SAGE-217 15/20 mg Oral Solution	Part B: Placebo	Part B: SAGE 217 30 mg Capsules
Arm/Group Description	Participants received SAGE-217, 15 milligrams (mg), oral solution, twice daily (BID) for first 2 days followed by SAGE-217, 15 or 20 mg, oral solution, BID, starting on Day 3 for up to 14 days as tolerated.	Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.
Period Title: Part A (Up to 75 Days)
STARTED	1	0	0
COMPLETED	1	0	0
NOT COMPLETED	0	0	0
Period Title: Part A (Up to 75 Days)
STARTED	0	76	77
Received Study Drug	0	73	78
Safety Set (Part B)	0	73	78
Efficacy Set (Part B)	0	74	76
COMPLETED	0	69	73
NOT COMPLETED	0	7	4

Baseline Characteristics

Arm/Group Title	Part A: SAGE-217 15/20 mg Oral Solution	Part B: Placebo	Part B: SAGE 217 30 mg Capsules	Total
Arm/Group Description	Participants received SAGE-217, 15 mg, oral solution, BID for first 2 days followed by SAGE-217, 15 or 20 mg, oral solution, BID, starting on Day 3 for up to 14 days as tolerated.	Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.	Total of all reporting groups
Overall Participants	1	74	76	151
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	1 100%	74 100%	76 100%	151 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	1 100%	74 100%	76 100%	151 100%
Male	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	18 1800%	16 21.6%	34 44.7%
Not Hispanic or Latino	56 5600%	60 81.1%	116 152.6%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 100%	1 1.4%	2 2.6%
Native Hawaiian or Other Pacific Islander	1 100%	0 0%	1 1.3%
Black or African American	31 3100%	31 41.9%	62 81.6%
White	40 4000%	44 59.5%	84 110.5%
More than one race	1 100%	0 0%	1 1.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
17-Item Hamilton Rating Scale for Depression (HAM-D) Total Score (score on a scale) [Mean (Full Range) ]
Mean (Full Range) [score on a scale]	28.8	28.4	28.6
HAM-D Subscales Scores (score on a scale) [Mean (Full Range) ]
Core	50.1	51.3	50.7
Anxiety	56.3	53.1	54.7
Bech-6	64.5	66.3	65.4
Meier	57.1	59.1	58.1
HAM-D Individual Item Scores (score on a scale) [Mean (Full Range) ]
Depressed Mood	3.1	3.1	3.1
Feelings of Guilt	2.2	2.5	2.35
Suicide	0.4	0.4	0.4
Insomnia Early - Early Night	1.8	1.8	1.8
Insomnia Middle - Middle Night	1.9	1.7	1.8
Insomnia Early Hours - Morning	1.5	1.6	1.55
Work and Activities	3.1	3.0	3.05
Retardation	1.2	1.2	1.2
Agitation	1.4	1.4	1.4
Anxiety Psychic	2.7	2.9	2.8
Anxiety Somatic	1.9	1.9	1.9
Somatic Symptoms Gastrointestinal	1.5	1.3	1.4
General Somatic Symptoms	1.8	1.8	1.8
Genital Symptoms	1.9	1.9	1.9
Hypochondriasis	1.3	1.0	1.15
Loss of Weight According to Patient	0.9	0.6	0.75
Insight	0.1	0.1	0.1
Montgomery and Åsberg Depression Rating Scale (MADRS) Total Score (score on a scale) [Mean (Full Range) ]
Mean (Full Range) [score on a scale]	36.3	34.9	35.6
Hamilton Anxiety Rating Scale (HAM-A) Total Score (score on a scale) [Mean (Full Range) ]
Mean (Full Range) [score on a scale]	27.2	26.1	26.65

Outcome Measures

1. Primary Outcome

Title	Parts A and B: Change From Baseline in the 17-Item Hamilton Rating Scale for Depression (HAM-D) Total Score at Day 15
Description	The 17-item HAM-D is used to rate the severity of depression in participants who are already diagnosed as depressed. 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 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. The HAM-D total score was calculated as the sum of the 17 individual item scores and could range from 0 to 52. Higher scores indicated more severe depression. A negative change from Baseline indicates less depression.
Time Frame	Parts A and B: Baseline, Day 15

Outcome Measure Data

Analysis Population Description

Only 1 participant was enrolled and treated in the Part A: SAGE-217 15/20 mg Oral Solution arm group and due to low number of participants, no efficacy analyses were conducted for Part A of the study. Part B: Efficacy Set included all participants who were administered study drug, had a valid Baseline and at least 1 post-baseline efficacy assessment.

Arm/Group Title	Part A: SAGE-217 15/20 mg Oral Solution	Part B: Placebo	Part B: SAGE 217 30 mg Capsules
Arm/Group Description	Participants received SAGE-217, 15 mg, oral solution, BID for first 2 days followed by SAGE-217, 15 or 20 mg, oral solution, BID, starting on Day 3 for up to 14 days as tolerated.	Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.
Measure Participants	0	74	76
Least Squares Mean (Standard Error) [score on a scale]	-13.6 (1.07)	-17.8 (1.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0028
	Comments	Mixed Model for Repeated Measures (MMRM) was used for estimation with treatment, baseline HAM-D total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares (LS) Mean Difference
	Estimated Value	-4.2
	Confidence Interval	(2-Sided) 95%; -6.9 to -1.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.37
	Estimation Comments

2. Secondary Outcome

Title	Parts A and B: Change From Baseline in the HAM-D Total Score at Days 3, 8, 21 and 45
Description	The 17-item HAM-D is used to rate the severity of depression in participants who are already diagnosed as depressed. 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 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. The HAM-D total score was calculated as the sum of the 17 individual item scores and could range from 0 to 52. Higher scores indicated more severe depression. A negative change from Baseline indicates less depression.
Time Frame	Part B: Baseline, Days 3, 8, 21 and 45

Outcome Measure Data

Analysis Population Description

Only 1 participant was enrolled and treated in the Part A: SAGE-217 15/20 mg Oral Solution arm group and due to low number of participants, no efficacy analyses were conducted for Part A of the study. Part B: Efficacy Set included all participants who were administered study drug, had a valid Baseline and at least 1 post-baseline efficacy assessment.

Arm/Group Title	Part A: SAGE-217 15/20 mg Oral Solution	Part B: Placebo	Part B: SAGE 217 30 mg Capsules
Arm/Group Description	Participants received SAGE-217, 15 mg, oral solution, BID for first 2 days followed by SAGE-217, 15 or 20 mg, oral solution, BID, starting on Day 3 for up to 14 days as tolerated.	Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.
Measure Participants	0	74	76
Change From Baseline at Day 3	-9.8 (0.95)	-12.5 (0.93)
Change From Baseline at Day 8	-12.9 (1.03)	-16.3 (1.00)
Change From Baseline at Day 21	-14.4 (1.11)	-17.6 (1.09)
Change From Baseline at Day 45	-15.1 (1.06)	-19.2 (1.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Change From Baseline in the HAM-D Total Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0252
	Comments	MMRM was used for estimation with treatment, baseline HAM-D total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.7
	Confidence Interval	(2-Sided) 95%; -5.1 to -0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.19
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Change From Baseline in the HAM-D Total Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0106
	Comments	MMRM was used for estimation with treatment, baseline HAM-D total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-3.4
	Confidence Interval	(2-Sided) 95%; -6.0 to -0.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.31
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Change From Baseline in the HAM-D Total Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0321
	Comments	MMRM was used for estimation with treatment, baseline HAM-D total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-3.1
	Confidence Interval	(2-Sided) 95%; -6.0 to -0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.44
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Change From Baseline in the HAM-D Total Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0027
	Comments	MMRM was used for estimation with treatment, baseline HAM-D total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.1
	Confidence Interval	(2-Sided) 95%; -6.7 to -1.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.34
	Estimation Comments

3. Secondary Outcome

Title	Parts A and B: Percentage of Participants With HAM-D Response
Description	HAM-D Response was defined as having a 50 percent (%) or greater reduction from Baseline in HAM-D total score. The HAM-D total score was calculated as the sum of the 17 individual item scores and could range from 0 to 52. The items on HAM-D included: depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, insomnia (early night, middle night, early hours [morning]), work and activities, retardation (slowness of thought and speech; impaired ability to concentrate; decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms (gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and insight. Higher scores indicated more depression.
Time Frame	Part B: Days 3, 8, 15, 21 and 45

Outcome Measure Data

Analysis Population Description

Only 1 participant was enrolled and treated in the Part A: SAGE-217 15/20 mg Oral Solution arm group and due to low number of participants, no efficacy analyses were conducted for Part A of the study. Part B: Efficacy Set included all participants who were administered study drug, had a valid Baseline and at least 1 post-baseline efficacy assessment. Here, 'number analyzed' signifies participants evaluable for this outcome measure at specified time points.

Arm/Group Title	Part A: SAGE-217 15/20 mg Oral Solution	Part B: Placebo	Part B: SAGE 217 30 mg Capsules
Arm/Group Description	Participants received SAGE-217, 15 mg, oral solution, BID for first 2 days followed by SAGE-217, 15 or 20 mg, oral solution, BID, starting on Day 3 for up to 14 days as tolerated.	Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.
Measure Participants	0	74	76
Day 3	27.0 2700%	40.5 54.7%
Day 8	44.6 4460%	65.3 88.2%
Day 15	47.9 4790%	71.6 96.8%
Day 21	56.2 5620%	71.6 96.8%
Day 45	56.5 5650%	75.3 101.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With HAM-D Response at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1004
	Comments	Generalized estimating equations (GEE) for binary response model was used for estimation with factors for treatment, baseline HAM-D total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.79
	Confidence Interval	(2-Sided) 95%; 0.89 to 3.60
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With HAM-D Response at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0127
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline HAM-D total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.31
	Confidence Interval	(2-Sided) 95%; 1.20 to 4.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With HAM-D Response at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0049
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline HAM-D total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.63
	Confidence Interval	(2-Sided) 95%; 1.34 to 5.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With HAM-D Response at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0763
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline HAM-D total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.85
	Confidence Interval	(2-Sided) 95%; 0.94 to 3.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With HAM-D Response at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0216
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline HAM-D total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.28
	Confidence Interval	(2-Sided) 95%; 1.13 to 4.60
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Parts A and B: Percentage of Participants With HAM-D Remission
Description	HAM-D Remission was defined as a HAM-D total score of less than or equal to (<=)7. The HAM-D total score was calculated as the sum of the 17 individual item scores and could range from 0 to 52. The items on HAM-D included: depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, insomnia (early night, middle night, early hours [morning]), work and activities, retardation (slowness of thought and speech; impaired ability to concentrate; decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms (gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and insight. Higher scores indicated more depression.
Time Frame	Part B: Days 3, 8, 15, 21 and 45

Outcome Measure Data

Analysis Population Description

Only 1 participant was enrolled and treated in the Part A: SAGE-217 15/20 mg Oral Solution arm group and due to low number of participants, no efficacy analyses were conducted for Part A of the study. Part B: Efficacy Set included all participants who were administered study drug, had a valid Baseline and at least 1 post-baseline efficacy assessment. Here, 'number analyzed' signifies participants evaluable for this outcome measure at specified time points.

Arm/Group Title	Part A: SAGE-217 15/20 mg Oral Solution	Part B: Placebo	Part B: SAGE 217 30 mg Capsules
Arm/Group Description	Participants received SAGE-217, 15 mg, oral solution, BID for first 2 days followed by SAGE-217, 15 or 20 mg, oral solution, BID, starting on Day 3 for up to 14 days as tolerated.	Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.
Measure Participants	0	74	76
Day 3	5.4 540%	18.9 25.5%
Day 8	18.9 1890%	32.0 43.2%
Day 15	23.3 2330%	44.6 60.3%
Day 21	28.8 2880%	41.9 56.6%
Day 45	30.4 3040%	53.4 72.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With HAM-D Remission at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0200
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline HAM-D total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.89
	Confidence Interval	(2-Sided) 95%; 1.24 to 12.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With HAM-D Remission at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0990
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline HAM-D total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.91
	Confidence Interval	(2-Sided) 95%; 0.89 to 4.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With HAM-D Remission at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0110
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline HAM-D total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.53
	Confidence Interval	(2-Sided) 95%; 1.24 to 5.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With HAM-D Remission at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1982
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline HAM-D total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.58
	Confidence Interval	(2-Sided) 95%; 0.79 to 3.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With HAM-D Remission at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0091
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline HAM-D total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.52
	Confidence Interval	(2-Sided) 95%; 1.26 to 5.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Parts A and B: Change From Baseline in HAM-D Subscales Scores
Description	HAM-D is used to rate the severity of depression in participants who are already diagnosed as depressed. HAM-D subscales: Core subscale (symptoms-depressed mood, feelings of guilt, suicide, work and activities, and retardation ); Anxiety subscale (symptoms-anxiety [psychic and somatic], somatic symptoms [gastrointestinal and general], hypochondriasis, loss of weight); Bech-6 subscale (symptoms-depressed mood, feelings of guilt, work and activities, retardation, anxiety psychic, and somatic symptoms general); Meier subscale (symptoms-depressed mood, feelings of guilt, work and activities, retardation, agitation, and anxiety psychic). Each item was scored in a range of 0 to 2 or 0 to 4, higher scores=greater degree of depression. Subscale scores were calculated as the sum of the individual item scores comprising each subscale. Scores were transformed to a scale of 0 to 100, with higher scores indicated more severe depression. A negative change from Baseline indicates less depression.
Time Frame	Part B: Baseline, Days 3, 8, 15, 21 and 45

Outcome Measure Data

Analysis Population Description

Only 1 participant was enrolled and treated in the Part A: SAGE-217 15/20 mg Oral Solution arm group and due to low number of participants, no efficacy analyses were conducted for Part A of the study. Part B: Efficacy Set included all participants who were administered study drug, had a valid Baseline and at least 1 post-baseline efficacy assessment. Here, 'number analyzed' signifies participants evaluable for this outcome measure at specified time points.

Arm/Group Title	Part A: SAGE-217 15/20 mg Oral Solution	Part B: Placebo	Part B: SAGE 217 30 mg Capsules
Arm/Group Description	Participants received SAGE-217, 15 mg, oral solution, BID for first 2 days followed by SAGE-217, 15 or 20 mg, oral solution, BID, starting on Day 3 for up to 14 days as tolerated.	Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.
Measure Participants	0	74	76
Core: Change From Baseline at Day 3	-16.7 (1.91)	-18.8 (1.88)
Core: Change From Baseline at Day 8	-23.4 (2.03)	-28.7 (1.99)
Core: Change From Baseline at Day 15	-26.8 (2.10)	-31.9 (2.06)
Core: Change From Baseline at Day 21	-27.3 (2.24)	-33.7 (2.20)
Core: Change From Baseline at Day 45	-29.5 (2.11)	-37.2 (2.05)
Anxiety: Change From Baseline at Day 3	-16.4 (1.98)	-23.5 (1.93)
Anxiety: Change From Baseline at Day 8	-23.2 (2.15)	-29.8 (2.09)
Anxiety: Change From Baseline at Day 15	-23.4 (2.19)	-33.2 (2.13)
Anxiety: Change From Baseline at Day 21	-27.3 (2.17)	-33.3 (2.11)
Anxiety: Change From Baseline at Day 45	-26.5 (2.19)	-34.5 (2.11)
Bech-6: Change From Baseline at Day 3	-19.5 (2.45)	-23.7 (2.41)
Bech-6: Change From Baseline at Day 8	-28.3 (2.58)	-34.9 (2.53)
Bech-6: Change From Baseline at Day 15	-30.9 (2.61)	-39.2 (2.56)
Bech-6: Change From Baseline at Day 21	-32.7 (2.72)	-40.7 (2.68)
Bech-6: Change From Baseline at Day 45	-34.6 (2.61)	-44.0 (2.54)
Meier: Change From Baseline at Day 3	-17.0 (2.17)	-21.7 (2.13)
Meier: Change From Baseline at Day 8	-25.0 (2.30)	-32.2 (2.24)
Meier: Change From Baseline at Day 15	-28.1 (2.35)	-35.5 (2.30)
Meier: Change From Baseline at Day 21	-29.9 (2.42)	-37.0 (2.37)
Meier: Change From Baseline at Day 45	-31.5 (2.32)	-41.0 (2.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Core: Change from Baseline in HAM-D Subscale Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3832
	Comments	MMRM was used for estimation with treatment, baseline HAM-D subscale score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.1
	Confidence Interval	(2-Sided) 95%; -6.9 to 2.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.41
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Core: Change from Baseline in HAM-D Subscale Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0415
	Comments	MMRM was used for estimation with treatment, baseline HAM-D subscale score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-5.4
	Confidence Interval	(2-Sided) 95%; -10.5 to -0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.60
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Core: Change from Baseline in HAM-D Subscale Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0606
	Comments	MMRM was used for estimation with treatment, baseline HAM-D subscale score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-5.1
	Confidence Interval	(2-Sided) 95%; -10.5 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.71
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Core: Change from Baseline in HAM-D Subscale Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0318
	Comments	MMRM was used for estimation with treatment, baseline HAM-D subscale score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-6.3
	Confidence Interval	(2-Sided) 95%; -12.1 to -0.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.91
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Core: Change from Baseline in HAM-D Subscale Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0047
	Comments	MMRM was used for estimation with treatment, baseline HAM-D subscale score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-7.7
	Confidence Interval	(2-Sided) 95%; -13.0 to -2.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.69
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Anxiety: Change from Baseline in HAM-D Subscale Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0053
	Comments	MMRM was used for estimation with treatment, baseline HAM-D subscale score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-7.1
	Confidence Interval	(2-Sided) 95%; -12.0 to -2.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.50
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Anxiety: Change from Baseline in HAM-D Subscale Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0181
	Comments	MMRM was used for estimation with treatment, baseline HAM-D subscale score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-6.6
	Confidence Interval	(2-Sided) 95%; -12.1 to -1.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.76
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Anxiety: Change from Baseline in HAM-D Subscale Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0007
	Comments
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-9.8
	Confidence Interval	(2-Sided) 95%; -15.3 to -4.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.82
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Anxiety: Change from Baseline in HAM-D Subscale Score at Day 21
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0332
	Comments
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-6.0
	Confidence Interval	(2-Sided) 95%; -11.5 to -0.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.79
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Anxiety: Change from Baseline in HAM-D Subscale Score at Day 45
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0048
	Comments	MMRM was used for estimation with treatment, baseline HAM-D subscale score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-8.0
	Confidence Interval	(2-Sided) 95%; -13.5 to -2.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.80
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Bech-6: Change from Baseline in HAM-D Subscale Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1840
	Comments	MMRM was used for estimation with treatment, baseline HAM-D subscale score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.2
	Confidence Interval	(2-Sided) 95%; -10.3 to 2.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.12
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Bech-6: Change from Baseline in HAM-D Subscale Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0462
	Comments	MMRM was used for estimation with treatment, baseline HAM-D subscale score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-6.7
	Confidence Interval	(2-Sided) 95%; -13.2 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.31
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Bech-6: Change from Baseline in HAM-D Subscale Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0150
	Comments	MMRM was used for estimation with treatment, baseline HAM-D subscale score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-8.3
	Confidence Interval	(2-Sided) 95%; -14.9 to -1.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.36
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Bech-6: Change from Baseline in HAM-D Subscale Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0245
	Comments	MMRM was used for estimation with treatment, baseline HAM-D subscale score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-8.0
	Confidence Interval	(2-Sided) 95%; -15.0 to -1.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.53
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Bech-6: Change from Baseline in HAM-D Subscale Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0054
	Comments	MMRM was used for estimation with treatment, baseline HAM-D subscale score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-9.4
	Confidence Interval	(2-Sided) 95%; -16.0 to -2.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.34
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Meier: Change from Baseline in HAM-D Subscale Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0972
	Comments	MMRM was used for estimation with treatment, baseline HAM-D subscale score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.6
	Confidence Interval	(2-Sided) 95%; -10.1 to 0.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.77
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Meier: Change from Baseline in HAM-D Subscale Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0155
	Comments	MMRM was used for estimation with treatment, baseline HAM-D subscale score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-7.2
	Confidence Interval	(2-Sided) 95%; -13.1 to -1.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.95
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Meier: Change from Baseline in HAM-D Subscale Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0149
	Comments	MMRM was used for estimation with treatment, baseline HAM-D subscale score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-7.5
	Confidence Interval	(2-Sided) 95%; -13.4 to -1.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.03
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Meier: Change from Baseline in HAM-D Subscale Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0250
	Comments	MMRM was used for estimation with treatment, baseline HAM-D subscale score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-7.1
	Confidence Interval	(2-Sided) 95%; -13.3 to -0.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.14
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo
	Comments	Meier: Change from Baseline in HAM-D Subscale Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0017
	Comments	MMRM was used for estimation with treatment, baseline HAM-D subscale score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-9.5
	Confidence Interval	(2-Sided) 95%; -15.3 to -3.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.96
	Estimation Comments

6. Secondary Outcome

Title	Parts A and B: Change From Baseline in HAM-D Individual Item Scores
Description	The 17-item HAM-D is used to rate the severity of depression in participants who are already diagnosed as depressed. Individual items on the scale were scored in a range of 0 to 2 or 0 to 4. Symptoms scored in a range of 0 to 2: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following symptoms were 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. Higher scores indicated a greater degree of depression. A negative change from Baseline indicates less depression.
Time Frame	Part B: Baseline, Days 3, 8, 15, 21 and 45

Outcome Measure Data

Analysis Population Description

Only 1 participant was enrolled and treated in the Part A: SAGE-217 15/20 mg Oral Solution arm group and due to low number of participants, no efficacy analyses were conducted for Part A of the study. Part B: Efficacy Set included all participants who were administered study drug, had a valid Baseline and at least 1 post-baseline efficacy assessment.

Arm/Group Title	Part A: SAGE-217 15/20 mg Oral Solution	Part B: Placebo	Part B: SAGE 217 30 mg Capsules
Arm/Group Description	Participants received SAGE-217, 15 mg, oral solution, BID for first 2 days followed by SAGE-217, 15 or 20 mg, oral solution, BID, starting on Day 3 for up to 14 days as tolerated.	Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.
Measure Participants	0	74	76
Depressed Mood: Change From Baseline at Day 3	-0.8 (0.13)	-1.1 (0.13)
Depressed Mood: Change From Baseline at Day 8	-1.3 (0.14)	-1.7 (0.13)
Depressed Mood: Change From Baseline at Day 15	-1.5 (0.15)	-1.8 (0.13)
Depressed Mood: Change From Baseline at Day 21	-1.5 (0.14)	-2.1 (0.13)
Depressed Mood: Change From Baseline at Day 45	-1.7 (0.15)	-2.1 (0.12)
Feelings of Guilt: Change From Baseline at Day 3	-0.9 (0.12)	-1.0 (0.13)
Feelings of Guilt: Change From Baseline at Day 8	-1.1 (0.13)	-1.4 (0.12)
Feelings of Guilt: Change From Baseline at Day 15	-1.3 (0.13)	-1.5 (0.11)
Feelings of Guilt: Change From Baseline at Day 21	-1.2 (0.13)	-1.6 (0.12)
Feelings of Guilt: Change From Baseline at Day 45	-1.5 (0.12)	-1.8 (0.11)
Suicide: Change From Baseline at Day 3	-0.2 (0.05)	-0.3 (0.04)
Suicide: Change From Baseline at Day 8	-0.2 (0.04)	-0.4 (0.03)
Suicide: Change From Baseline at Day 15	-0.3 (0.04)	-0.3 (0.04)
Suicide: Change From Baseline at Day 21	-0.2 (0.05)	-0.3 (0.05)
Suicide: Change From Baseline at Day 45	-0.2 (0.05)	-0.4 (0.03)
Insomnia Early - Early Night: Change From Baseline at Day 3	-0.9 (0.11)	-1.2 (0.10)
Insomnia Early - Early Night: Change From Baseline at Day 8	-0.9 (0.11)	-1.3 (0.10)
Insomnia Early - Early Night: Change From Baseline at Day 15	-0.9 (0.11)	-1.3 (0.10)
Insomnia Early - Early Night: Change From Baseline at Day 21	-0.9 (0.11)	-1.1 (0.10)
Insomnia Early - Early Night: Change From Baseline at Day 45	-1.0 (0.12)	-1.1 (0.11)
Insomnia Middle - Middle Night: Change From Baseline at Day 3	-1.0 (0.11)	-1.3 (0.10)
Insomnia Middle - Middle Night: Change From Baseline at Day 8	-1.0 (0.11)	-1.3 (0.09)
Insomnia Middle - Middle Night: Change From Baseline at Day 15	-0.9 (0.11)	-1.3 (0.09)
Insomnia Middle - Middle Night: Change From Baseline at Day 21	-0.8 (0.11)	-1.2 (0.09)
Insomnia Middle - Middle Night: Change From Baseline at Day 45	-0.9 (0.11)	-1.3 (0.10)
Insomnia Early Hours - Morning: Change From Baseline at Day 3	-0.8 (0.11)	-1.1 (0.10)
Insomnia Early Hours - Morning: Change From Baseline at Day 8	-0.9 (0.10)	-1.2 (0.09)
Insomnia Early Hours - Morning: Change From Baseline at Day 15	-1.0 (0.11)	-1.2 (0.09)
Insomnia Early Hours - Morning: Change From Baseline at Day 21	-0.9 (0.11)	-1.0 (0.10)
Insomnia Early Hours - Morning: Change From Baseline at Day 45	-0.9 (0.10)	-1.3 (0.08)
Work and Activities: Change From Baseline at Day 3	-0.8 (0.12)	-0.9 (0.13)
Work and Activities: Change From Baseline at Day 8	-1.3 (0.14)	-1.4 (0.14)
Work and Activities: Change From Baseline at Day 15	-1.4 (0.14)	-1.8 (0.13)
Work and Activities: Change From Baseline at Day 21	-1.7 (0.16)	-1.9 (0.14)
Work and Activities: Change From Baseline at Day 45	-1.7 (0.16)	-2.1 (0.14)
Retardation: Change From Baseline at Day 3	-0.5 (0.07)	-0.4 (0.10)
Retardation: Change From Baseline at Day 8	-0.7 (0.08)	-0.8 (0.07)
Retardation: Change From Baseline at Day 15	-0.8 (0.07)	-0.8 (0.07)
Retardation: Change From Baseline at Day 21	-0.8 (0.08)	-0.8 (0.07)
Retardation: Change From Baseline at Day 45	-0.9 (0.07)	-1.0 (0.07)
Agitation: Change From Baseline at Day 3	-0.4 (0.09)	-0.7 (0.09)
Agitation: Change From Baseline at Day 8	-0.6 (0.09)	-0.9 (0.08)
Agitation: Change From Baseline at Day 15	-0.6 (0.09)	-0.9 (0.09)
Agitation: Change From Baseline at Day 21	-0.8 (0.09)	-0.9 (0.08)
Agitation: Change From Baseline at Day 45	-0.8 (0.09)	-1.1 (0.07)
Anxiety Psychic: Change From Baseline at Day 3	-0.7 (0.12)	-1.1 (0.13)
Anxiety Psychic: Change From Baseline at Day 8	-1.1 (0.14)	-1.5 (0.13)
Anxiety Psychic: Change From Baseline at Day 15	-1.2 (0.13)	-1.6 (0.13)
Anxiety Psychic: Change From Baseline at Day 21	-1.3 (0.14)	-1.6 (0.12)
Anxiety Psychic: Change From Baseline at Day 45	-1.3 (0.14)	-1.7 (0.12)
Anxiety Somatic: Change From Baseline at Day 3	-0.6 (0.10)	-0.7 (0.10)
Anxiety Somatic: Change From Baseline at Day 8	-0.7 (0.10)	-0.9 (0.10)
Anxiety Somatic: Change From Baseline at Day 15	-0.8 (0.11)	-0.9 (0.10)
Anxiety Somatic: Change From Baseline at Day 21	-0.9 (0.11)	-1.0 (0.11)
Anxiety Somatic: Change From Baseline at Day 45	-0.8 (0.11)	-1.0 (0.10)
Somatic Symptoms Gastrointestinal: Change From Baseline at Day 3	-0.3 (0.09)	-0.6 (0.10)
Somatic Symptoms Gastrointestinal: Change From Baseline at Day 8	-0.6 (0.10)	-0.8 (0.09)
Somatic Symptoms Gastrointestinal: Change From Baseline at Day 15	-0.7 (0.11)	-1.0 (0.08)
Somatic Symptoms Gastrointestinal: Change From Baseline at Day 21	-0.8 (0.11)	-0.9 (0.09)
Somatic Symptoms Gastrointestinal: Change From Baseline at Day 45	-0.8 (0.10)	-1.0 (0.09)
General Somatic Symptoms: Change From Baseline at Day 3	-0.6 (0.08)	-0.7 (0.09)
General Somatic Symptoms: Change From Baseline at Day 8	-0.8 (0.09)	-0.9 (0.09)
General Somatic Symptoms: Change From Baseline at Day 15	-0.6 (0.08)	-1.1 (0.09)
General Somatic Symptoms: Change From Baseline at Day 21	-0.7 (0.10)	-1.0 (0.08)
General Somatic Symptoms: Change From Baseline at Day 45	-0.8 (0.09)	-1.0 (0.09)
Genital Symptoms: Change From Baseline at Day 3	-0.3 (0.08)	-0.4 (0.09)
Genital Symptoms: Change From Baseline at Day 8	-0.6 (0.10)	-0.6 (0.09)
Genital Symptoms: Change From Baseline at Day 15	-0.7 (0.10)	-0.9 (0.10)
Genital Symptoms: Change From Baseline at Day 21	-0.7 (0.10)	-0.8 (0.10)
Genital Symptoms: Change From Baseline at Day 45	-0.8 (0.10)	-1.0 (0.10)
Hypochondriasis: Change From Baseline at Day 3	-0.5 (0.09)	-0.7 (0.08)
Hypochondriasis: Change From Baseline at Day 8	-0.6 (0.08)	-0.8 (0.07)
Hypochondriasis: Change From Baseline at Day 15	-0.5 (0.10)	-1.0 (0.06)
Hypochondriasis: Change From Baseline at Day 21	-0.6 (0.08)	-0.9 (0.06)
Hypochondriasis: Change From Baseline at Day 45	-0.7 (0.09)	-0.9 (0.07)
Loss of Weight According to Patient: Change From Baseline at Day 3	-0.3 (0.08)	-0.5 (0.07)
Loss of Weight According to Patient: Change From Baseline at Day 8	-0.4 (0.07)	-0.5 (0.07)
Loss of Weight According to Patient: Change From Baseline at Day 15	-0.5 (0.07)	-0.5 (0.06)
Loss of Weight According to Patient: Change From Baseline at Day 21	-0.6 (0.06)	-0.6 (0.05)
Loss of Weight According to Patient: Change From Baseline at Day 45	-0.5 (0.08)	-0.6 (0.05)
Insight: Change From Baseline at Day 3	0.0 (0.02)	-0.1 (0.02)
Insight: Change From Baseline at Day 8	0.0 (0.02)	-0.1 (0.02)
Insight: Change From Baseline at Day 15	0.0 (0.02)	-0.1 (0.02)
Insight: Change From Baseline at Day 21	0.0 (0.02)	-0.1 (0.02)
Insight: Change From Baseline at Day 45	0.0 (0.04)	-0.1 (0.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Depressed Mood: Change From Baseline in HAM-D Individual Item Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1569
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.16
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Depressed Mood: Change From Baseline in HAM-D Individual Item Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0376
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.7 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.18
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Depressed Mood: Change From Baseline in HAM-D Individual Item Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1035
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.6 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.18
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Depressed Mood: Change From Baseline in HAM-D Individual Item Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0037
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -0.9 to -0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.18
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Depressed Mood: Change From Baseline in HAM-D Individual Item Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0061
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -0.8 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.18
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Feelings of Guilt: Change From Baseline in HAM-D Individual Item Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7878
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.16
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Feelings of Guilt: Change From Baseline in HAM-D Individual Item Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0498
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.6 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.16
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Feelings of Guilt: Change From Baseline in HAM-D Individual Item Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1719
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.16
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Feelings of Guilt: Change From Baseline in HAM-D Individual Item Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0161
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.7 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.16
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Feelings of Guilt: Change From Baseline in HAM-D Individual Item Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0191
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.6 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.15
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Suicide: Change From Baseline in HAM-D Individual Item Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2537
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.06
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Suicide: Change From Baseline in HAM-D Individual Item Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0018
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.04
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Suicide: Change From Baseline in HAM-D Individual Item Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2878
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.05
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Suicide: Change From Baseline in HAM-D Individual Item Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2594
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.07
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Suicide: Change From Baseline in HAM-D Individual Item Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0086
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.3 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.06
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insomnia Early - Early Night: Change From Baseline in HAM-D Individual Item Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0424
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.6 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.14
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insomnia Early - Early Night: Change From Baseline in HAM-D Individual Item Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0207
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.6 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.14
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insomnia Early - Early Night: Change From Baseline in HAM-D Individual Item Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0010
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -0.7 to -0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.14
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insomnia Early - Early Night: Change From Baseline in HAM-D Individual Item Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0871
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.14
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insomnia Early - Early Night: Change From Baseline in HAM-D Individual Item Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5680
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.15
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insomnia Middle - Middle Night: Change From Baseline in HAM-D Individual Item Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0143
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.6 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.14
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insomnia Middle - Middle Night: Change From Baseline in HAM-D Individual Item Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0063
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.6 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.13
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insomnia Middle - Middle Night: Change From Baseline in HAM-D Individual Item Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0042
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.6 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.13
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insomnia Middle - Middle Night: Change From Baseline in HAM-D Individual Item Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0137
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.6 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.13
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insomnia Middle - Middle Night: Change From Baseline in HAM-D Individual Item Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0099
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.6 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.14
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insomnia Early Hours - Morning: Change From Baseline in HAM-D Individual Item Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0507
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.14
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insomnia Early Hours - Morning: Change From Baseline in HAM-D Individual Item Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0205
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.13
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insomnia Early Hours - Morning: Change From Baseline in HAM-D Individual Item Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1409
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.13
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insomnia Early Hours - Morning: Change From Baseline in HAM-D Individual Item Score at Day 21
	Type of Statistical Test	Superiority
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
Statistical Test of Hypothesis	p-Value	0.2021
	Comments
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.14
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insomnia Early Hours - Morning: Change From Baseline in HAM-D Individual Item Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0117
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.6 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Work and Activities: Change From Baseline in HAM-D Individual Item Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5511
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.15
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Work and Activities: Change From Baseline in HAM-D Individual Item Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4949
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.18
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Work and Activities: Change From Baseline in HAM-D Individual Item Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0203
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.7 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.17
	Estimation Comments

Statistical Analysis 34

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Work and Activities: Change From Baseline in HAM-D Individual Item Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2076
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.6 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.19
	Estimation Comments

Statistical Analysis 35

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Work and Activities: Change From Baseline in HAM-D Individual Item Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0362
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.8 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.19
	Estimation Comments

Statistical Analysis 36

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Retardation: Change From Baseline in HAM-D Individual Item Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3589
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 37

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Retardation: Change From Baseline in HAM-D Individual Item Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6991
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments

Statistical Analysis 38

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Retardation: Change From Baseline in HAM-D Individual Item Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9655
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments

Statistical Analysis 39

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Retardation: Change From Baseline in HAM-D Individual Item Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8699
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments

Statistical Analysis 40

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Retardation: Change From Baseline in HAM-D Individual Item Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3715
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.3 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.09
	Estimation Comments

Statistical Analysis 41

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Agitation: Change From Baseline in HAM-D Individual Item Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0670
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 42

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Agitation: Change From Baseline in HAM-D Individual Item Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0104
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.5 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments

Statistical Analysis 43

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Agitation: Change From Baseline in HAM-D Individual Item Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0122
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.5 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 44

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Agitation: Change From Baseline in HAM-D Individual Item Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3157
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.3 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 45

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Agitation: Change From Baseline in HAM-D Individual Item Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0077
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.5 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments

Statistical Analysis 46

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Anxiety Psychic: Change From Baseline in HAM-D Individual Item Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0078
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.8 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.16
	Estimation Comments

Statistical Analysis 47

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Anxiety Psychic: Change From Baseline in HAM-D Individual Item Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0372
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.7 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.18
	Estimation Comments

Statistical Analysis 48

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Anxiety Psychic: Change From Baseline in HAM-D Individual Item Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0244
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.7 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.17
	Estimation Comments

Statistical Analysis 49

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Anxiety Psychic: Change From Baseline in HAM-D Individual Item Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0993
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.6 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.17
	Estimation Comments

Statistical Analysis 50

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Anxiety Psychic: Change From Baseline in HAM-D Individual Item Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0185
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.7 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.17
	Estimation Comments

Statistical Analysis 51

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Anxiety Somatic: Change From Baseline in HAM-D Individual Item Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2471
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 52

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Anxiety Somatic: Change From Baseline in HAM-D Individual Item Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1076
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.14
	Estimation Comments

Statistical Analysis 53

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Anxiety Somatic: Change From Baseline in HAM-D Individual Item Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2782
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.14
	Estimation Comments

Statistical Analysis 54

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Anxiety Somatic: Change From Baseline in HAM-D Individual Item Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4646
	Comments
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.15
	Estimation Comments

Statistical Analysis 55

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Anxiety Somatic: Change From Baseline in HAM-D Individual Item Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1600
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.14
	Estimation Comments

Statistical Analysis 56

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Somatic Symptoms Gastrointestinal: Change From Baseline in HAM-D Individual Item Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0474
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 57

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Somatic Symptoms Gastrointestinal: Change From Baseline in HAM-D Individual Item Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0446
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 58

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Somatic Symptoms Gastrointestinal: Change From Baseline in HAM-D Individual Item Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0093
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.6 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 59

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Somatic Symptoms Gastrointestinal: Change From Baseline in HAM-D Individual Item Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2998
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 60

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Somatic Symptoms Gastrointestinal: Change From Baseline in HAM-D Individual Item Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0545
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 61

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	General Somatic Symptoms: Change From Baseline in HAM-D Individual Item Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2177
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 62

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	General Somatic Symptoms: Change From Baseline in HAM-D Individual Item Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2300
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 63

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	General Somatic Symptoms: Change From Baseline in HAM-D Individual Item Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.7 to -0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 64

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	General Somatic Symptoms: Change From Baseline in HAM-D Individual Item Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0151
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.5 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 65

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	General Somatic Symptoms: Change From Baseline in HAM-D Individual Item Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0502
	Comments
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.13
	Estimation Comments

Statistical Analysis 66

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Genital Symptoms: Change From Baseline in HAM-D Individual Item Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3659
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.3 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments

Statistical Analysis 67

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Genital Symptoms: Change From Baseline in HAM-D Individual Item Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6003
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.3 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 68

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Genital Symptoms: Change From Baseline in HAM-D Individual Item Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0785
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.13
	Estimation Comments

Statistical Analysis 69

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Genital Symptoms: Change From Baseline in HAM-D Individual Item Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3668
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.13
	Estimation Comments

Statistical Analysis 70

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Genital Symptoms: Change From Baseline in HAM-D Individual Item Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1827
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.13
	Estimation Comments

Statistical Analysis 71

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Hypochondriasis: Change From Baseline in HAM-D Individual Item Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1327
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 72

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Hypochondriasis: Change From Baseline in HAM-D Individual Item Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0993
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments

Statistical Analysis 73

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Hypochondriasis: Change From Baseline in HAM-D Individual Item Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.6 to -0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments

Statistical Analysis 74

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Hypochondriasis: Change From Baseline in HAM-D Individual Item Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0056
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.5 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments

Statistical Analysis 75

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Hypochondriasis: Change From Baseline in HAM-D Individual Item Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0122
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.5 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments

Statistical Analysis 76

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Loss of Weight According to Patient: Change From Baseline in HAM-D Individual Item Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1305
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.3 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments

Statistical Analysis 77

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Loss of Weight According to Patient: Change From Baseline in HAM-D Individual Item Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6638
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.09
	Estimation Comments

Statistical Analysis 78

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Loss of Weight According to Patient: Change From Baseline in HAM-D Individual Item Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4341
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.08
	Estimation Comments

Statistical Analysis 79

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Loss of Weight According to Patient: Change From Baseline in HAM-D Individual Item Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9085
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.07
	Estimation Comments

Statistical Analysis 80

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Loss of Weight According to Patient: Change From Baseline in HAM-D Individual Item Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1820
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.3 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.09
	Estimation Comments

Statistical Analysis 81

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insight: Change From Baseline in HAM-D Individual Item Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1593
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.03
	Estimation Comments

Statistical Analysis 82

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insight: Change From Baseline in HAM-D Individual Item Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6555
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.03
	Estimation Comments

Statistical Analysis 83

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insight: Change From Baseline in HAM-D Individual Item Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0170
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.03
	Estimation Comments

Statistical Analysis 84

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insight: Change From Baseline in HAM-D Individual Item Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0188
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.03
	Estimation Comments

Statistical Analysis 85

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Insight: Change From Baseline in HAM-D Individual Item Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0726
	Comments	MMRM was used for estimation with treatment, baseline HAM-D individual item score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.05
	Estimation Comments

7. Secondary Outcome

Title	Parts A and B: Change From Baseline in Montgomery and Åsberg Depression Rating Scale (MADRS) Total Score
Description	The MADRS is a 10-item questionnaire used to measure the severity of depressive episodes in participants with mood disorders. It includes questions on the following symptoms: apparent sadness; reported sadness; inner tension; reduced sleep; reduced appetite; concentration difficulties; lassitude; inability to feel; pessimistic thoughts; and suicidal thoughts. Each item was scored in a range of 0 (no symptoms) to 6 (symptoms of maximum severity). The MADRS total score was calculated as the sum of the 10 individual item scores and could range from 0 to 60. Higher scores indicated more severe depression. A negative change from Baseline indicates less depression.
Time Frame	Part B: Baseline, Days 3, 8, 15, 21 and 45

Outcome Measure Data

Analysis Population Description

Only 1 participant was enrolled and treated in the Part A: SAGE-217 15/20 mg Oral Solution arm group and due to low number of participants, no efficacy analyses were conducted for Part A of the study. Part B: Efficacy Set included all participants who were administered study drug, had a valid Baseline and at least 1 post-baseline efficacy assessment.

Arm/Group Title	Part A: SAGE-217 15/20 mg Oral Solution	Part B: Placebo	Part B: SAGE 217 30 mg Capsules
Arm/Group Description	Participants received SAGE-217, 15 mg, oral solution, BID for first 2 days followed by SAGE-217, 15 or 20 mg, oral solution, BID, starting on Day 3 for up to 14 days as tolerated.	Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.
Measure Participants	0	74	76
Change From Baseline at Day 3	-11.7 (1.36)	-14.8 (1.33)
Change From Baseline at Day 8	-16.3 (1.45)	-20.3 (1.42)
Change From Baseline at Day 15	-17.6 (1.48)	-22.1 (1.45)
Change From Baseline at Day 21	-17.8 (1.49)	-22.1 (1.46)
Change From Baseline at Day 45	-19.0 (1.44)	-24.8 (1.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Change From Baseline in MADRS Total Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0791
	Comments	MMRM was used for estimation with treatment with treatment, baseline MADRS total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-3.0
	Confidence Interval	(2-Sided) 95%; -6.5 to 0.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.72
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Change From Baseline in MADRS Total Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0322
	Comments	MMRM was used for estimation with treatment with treatment, baseline MADRS total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.0
	Confidence Interval	(2-Sided) 1.86%; -7.7 to -0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.86
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Change From Baseline in MADRS Total Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0180
	Comments	MMRM was used for estimation with treatment with treatment, baseline MADRS total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.6
	Confidence Interval	(2-Sided) 95%; -8.3 to -0.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.91
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Change from Baseline in MADRS Total Score at 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0271
	Comments	MMRM was used for estimation with treatment with treatment, baseline MADRS total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.3
	Confidence Interval	(2-Sided) 95%; -8.1 to -0.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.92
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Change from Baseline in MADRS Total Score at 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0018
	Comments	MMRM was used for estimation with treatment with treatment, baseline MADRS total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-5.8
	Confidence Interval	(2-Sided) 95%; -9.4 to -2.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.82
	Estimation Comments

8. Secondary Outcome

Title	Parts A and B: Percentage of Participants With Clinical Global Impression - Improvement (CGI-I) Response
Description	The Clinical Global Impression - Improvement (CGI-I) item of the CGI scale uses a 7-point Likert scale to measure the overall improvement in the participant's condition posttreatment. The investigator rated the participant's total improvement whether or not it was due entirely to drug treatment. Response choices included: 0=not assessed, 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse. CGI response was defined as a CGI-I score of 1 (very much improved) or 2 (much improved). The percentage of participants with overall improvement in post-treatment condition, rated by investigator as very much improved (CGI-I score of 1) or much improved (CGI-I score of 2) is reported.
Time Frame	Part B: Days 3, 8, 15, 21 and 45

Outcome Measure Data

Analysis Population Description

Only 1 participant was enrolled and treated in the Part A: SAGE-217 15/20 mg Oral Solution arm group and due to low number of participants, no efficacy analyses were conducted for Part A of the study. Part B: Efficacy Set included all participants who were administered study drug, had a valid Baseline and at least 1 post-baseline efficacy assessment. Here, 'number analyzed' signifies participants evaluable for this outcome measure at specified time points.

Arm/Group Title	Part A: SAGE-217 15/20 mg Oral Solution	Part B: Placebo	Part B: SAGE 217 30 mg Capsules
Arm/Group Description	Participants received SAGE-217, 15 mg, oral solution, BID for first 2 days followed by SAGE-217, 15 or 20 mg, oral solution, BID, starting on Day 3 for up to 14 days as tolerated.	Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.
Measure Participants	0	74	76
Day 3	28.4 2840%	37.8 51.1%
Day 8	50.0 5000%	65.3 88.2%
Day 15	52.1 5210%	71.6 96.8%
Day 21	54.8 5480%	70.3 95%
Day 45	55.9 5590%	71.2 96.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With CGI-I Response at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3372
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline CGI-S score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.40
	Confidence Interval	(2-Sided) 95%; 0.70 to 2.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With CGI-I Response at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0935
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline CGI-S score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.77
	Confidence Interval	(2-Sided) 95%; 0.91 to 3.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With CGI-I Response at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0276
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline CGI-S score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.16
	Confidence Interval	(2-Sided) 95%; 1.09 to 4.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With CGI-I Response at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0920
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment: Baseline CGI-S score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.79
	Confidence Interval	(2-Sided) 95%; 0.91 to 3.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With CGI-I Response at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1109
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline CGI-S score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.76
	Confidence Interval	(2-Sided) 95%; 0.88 to 3.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Parts A and B: Change From Baseline in Hamilton Anxiety Rating Scale (HAM-A) Total Score
Description	The 14-item HAM-A was used to rate the severity of symptoms of anxiety. Each of the 14 items was defined by a series of symptoms and measured both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). The individual items were scored in a range of 0 (not present) to 4 (very severe). The HAM-A total score was calculated as the sum of the 14 individual item scores and could range from 0 to 56 where a score of <17=mild severity; 18-24= mild to moderate severity and 25-30=moderate to severe severity. A negative change from Baseline indicates less anxiety.
Time Frame	Part B: Baseline, Days 3, 8, 15, 21 and 45

Outcome Measure Data

Analysis Population Description

Only 1 participant was enrolled and treated in the Part A: SAGE-217 15/20 mg Oral Solution arm group and due to low number of participants, no efficacy analyses were conducted for Part A of the study. Part B: Efficacy Set included all participants who were administered study drug, had a valid Baseline and at least 1 post-baseline efficacy assessment.

Arm/Group Title	Part A: SAGE-217 15/20 mg Oral Solution	Part B: Placebo	Part B: SAGE 217 30 mg Capsules
Arm/Group Description	Participants received SAGE-217, 15 mg, oral solution, BID for first 2 days followed by SAGE-217, 15 or 20 mg, oral solution, BID, starting on Day 3 for up to 14 days as tolerated.	Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.
Measure Participants	0	74	76
Change From Baseline at Day 3	-8.9 (1.02)	-12.0 (0.99)
Change From Baseline at Day 8	-11.7 (1.04)	-16.1 (1.01)
Change From Baseline at Day 15	-12.7 (1.09)	-16.6 (1.07)
Change From Baseline at Day 21	-13.1 (1.07)	-16.6 (1.05)
Change From Baseline at Day 45	-13.6 (1.02)	-18.6 (0.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Change from Baseline in HAM-A Total Score at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0169
	Comments	MMRM was used for estimation with treatment, baseline HAM-A total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-3.1
	Confidence Interval	(2-Sided) 95%; -5.7 to -0.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.29
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Change from Baseline in HAM-A Total Score at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0010
	Comments	MMRM was used for estimation with treatment, baseline HAM-A total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.4
	Confidence Interval	(2-Sided) 95%; -7.0 to -1.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.32
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Change from Baseline in HAM-A Total Score at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0063
	Comments	MMRM was used for estimation with treatment, baseline HAM-A total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-3.9
	Confidence Interval	(2-Sided) 95%; -6.7 to -1.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.41
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Change from Baseline in HAM-A Total Score at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0119
	Comments	MMRM was used for estimation with treatment, baseline HAM-A total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-3.5
	Confidence Interval	(2-Sided) 95%; -6.2 to -0.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.37
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Change from Baseline in HAM-A Total Score at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	MMRM was used for estimation with treatment, baseline HAM-A total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction as fixed effects.
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-5.0
	Confidence Interval	(2-Sided) 95%; -7.5 to -2.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.28
	Estimation Comments

10. Secondary Outcome

Title	Parts A and B: Percentage of Participants With MADRS Response
Description	MADRS response was defined as having a 50% or greater reduction from Baseline in MADRS total score. The MADRS is a 10-item questionnaire used to measure the severity of depressive episodes in participants with mood disorders. It includes questions on the following symptoms: apparent sadness; reported sadness; inner tension; reduced sleep; reduced appetite; concentration difficulties; lassitude; inability to feel; pessimistic thoughts; and suicidal thoughts. Each item was scored in a range of 0 (no symptoms) to 6 (symptoms of maximum severity). The MADRS total score was calculated as the sum of the 10 individual item scores and could range from 0 to 60. Higher scores indicated more depression.
Time Frame	Part B: Days 3, 8, 15, 21 and 45

Outcome Measure Data

Analysis Population Description

Only 1 participant was enrolled and treated in the Part A: SAGE-217 15/20 mg Oral Solution arm group and due to low number of participants, no efficacy analyses were conducted for Part A of the study. Part B: Efficacy Set included all participants who were administered study drug, had a valid Baseline and at least 1 post-baseline efficacy assessment. Here, 'number analyzed' signifies participants evaluable for this outcome measure at specified time points.

Arm/Group Title	Part A: SAGE-217 15/20 mg Oral Solution	Part B: Placebo	Part B: SAGE 217 30 mg Capsules
Arm/Group Description	Participants received SAGE-217, 15 mg, oral solution, BID for first 2 days followed by SAGE-217, 15 or 20 mg, oral solution, BID, starting on Day 3 for up to 14 days as tolerated.	Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.
Measure Participants	0	74	76
Day 3	27.0 2700%	40.5 54.7%
Day 8	50.0 5000%	64.0 86.5%
Day 15	47.9 4790%	73.0 98.6%
Day 21	52.1 5210%	70.3 95%
Day 45	56.5 5650%	74.0 100%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With MADRS Response at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1145
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline MADRS total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.75
	Confidence Interval	(2-Sided) 95%; 0.87 to 3.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With MADRS Response at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1069
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline MADRS total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.71
	Confidence Interval	(2-Sided) 95%; 0.89 to 3.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With MADRS Response at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0045
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline MADRS total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.67
	Confidence Interval	(2-Sided) 95%; 1.36 to 5.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With MADRS Response at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0421
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline MADRS total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.01
	Confidence Interval	(2-Sided) 95%; 1.03 to 3.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With MADRS Response at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0541
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline MADRS total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.99
	Confidence Interval	(2-Sided) 95%; 0.99 to 4.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Parts A and B: Percentage of Participants With MADRS Remission
Description	MADRS Remission was defined as a MADRS total score of <=10. The MADRS is a 10-item questionnaire used to measure the severity of depressive episodes in participants with mood disorders. It includes questions on the following symptoms: apparent sadness; reported sadness; inner tension; reduced sleep; reduced appetite; concentration difficulties; lassitude; inability to feel; pessimistic thoughts; and suicidal thoughts. Each item was scored in a range of 0 (no symptoms) to 6 (symptoms of maximum severity). The MADRS total score was calculated as the sum of the 10 individual item scores and could range from 0 to 60. Higher scores indicated more depression.
Time Frame	Part B: Days 3, 8, 15, 21 and 45

Outcome Measure Data

Analysis Population Description

Only 1 participant was enrolled and treated in the Part A: SAGE-217 15/20 mg Oral Solution arm group and due to low number of participants, no efficacy analyses were conducted for Part A of the study. Part B: Efficacy Set included all participants who were administered study drug, had a valid baseline and at least 1 post-baseline efficacy assessment. Here, 'number analyzed' signifies participants evaluable for this outcome measure at specified time points.

Arm/Group Title	Part A: SAGE-217 15/20 mg Oral Solution	Part B: Placebo	Part B: SAGE 217 30 mg Capsules
Arm/Group Description	Participants received SAGE-217, 15 mg, oral solution, BID for first 2 days followed by SAGE-217, 15 or 20 mg, oral solution, BID, starting on Day 3 for up to 14 days as tolerated.	Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.
Measure Participants	0	74	76
Day 3	9.5 950%	24.3 32.8%
Day 8	28.4 2840%	37.3 50.4%
Day 15	30.1 3010%	54.1 73.1%
Day 21	31.5 3150%	52.7 71.2%
Day 45	37.7 3770%	58.9 79.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With MADRS Remission at Day 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0326
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline MADRS total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.84
	Confidence Interval	(2-Sided) 95%; 1.09 to 7.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With MADRS Remission at Day 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3749
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline MADRS total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.38
	Confidence Interval	(2-Sided) 95%; 0.68 to 2.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With MADRS Remission at Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0087
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline MADRS total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.49
	Confidence Interval	(2-Sided) 95%; 1.26 to 4.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With MADRS Remission at Day 21
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0257
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline MADRS total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.18
	Confidence Interval	(2-Sided) 95%; 1.10 to 4.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Part B: Placebo, Part B: SAGE 217 30 mg Capsules
	Comments	Percentage of Participants With MADRS Remission at Day 45
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0339
	Comments	Generalized estimating equations for binary response model was used for estimation with factors for treatment, baseline MADRS total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction.
	Method	GEE for binary response model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.08
	Confidence Interval	(2-Sided) 95%; 1.06 to 4.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Parts A and B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Description	An Adverse Event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE was defined as an AE with an onset that occurs after receiving study drug.
Time Frame	Part A: Up to Day 75; Part B: Up to Day 45

Outcome Measure Data

Analysis Population Description

Part A: All randomized participants; Part B: Safety Set included all participants who were administered study drug in Part B of the study and analyzed as per actual treatment received.

Arm/Group Title	Part A: SAGE-217 15/20 mg Oral Solution	Part B: Placebo	Part B: SAGE 217 30 mg Capsules
Arm/Group Description	Participants received SAGE-217, 15 mg, oral solution, BID for first 2 days followed by SAGE-217, 15 or 20 mg, oral solution, BID, starting on Day 3 for up to 14 days as tolerated.	Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.
Measure Participants	1	73	78
Count of Participants [Participants]	1 100%	38 51.4%	47 61.8%

13. Secondary Outcome

Title	Part B: Number of Participants With Potentially Clinically Significant Vital Sign Measurements
Description	Vital signs included assessments of supine and standing systolic blood pressure (SBP), supine and standing diastolic blood pressure (DBP), and heart rate.
Time Frame	Part B: From first dose of study drug up to 45 days

Outcome Measure Data

Analysis Population Description

Safety Set (Part B) included all participants who were administered study drug in Part B of the study and analyzed by treatment actually received.

Arm/Group Title	Part B: Placebo	Part B: SAGE 217 30 mg Capsules
Arm/Group Description	Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.
Measure Participants	73	78
Supine SBP: <90 millimeter of mercury (mmHg)	0 0%	3 4.1%
Supine SBP: Decrease From Baseline of >=30	2 200%	1 1.4%
Supine SBP: Increase From Baseline of >=30	1 100%	0 0%
Standing SBP: <90 mmHg	5 500%	4 5.4%
Standing SBP: Decrease From Baseline of >=30	4 400%	1 1.4%
Standing SBP: Increase From Baseline of >=30	1 100%	2 2.7%
Supine DBP: <50 mmHg	1 100%	1 1.4%
Supine DBP: Decrease From Baseline of >=20	5 500%	3 4.1%
Supine DBP: Increase From Baseline of >=20	1 100%	5 6.8%
Standing DBP: <50 mmHg	1 100%	1 1.4%
Standing DBP: >110 mmHg	0 0%	1 1.4%
Standing DBP: Decrease From Baseline of >=20	3 300%	7 9.5%
Standing DBP: Increase From Baseline of >=20	3 300%	4 5.4%

14. Secondary Outcome

Title	Part B: Number of Participants With Potentially Clinically Significant Laboratory Evaluations
Description	Laboratory tests included tests of Hematology, Chemistry, and Urinalysis.
Time Frame	Part B: From first dose of study drug up to 45 days

Outcome Measure Data

Analysis Population Description

Safety Set (Part B) included all participants who were administered study drug in Part B and analyzed by treatment actually received.

Arm/Group Title	Part B: Placebo	Part B: SAGE 217 30 mg Capsules
Arm/Group Description	Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.
Measure Participants	73	78
Hematology: Eosinophils >1.5 10^9/Liter(L)	0 0%	1 1.4%
Hematology: Hematocrit <0.359	11 1100%	8 10.8%
Hematology: Hematocrit >0.446	10 1000%	12 16.2%
Hematology: Hemoglobin <110 g/L	12 1200%	6 8.1%
Hematology: Leukocytes <2.5 10^9/L	2 200%	2 2.7%
Hematology: Neutrophils <1.5 10^9/L	15 1500%	11 14.9%
Serum Chemistry: Alanine Aminotransferase >3xUpper Limit of Normal Value (ULN)	1 100%	0 0%
Serum Chemistry: Calcium <2.0 millimoles (mmol)/L	0 0%	1 1.4%
Serum Chemistry: Chloride <90 mmol/L	1 100%	2 2.7%
Serum Chemistry: Glucose <2.8 mmol/L	0 0%	1 1.4%
Serum Chemistry: Glucose >13.9 mmol/L	0 0%	1 1.4%
Serum Chemistry: Phosphate >5 milligrams/deciliter (mg/dL)	2 200%	1 1.4%
Serum Chemistry: Potassium <3.5 mmol/L	0 0%	1 1.4%
Serum Chemistry: Potassium >5.2 mmol/L	6 600%	5 6.8%
Serum Chemistry: Sodium >145 mmol/L	3 300%	5 6.8%

15. Secondary Outcome

Title	Part B: Change From Baseline in Electrocardiogram (ECG) Parameter Heart Rate
Description	ECG parameters included assessment of the standard 12-lead ECG intervals: QT, QTcF, PR, RR, QRS, and heart rate. Heart rate was measured in terms of beats per minute. Change from Baseline in heart rate at specified time points were reported.
Time Frame	Part B: Baseline, Days 8, 15, and 21

Outcome Measure Data

Analysis Population Description

Safety Set (Part B) included all participants who were administered study drug in Part B and analyzed by treatment actually received. Here, 'number analyzed' signifies participants evaluable for this outcome measure at specified time points.

Arm/Group Title	Part B: Placebo	Part B: SAGE 217 30 mg Capsules
Arm/Group Description	Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.
Measure Participants	73	78
Baseline	68.2 (9.55)	69.9 (10.85)
Change From Baseline at Day 8	0.8 (9.91)	1.5 (12.62)
Change From Baseline at Day 15	-0.1 (8.16)	0.9 (12.69)
Change From Baseline at Day 21	2.5 (8.93)	-0.6 (11.33)

16. Secondary Outcome

Title	Part B: Change From Baseline in ECG Parameters-PR Interval, RR Interval, QRS Duration, QT Interval, QTcF Interval
Description	ECG parameters included assessment of the standard 12-lead ECG intervals: QT, QTcF, PR, RR, QRS, and heart rate. Change from Baseline in PR Interval, RR Interval, QRS Duration, QT Interval, QTcF Interval is reported.
Time Frame	Part B: Baseline, Days 8, 15, and 21

Outcome Measure Data

Analysis Population Description

Safety Set (Part B) included all participants who were administered study drug in Part B and analyzed by treatment actually received.

Arm/Group Title	Part B: Placebo	Part B: SAGE 217 30 mg Capsules
Arm/Group Description	Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.
Measure Participants	73	78
PR Interval: Baseline	151.4 (20.38)	151.7 (17.12)
PR Interval: Change From Baseline at Day 8	3.4 (26.97)	0.6 (11.95)
PR Interval: Change From Baseline at Day 15	1.1 (11.81)	0.8 (11.02)
PR Interval: Change From Baseline at Day 21	2.5 (14.66)	2.5 (11.82)
RR Interval: Baseline	892.2 (131.63)	871.6 (124.16)
RR Interval: Change From Baseline at Day 8	-9.9 (137.12)	-16.9 (149.42)
RR Interval: Change From Baseline at Day 15	-1.9 (107.37)	-8.4 (147.36)
RR Interval: Change From Baseline at Day 21	-32.0 (113.89)	13.9 (141.69)
QRS Duration: Baseline	87.3 (9.50)	90.2 (9.81)
QRS Duration: Change From Baseline at Day 8	0.0 (8.19)	-0.3 (6.98)
QRS Duration: Change From Baseline at Day 15	-0.7 (7.14)	-0.3 (6.69)
QRS Duration: Change From Baseline at Day 21	0.1 (7.58)	0.0 (6.84)
QT Interval: Baseline	395.1 (28.85)	393.0 (28.66)
QT Interval: Change From Baseline at Day 8	-5.5 (24.23)	-4.3 (29.89)
QT Interval: Change From Baseline at Day 15	-1.4 (22.96)	-2.7 (28.53)
QT Interval: Change From Baseline at Day 21	-5.9 (23.70)	0.1 (30.60)
QTcF Interval: Baseline	411.3 (20.92)	412.2 (18.83)
QTcF Interval: Change From Baseline at Day 8	-4.1 (15.80)	-1.7 (15.57)
QTcF Interval: Change From Baseline at Day 15	-1.2 (14.75)	-1.5 (14.94)
QTcF Interval: Change From Baseline at Day 21	-1.1 (19.39)	-1.8 (20.77)

17. Secondary Outcome

Title	Part B: Number of Participants With a Response of "Yes" to Any Suicidal Ideation or Suicidal Behaviors Item Using the Columbia Suicide Severity Rating Scale (C-SSRS)
Description	C-SSRS was used to assess the suicidality of participants during the study. The assessment included "yes" or "no" responses for 5 questions, each related to suicidal ideation (wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods, active suicidal ideation with some intent, active suicidal ideation with specific plan) and suicidal behavior (preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, suicide). Numeric ratings were provided for severity of ideation (if present), from 1 to 5, with 5 being the most severe. Number of participants with a response of 'yes' to any suicidal ideation or suicidal behavior item as measured by C-SSRS is reported.
Time Frame	Part B: Up to Day 45

Outcome Measure Data

Analysis Population Description

Safety Set (Part B) included all participants who were administered study drug in Part B and analyzed by treatment actually received.

Arm/Group Title	Part B: Placebo	Part B: SAGE 217 30 mg Capsules
Arm/Group Description	Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.	Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.
Measure Participants	73	78
Suicidal Ideation	13 1300%	6 8.1%
Suicidal Behavior	0 0%	0 0%

Adverse Events

Time Frame	Part A: Up to Day 75; Part B: Up to Day 45
Adverse Event Reporting Description	Part A: All randomized participants; Part B: Safety Set included all participants who were administered study drug in Part B of the study and analyzed as per actual treatment received.
Arm/Group Title	Part A: SAGE-217 15/20 mg Oral Solution		Part B: Placebo		Part B: SAGE 217 30 mg Capsules
Arm/Group Description	Participants received SAGE-217, 15 mg, oral solution, BID for first 2 days followed by SAGE-217, 15 or 20 mg, oral solution, BID, starting on Day 3 for up to 14 days as tolerated.		Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days.		Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.
All Cause Mortality
	Part A: SAGE-217 15/20 mg Oral Solution		Part B: Placebo		Part B: SAGE 217 30 mg Capsules
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/73 (0%)		0/78 (0%)
Serious Adverse Events
	Part A: SAGE-217 15/20 mg Oral Solution		Part B: Placebo		Part B: SAGE 217 30 mg Capsules
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		1/73 (1.4%)		1/78 (1.3%)
Gastrointestinal disorders
Pancreatitis	0/1 (0%)		1/73 (1.4%)		0/78 (0%)
Psychiatric disorders
Confusional state	0/1 (0%)		0/73 (0%)		1/78 (1.3%)
Other (Not Including Serious) Adverse Events
	Part A: SAGE-217 15/20 mg Oral Solution		Part B: Placebo		Part B: SAGE 217 30 mg Capsules
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		26/73 (35.6%)		31/78 (39.7%)
Gastrointestinal disorders
Diarrhoea	0/1 (0%)		2/73 (2.7%)		5/78 (6.4%)
Nausea	0/1 (0%)		6/73 (8.2%)		3/78 (3.8%)
Vomiting	0/1 (0%)		4/73 (5.5%)		1/78 (1.3%)
Infections and infestations
Upper respiratory tract infection	0/1 (0%)		1/73 (1.4%)		6/78 (7.7%)
Nervous system disorders
Somnolence	0/1 (0%)		8/73 (11%)		12/78 (15.4%)
Headache	0/1 (0%)		9/73 (12.3%)		7/78 (9%)
Dizziness	0/1 (0%)		4/73 (5.5%)		6/78 (7.7%)
Sedation	0/1 (0%)		0/73 (0%)		4/78 (5.1%)
Psychiatric disorders
Abnormal dreams	0/1 (0%)		4/73 (5.5%)		0/78 (0%)
Insomnia	1/1 (100%)		0/73 (0%)		0/78 (0%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	0/1 (0%)		4/73 (5.5%)		0/78 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The PI can either be a party and subject to the same restrictions as the institution, or if not a party, the restrictions are described on the face of the contract (i.e., PI is a contractor of the institution; PI is part of a larger group of study personnel; institution has contracted with or otherwise bound all study personnel under confidentiality obligations and requirements to vest intellectual property to the institution).