A Study to Evaluate Safety and Efficacy of SAGE-547 in Participants With Moderate Postpartum Depression (547-PPD-202C)

• Sponsor: Sage Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02942017
• Collaborator: (none)
• Enrollment: 108
• Locations: 32
• Arms: 2
• Duration (Months): 15.3
• Patients Per Site: 3.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study was to determine if SAGE-547 Injection infused intravenously at up to 90 μg/kg/h for 60 hours reduces depressive symptoms in participants with moderate postpartum depression (PPD) compared to placebo injection as assessed by the change from baseline in Hamilton Rating Scale for Depression (HAM-D) total score.

Condition or Disease	Intervention/Treatment	Phase
Postpartum Depression	Drug: Placebo; Drug: SAGE-547 90 μg/kg/h	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 108 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-547 Injection in the Treatment of Adult Female Subjects With Severe Postpartum Depression and Adult Female Subjects With Moderate Postpartum Depression
• Study Start Date: Jul 1, 2016
• Actual Primary Completion Date: Sep 17, 2017
• Actual Study Completion Date: Oct 11, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants received an infusion rate equivalent to the 90 micrograms per kilogram per hour (μg/kg/h) group.	Drug: Placebo; Intravenous infusion of matching placebo for SAGE-547.
Experimental: SAGE-547 90 μg/kg/h Participants received a 4-hour dose titration period of 30 μg/kg/h (0 to 4 hours), then 60 μg/kg/h (4 to 24 hours), then 90 μg/kg/h (24 to 52 hours), followed by a taper to 60 μg/kg/h (52 to 56 hours), and 30 μg/kg/h (56 to 60 hours).	Drug: SAGE-547 90 μg/kg/h; Intravenous infusion of SAGE-547

Outcome Measures

Primary Outcome Measures

1. Change From Baseline at 60 Hours in 17-Item Hamilton Rating Scale for Depression (HAM-D) Total Score [Baseline, Hour 60]

   The HAM-D Total Score comprises a sum of the 17 individual item scores. 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 Total Score can range from 0 to 52, and higher scores indicate a greater degree of depression. Higher scores indicate a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression.

Secondary Outcome Measures

1. Change From Baseline in HAM-D Total Score at Day 30 [Baseline, Day 30]

   The HAM-D Total Score comprises a sum of the 17 individual item scores. 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 Total Score can range from 0 to 52, and higher scores indicate a greater degree of depression. Higher scores indicate a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression.

2. Change From Baseline in HAM-D Total Score [Baseline, Hours 2, 4, 8, 12, 24, 36, 48, 72, and Days 7, 14 and 21]

   The HAM-D Total Score comprises a sum of the 17 individual item scores. 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 Total Score can range from 0 to 52, and higher scores indicate a greater degree of depression. Higher scores indicate a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression.

3. Percentage of Participants With HAM-D Response [Hour 60, Days 7 and 30]

   The HAM-D response is defined as having a 50% or greater reduction from baseline in HAM-D total score. The HAM-D Total Score comprises a sum of the 17 individual item scores. 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 Total Score can range from 0 to 52, and higher scores indicate a greater degree of depression. Higher scores indicate a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression.

4. Percentage of Participants With HAM-D Remission [Hour 60, Days 7 and 30]

   HAM-D remission is defined as having a HAM-D total score of ≤7. The HAM-D Total Score comprises a sum of the 17 individual item scores. 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 Total Score can range from 0 to 52, and higher scores indicate a greater degree of depression. Higher scores indicate a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression.

5. Change From Baseline in HAM-D Bech 6 Subscale [Baseline, Hour 60, Days 7 and 30]

   The HAM-D Bech 6 subscale score is calculated as the sum of the following six items: Item # 1 (depressed mood), Item # 2 (feelings of guilt), Item # 7 (work and activities), Item # 8 (retardation), Item # 10 (anxiety psychic), and Item # 13 (general somatic symptoms). Each item is scored in a range of 0 to 2 or 0 to 4, with higher scores indicating a greater degree of depression. The scores were transformed to a 100-point scale with a higher score indicating a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression.

6. Change From Baseline in HAM-D Individual Item Scores [Baseline, Hours 2, 4, 8, 12, 24, 36, 48, 60, 72, and Days 7, 14, 21, and 30]

   The HAM-D comprises individual ratings of the following symptoms scored in a range of 0 to 2: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following symptoms are scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. Higher scores indicate a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression.

7. Change From Baseline at Key Time Points in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score [Baseline, Hour 60, Days 7 and 30]

   The MADRS is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in participants with mood disorders. It was designed as an adjunct to the HAM-D, to be more sensitive than the Hamilton Scale to the changes brought on by antidepressants and other forms of treatment. Each item yielded a score of 0 to 6. The MADRS total score was calculated as the sum of the 10 individual item scores, which ranged from 0 to 60. Higher MADRS scores indicates more severe depression. A negative change from baseline indicates less severe depression. A positive change from baseline indicates more severe depression.

8. Percentage of Participants With Clinical Global Impression - Improvement (CGI-I) Response [Hour 60, Days 7 and 30]

   The CGI-I response was defined as having a score of 1 (very much improved) or 2 (much improved). CGI-I item employs a 7-point Likert scale to measure the overall improvement in the participant's condition post-treatment. The investigator rated the participant's total improvement whether or not it was due entirely to drug treatment. Response choices include: 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. The CGI-I was only rated at post-treatment assessments. By definition, all CGI-I assessments were evaluated against baseline conditions.

9. Change From Baseline in the Generalized Anxiety Disorder 7-Item Scale (GAD-7) Total Score [Baseline, Hour 60, Days 7, 14, 21 and 30]

   The GAD-7 is a participant-rated, generalized anxiety symptom severity scale. Scoring for GAD-7 generalized anxiety is calculated by assigning scores of 0 = "not at all sure," 1 = "several days," 2 = "over half the days," and 3 = "nearly every day" to the response categories. The GAD-7 total score for the seven items ranges from 0 to 21, where a score of 0 to 4 = minimal anxiety, 5 to 9 = mild anxiety, 10 to 14 = moderate anxiety, and 15 to 21 = severe anxiety. The GAD-7 total score was calculated as the sum of the seven individual item scores. A negative change from baseline indicates less anxiety. A positive change from baseline indicates more anxiety.

10. Percentage of Participants With Treatment Emergent Adverse Event (TEAE) [Up to approximately 37 days]

    An Adverse Event (AE) is 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 (eg, 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 is defined as an AE with onset on or after the start of study drug infusion, or any worsening of a pre-existing medical condition/AE with onset on or after the start of study drug infusion.

11. Time to Change in Antidepressant Medication [Up to approximately 37 days]

    The time to first start or increase in the dose and time to first stop or decrease in the dose of any antidepressant medication.

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, agreed to temporarily cease giving breastmilk to their infant(s).

• Participant 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 Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I).

• Participant had a HAM-D total score of ≥20 and ≤25 at screening and Day 1 (prior to dosing).

• Participant was ≤ six months postpartum.

• Participant was amenable to intravenous therapy.

Key Exclusion Criteria:

• Active psychosis.

• Attempted suicide associated with index case of postpartum depression.

• Medical history of bipolar disorder.

Note: Other protocol-defined inclusion/exclusion criteria applied.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sage Investigational Site	Chandler	Arizona	United States	85226
2	Sage Investigational Site	Rogers	Arkansas	United States	72758
3	Sage Investigational Site	Lemon Grove	California	United States	91945
4	Sage Investigational Site	Orange	California	United States	92868
5	Sage Investigational Site	Ventura	California	United States	93003
6	Sage Investigational Site	Gainesville	Florida	United States	32607
7	Sage Investigational Site	Miami	Florida	United States	33147
8	Sage Investigational Site	Miramar	Florida	United States	33027
9	Sage Investigational Site	Orlando	Florida	United States	32807
10	Sage Investigational Site	Pensacola	Florida	United States	32502
11	Sage Investigational Site	Pinellas Park	Florida	United States	33782
12	Sage Investigational Site	Atlanta	Georgia	United States	30331
13	Sage Investigational Site	Hoffman Estates	Illinois	United States	60169
14	Sage Investigational Site	Wichita	Kansas	United States	67226
15	Sage Investigational Site	Edgewood	Kentucky	United States	41017
16	Sage Investigational Site	Owensboro	Kentucky	United States	42303
17	Sage Investigational Site	Boston	Massachusetts	United States	02114
18	Sage Investigational Site	Flowood	Mississippi	United States	39232
19	Sage Investigational Site	Marlton	New Jersey	United States	08053
20	Sage Investigational Site	Glen Oaks	New York	United States	11004
21	Sage Investigational Site	Chapel Hill	North Carolina	United States	27514
22	Sage Investigational Site	Charlotte	North Carolina	United States	28211
23	Sage Investigational Site	Raleigh	North Carolina	United States	27612
24	Sage Investigational Site	Columbus	Ohio	United States	43210
25	Sage Investigational Site	Dayton	Ohio	United States	45417
26	Sage Investigational Site	Philadelphia	Pennsylvania	United States	19104
27	Sage Investigational Site	Baytown	Texas	United States	77521
28	Sage Investigational Site	Houston	Texas	United States	77030
29	Sage Investigational Site	Houston	Texas	United States	77058
30	Sage Investigational Site	Richardson	Texas	United States	75080
31	Sage Investigational Site	San Antonio	Texas	United States	78229
32	Sage Investigational Site	Orem	Utah	United States	84058

Sponsors and Collaborators

• Sage Therapeutics

Investigators

• Study Director: Helen Colquhoun, MD, Sage Therapeutics

Study Documents (Full-Text)

• Study Protocol - Mar 16, 2017
• Statistical Analysis Plan - Oct 27, 2017

More Information

Additional Information:

• Related Info
• Related Info

Publications

None provided.

• Responsible Party: Sage Therapeutics
• ClinicalTrials.gov Identifier: NCT02942017
• Other Study ID Numbers: 547-PPD-202 C
• First Posted: Oct 21, 2016
• Last Update Posted: Jan 28, 2022
• Last Verified: Jan 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: Moderate Postpartum Depression; SAGE-547
• Additional relevant MeSH terms: Depression, Postpartum; Depression; Depressive Disorder; Brexanolone

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 32 centers in United States from 25 July 2016 to 11 October 2017.
Pre-assignment Detail	A total of 108 participants were randomized into the study to receive either placebo or SAGE-547, 104 of whom received the study drug.

Arm/Group Title	Placebo	SAGE-547 90 μg/kg/h
Arm/Group Description	Participants received an infusion rate equivalent to the 90 micrograms per kilogram per hour (μg/kg/h) group.	Participants received a 4-hour dose titration period of 30 μg/kg/h (0 to 4 hours), then 60 μg/kg/h (4 to 24 hours), then 90 μg/kg/h (24 to 52 hours), followed by a taper to 60 μg/kg/h (52 to 56 hours), and 30 μg/kg/h (56 to 60 hours).
Period Title: Overall Study
STARTED	54	54
Treated	53	51
COMPLETED	52	48
NOT COMPLETED	2	6

Baseline Characteristics

Arm/Group Title	Placebo	SAGE-547 90 μg/kg/h	Total
Arm/Group Description	Participants received an infusion rate equivalent to the 90 μg/kg/h group.	Participants received a 4-hour dose titration period of 30 μg/kg/h (0 to 4 hours), then 60 μg/kg/h (4 to 24 hours), then 90 μg/kg/h (24 to 52 hours), followed by a taper to 60 μg/kg/h (52 to 56 hours), and 30 μg/kg/h (56 to 60 hours).	Total of all reporting groups
Overall Participants	53	51	104
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	27.3 (5.90)	28.2 (6.09)	27.8 (5.98)
Sex: Female, Male (Count of Participants)
Female	53 100%	51 100%	104 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	19 35.8%	22 43.1%	41 39.4%
White	33 62.3%	29 56.9%	62 59.6%
Other	1 1.9%	0 0%	1 1%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latina	14 26.4%	10 19.6%	24 23.1%
Not Hispanic or Latina	39 73.6%	41 80.4%	80 76.9%
Hamilton Rating Scale for Depression (HAMD) Total Score (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	22.7 (1.59)	22.6 (1.56)	22.7 (1.57)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline at 60 Hours in 17-Item Hamilton Rating Scale for Depression (HAM-D) Total Score
Description	The HAM-D Total Score comprises a sum of the 17 individual item scores. 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 Total Score can range from 0 to 52, and higher scores indicate a greater degree of depression. Higher scores indicate a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression.
Time Frame	Baseline, Hour 60

Outcome Measure Data

Analysis Population Description

All randomized participants who started study drug infusion, had a valid baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Overall number of participants analyzed is the number of participants with data available for analysis at the given time-point.

Arm/Group Title	Placebo	SAGE-547 90 μg/kg/h
Arm/Group Description	Participants received an infusion rate equivalent to the 90 μg/kg/h group.	Participants received a 4-hour dose titration period of 30 μg/kg/h (0 to 4 hours), then 60 μg/kg/h (4 to 24 hours), then 90 μg/kg/h (24 to 52 hours), followed by a taper to 60 μg/kg/h (52 to 56 hours), and 30 μg/kg/h (56 to 60 hours).
Measure Participants	52	49
Least Squares Mean (Standard Error) [score on a scale]	-12.12 (0.773)	-14.62 (0.782)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Mixed effect model for repeated measures (MMRM) was used for analysis. The change from baseline in HAM-D total score at each visit was the dependent variable. Treatment, baseline HAM-D total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0160
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	-2.50
	Confidence Interval	(2-Sided) 95%; -4.52 to -0.48
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.019
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in HAM-D Total Score at Day 30
Description	The HAM-D Total Score comprises a sum of the 17 individual item scores. 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 Total Score can range from 0 to 52, and higher scores indicate a greater degree of depression. Higher scores indicate a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression.
Time Frame	Baseline, Day 30

Outcome Measure Data

Analysis Population Description

All randomized participants who started study drug infusion, had a valid baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Overall number of participants analyzed is the number of participants with data available for analysis at the given time-point.

Arm/Group Title	Placebo	SAGE-547 90 μg/kg/h
Arm/Group Description	Participants received an infusion rate equivalent to the 90 μg/kg/h group.	Participants received a 4-hour dose titration period of 30 μg/kg/h (0 to 4 hours), then 60 μg/kg/h (4 to 24 hours), then 90 μg/kg/h (24 to 52 hours), followed by a taper to 60 μg/kg/h (52 to 56 hours), and 30 μg/kg/h (56 to 60 hours).
Measure Participants	52	48
Least Squares Mean (Standard Error) [score on a scale]	-15.23 (0.934)	-14.69 (0.955)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	MMRM was used for analysis. The change from baseline in HAM-D total score at each visit was the dependent variable. Treatment, baseline HAM-D total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6710
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 95%; -1.98 to 3.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.271
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in HAM-D Total Score
Description	The HAM-D Total Score comprises a sum of the 17 individual item scores. 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 Total Score can range from 0 to 52, and higher scores indicate a greater degree of depression. Higher scores indicate a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression.
Time Frame	Baseline, Hours 2, 4, 8, 12, 24, 36, 48, 72, and Days 7, 14 and 21

Outcome Measure Data

Analysis Population Description

All randomized participants who started study drug infusion, had a valid baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Placebo	SAGE-547 90 μg/kg/h
Arm/Group Description	Participants received an infusion rate equivalent to the 90 μg/kg/h group.	Participants received a 4-hour dose titration period of 30 μg/kg/h (0 to 4 hours), then 60 μg/kg/h (4 to 24 hours), then 90 μg/kg/h (24 to 52 hours), followed by a taper to 60 μg/kg/h (52 to 56 hours), and 30 μg/kg/h (56 to 60 hours).
Measure Participants	53	51
Change at Hour 2	-4.00 (0.598)	-4.60 (0.595)
Change at Hour 4	-6.55 (0.701)	-7.32 (0.702)
Change at Hour 8	-7.44 (0.738)	-8.38 (0.740)
Change at Hour 12	-7.96 (0.758)	-9.10 (0.762)
Change at Hour 24	-9.81 (0.820)	-11.42 (0.827)
Change at Hour 36	-10.45 (0.833)	-12.31 (0.843)
Change at Hour 48	-10.59 (0.860)	-13.00 (0.873)
Change at Hour 72	-11.83 (0.829)	-15.31 (0.841)
Change at Day 7	-10.74 (1.042)	-13.98 (1.061)
Change at Day 14	-11.40 (0.989)	-13.43 (1.013)
Change at Day 21	-13.26 (1.022)	-13.59 (1.041)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Hour 2: MMRM was used for analysis. The change from baseline in HAM-D total score at each visit was the dependent variable. Treatment, baseline HAM-D total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4216
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.60
	Confidence Interval	(2-Sided) 95%; -2.06 to 0.87
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.738
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Hour 4: MMRM was used for analysis. The change from baseline in HAM-D total score at each visit was the dependent variable. Treatment, baseline HAM-D total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3947
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.77
	Confidence Interval	(2-Sided) 95%; -2.57 to 1.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.905
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Hour 8: MMRM was used for analysis. The change from baseline in HAM-D total score at each visit was the dependent variable. Treatment, baseline HAM-D total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3280
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.95
	Confidence Interval	(2-Sided) 95%; -2.86 to 0.96
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.962
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Hour 12: MMRM was used for analysis. The change from baseline in HAM-D total score at each visit was the dependent variable. Treatment, baseline HAM-D total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2522
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.14
	Confidence Interval	(2-Sided) 95%; -3.12 to 0.83
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.994
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Hour 24: MMRM was used for analysis. The change from baseline in HAM-D total score at each visit was the dependent variable. Treatment, baseline HAM-D total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1431
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.61
	Confidence Interval	(2-Sided) 95%; -3.78 to 0.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.091
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Hour 36: MMRM was used for analysis. The change from baseline in HAM-D total score at each visit was the dependent variable. Treatment, baseline HAM-D total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0991
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.85
	Confidence Interval	(2-Sided) 95%; -4.06 to 0.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.113
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Hour 48: MMRM was used for analysis. The change from baseline in HAM-D total score at each visit was the dependent variable. Treatment, baseline HAM-D total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0389
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.42
	Confidence Interval	(2-Sided) 95%; -4.71 to -0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.155
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Hour 72: MMRM was used for analysis. The change from baseline in HAM-D total score at each visit was the dependent variable. Treatment, baseline HAM-D total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0022
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-3.48
	Confidence Interval	(2-Sided) 95%; -5.67 to -1.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.108
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Day 7: MMRM was used for analysis. The change from baseline in HAM-D total score at each visit was the dependent variable. Treatment, baseline HAM-D total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0255
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-3.24
	Confidence Interval	(2-Sided) 95%; -6.08 to -0.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.429
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Day 14: MMRM was used for analysis. The change from baseline in HAM-D total score at each visit was the dependent variable. Treatment, baseline HAM-D total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1375
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.03
	Confidence Interval	(2-Sided) 95%; -4.73 to 0.66
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.356
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Day 21: MMRM was used for analysis. The change from baseline in HAM-D total score at each visit was the dependent variable. Treatment, baseline HAM-D total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8170
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.33
	Confidence Interval	(2-Sided) 95%; -3.11 to 2.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.400
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Participants With HAM-D Response
Description	The HAM-D response is defined as having a 50% or greater reduction from baseline in HAM-D total score. The HAM-D Total Score comprises a sum of the 17 individual item scores. 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 Total Score can range from 0 to 52, and higher scores indicate a greater degree of depression. Higher scores indicate a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression.
Time Frame	Hour 60, Days 7 and 30

Outcome Measure Data

Analysis Population Description

All randomized participants who started study drug infusion, had a valid baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Placebo	SAGE-547 90 μg/kg/h
Arm/Group Description	Participants received an infusion rate equivalent to the 90 μg/kg/h group.	Participants received a 4-hour dose titration period of 30 μg/kg/h (0 to 4 hours), then 60 μg/kg/h (4 to 24 hours), then 90 μg/kg/h (24 to 52 hours), followed by a taper to 60 μg/kg/h (52 to 56 hours), and 30 μg/kg/h (56 to 60 hours).
Measure Participants	53	51
Hour 60	59.6 112.5%	75.5 148%
Day 7	50.9 96%	66.0 129.4%
Day 30	78.8 148.7%	70.8 138.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Hour 60: Generalized estimating equation (GEE) method was used for analysis. The HAM-D response at each visit was the dependent variable. Treatment, baseline HAM-D total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0168
	Comments
	Method	GEE method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.9
	Confidence Interval	(2-Sided) 95%; 1.2 to 6.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Day 7: GEE method was used for analysis. The HAM-D response at each visit was the dependent variable. Treatment, baseline HAM-D total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0482
	Comments
	Method	GEE method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.6
	Confidence Interval	(2-Sided) 95%; 1.0 to 6.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Day 30: GEE method was used for analysis. The HAM-D response at each visit was the dependent variable. Treatment, baseline HAM-D total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. An exchangeable working correlation structure is assumed for the model parameters estimation.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5857
	Comments
	Method	GEE method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; 0.3 to 2.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Percentage of Participants With HAM-D Remission
Description	HAM-D remission is defined as having a HAM-D total score of ≤7. The HAM-D Total Score comprises a sum of the 17 individual item scores. 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 Total Score can range from 0 to 52, and higher scores indicate a greater degree of depression. Higher scores indicate a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression.
Time Frame	Hour 60, Days 7 and 30

Outcome Measure Data

Analysis Population Description

All randomized participants who started study drug infusion, had a valid baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Placebo	SAGE-547 90 μg/kg/h
Arm/Group Description	Participants received an infusion rate equivalent to the 90 μg/kg/h group.	Participants received a 4-hour dose titration period of 30 μg/kg/h (0 to 4 hours), then 60 μg/kg/h (4 to 24 hours), then 90 μg/kg/h (24 to 52 hours), followed by a taper to 60 μg/kg/h (52 to 56 hours), and 30 μg/kg/h (56 to 60 hours).
Measure Participants	53	51
Hour 60	38.5 72.6%	61.2 120%
Day 7	32.1 60.6%	56.0 109.8%
Day 30	61.5 116%	47.9 93.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Hour 60: GEE method was used for analysis. The HAM-D remission at each visit was the dependent variable. Treatment, baseline HAM-D total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0033
	Comments	Hour 60:
	Method	GEE method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.4
	Confidence Interval	(2-Sided) 95%; 1.5 to 7.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Day 7: GEE method was used for analysis. The HAM-D remission at each visit was the dependent variable. Treatment, baseline HAM-D total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0046
	Comments
	Method	GEE method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.7
	Confidence Interval	(2-Sided) 95%; 1.5 to 9.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Day 30: GEE method was used for analysis. The HAM-D remission at each visit was the dependent variable. Treatment, baseline HAM-D total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3085
	Comments
	Method	GEE method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.6
	Confidence Interval	(2-Sided) 95%; 0.3 to 1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in HAM-D Bech 6 Subscale
Description	The HAM-D Bech 6 subscale score is calculated as the sum of the following six items: Item # 1 (depressed mood), Item # 2 (feelings of guilt), Item # 7 (work and activities), Item # 8 (retardation), Item # 10 (anxiety psychic), and Item # 13 (general somatic symptoms). Each item is scored in a range of 0 to 2 or 0 to 4, with higher scores indicating a greater degree of depression. The scores were transformed to a 100-point scale with a higher score indicating a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression.
Time Frame	Baseline, Hour 60, Days 7 and 30

Outcome Measure Data

Analysis Population Description

All randomized participants who started study drug infusion, had a valid baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Placebo	SAGE-547 90 μg/kg/h
Arm/Group Description	Participants received an infusion rate equivalent to the 90 μg/kg/h group.	Participants received a 4-hour dose titration period of 30 μg/kg/h (0 to 4 hours), then 60 μg/kg/h (4 to 24 hours), then 90 μg/kg/h (24 to 52 hours), followed by a taper to 60 μg/kg/h (52 to 56 hours), and 30 μg/kg/h (56 to 60 hours).
Measure Participants	53	51
Change at Hour 60	-29.23 (2.248)	-37.59 (2.276)
Change at Day 7	-25.05 (2.624)	-34.80 (2.668)
Change at Day 30	-36.24 (2.345)	-34.86 (2.390)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Hour 60: MMRM was used for analysis. The change from baseline in HAM-D subscales at each visit was the dependent variable. Treatment, baseline HAM-D subscales, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0063
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-8.35
	Confidence Interval	(2-Sided) 95%; -14.29 to -2.42
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.989
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Day 7: MMRM was used for analysis. The change from baseline in HAM-D subscales at each visit was the dependent variable. Treatment, baseline HAM-D subscales, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0074
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-9.75
	Confidence Interval	(2-Sided) 95%; -16.83 to -2.68
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.566
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Day 30: MMRM was used for analysis. The change from baseline in HAM-D subscales at each visit was the dependent variable. Treatment, baseline HAM-D subscales, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6637
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.37
	Confidence Interval	(2-Sided) 95%; -4.88 to 7.63
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.149
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in HAM-D Individual Item Scores
Description	The HAM-D comprises individual ratings of the following symptoms scored in a range of 0 to 2: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following symptoms are scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. Higher scores indicate a greater degree of depression. A negative change from baseline indicates less depression. A positive change from baseline indicates more depression.
Time Frame	Baseline, Hours 2, 4, 8, 12, 24, 36, 48, 60, 72, and Days 7, 14, 21, and 30

Outcome Measure Data

Analysis Population Description

All randomized participants who started study drug infusion, had a valid baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Placebo	SAGE-547 90 μg/kg/h
Arm/Group Description	Participants received an infusion rate equivalent to the 90 μg/kg/h group.	Participants received a 4-hour dose titration period of 30 μg/kg/h (0 to 4 hours), then 60 μg/kg/h (4 to 24 hours), then 90 μg/kg/h (24 to 52 hours), followed by a taper to 60 μg/kg/h (52 to 56 hours), and 30 μg/kg/h (56 to 60 hours).
Measure Participants	53	51
Depressed Mood, Change at Hour 2	-0.35 (0.121)	-0.45 (0.121)
Depressed Mood, Change at Hour 4	-0.67 (0.137)	-0.92 (0.138)
Depressed Mood, Change at Hour 8	-0.90 (0.136)	-1.20 (0.136)
Depressed Mood, Change at Hour 12	-1.05 (0.139)	-1.18 (0.140)
Depressed Mood, Change at Hour 24	-1.01 (0.143)	-1.34 (0.145)
Depressed Mood, Change at Hour 36	-1.35 (0.145)	-1.64 (0.147)
Depressed Mood, Change at Hour 48	-1.33 (0.144)	-1.74 (0.146)
Depressed Mood, Change at Hour 60	-1.62 (0.142)	-1.91 (0.144)
Depressed Mood, Change at Hour 72	-1.63 (0.137)	-1.93 (0.140)
Depressed Mood, Change at Day 7	-1.43 (0.159)	-1.82 (0.161)
Depressed Mood, Change at Day 14	-1.42 (0.170)	-1.59 (0.174)
Depressed Mood, Change at Day 21	-1.80 (0.168)	-1.56 (0.170)
Depressed Mood, Change at Day 30	-2.07 (0.137)	-1.89 (0.140)
Feelings of Guilt, Change at Hour 2	-0.37 (0.125)	-0.59 (0.125)
Feelings of Guilt, Change at Hour 4	-0.56 (0.127)	-1.00 (0.127)
Feelings of Guilt, Change at Hour 8	-0.81 (0.124)	-1.04 (0.124)
Feelings of Guilt, Change at Hour 12	-0.69 (0.127)	-0.98 (0.128)
Feelings of Guilt, Change at Hour 24	-0.86 (0.122)	-1.16 (0.123)
Feelings of Guilt, Change at Hour 36	-0.75 (0.127)	-1.09 (0.129)
Feelings of Guilt, Change at Hour 48	-0.90 (0.129)	-1.11 (0.131)
Feelings of Guilt, Change at Hour 60	-0.99 (0.119)	-1.28 (0.120)
Feelings of Guilt, Change at Hour 72	-0.94 (0.121)	-1.34 (0.123)
Feelings of Guilt, Change at Day 7	-0.82 (0.135)	-1.14 (0.137)
Feelings of Guilt, Change at Day 14	-0.90 (0.133)	-1.00 (0.136)
Feelings of Guilt, Change at Day 21	-1.01 (0.126)	-1.11 (0.128)
Feelings of Guilt, Change at Day 30	-1.31 (0.111)	-1.20 (0.112)
Suicide, Change at Hour 2	-0.11 (0.062)	-0.19 (0.062)
Suicide, Change at Hour 4	-0.20 (0.062)	-0.28 (0.062)
Suicide, Change at Hour 8	-0.26 (0.062)	-0.32 (0.062)
Suicide, Change at Hour 12	-0.27 (0.062)	-0.36 (0.062)
Suicide, Change at Hour 24	-0.31 (0.062)	-0.38 (0.062)
Suicide, Change at Hour 36	-0.29 (0.062)	-0.38 (0.063)
Suicide, Change at Hour 48	-0.29 (0.062)	-0.40 (0.063)
Suicide, Change at Hour 60	-0.33 (0.062)	-0.40 (0.063)
Suicide, Change at Hour 72	-0.33 (0.062)	-0.40 (0.063)
Suicide, Change at Day 7	-0.29 (0.062)	-0.30 (0.062)
Suicide, Change at Day 14	-0.35 (0.068)	-0.32 (0.069)
Suicide, Change at Day 21	-0.36 (0.068)	-0.36 (0.068)
Suicide, Change at Day 30	-0.37 (0.062)	-0.38 (0.063)
Insomnia - Early, Change at Hour 2	-0.18 (0.077)	-0.22 (0.077)
Insomnia - Early, Change at Hour 4	-0.35 (0.092)	-0.26 (0.092)
Insomnia - Early, Change at Hour 8	-0.28 (0.085)	-0.26 (0.085)
Insomnia - Early, Change at Hour 12	-0.36 (0.090)	-0.25 (0.091)
Insomnia - Early, Change at Hour 24	-0.54 (0.111)	-0.81 (0.113)
Insomnia - Early, Change at Hour 36	-0.62 (0.115)	-0.80 (0.117)
Insomnia - Early, Change at Hour 48	-0.62 (0.122)	-0.94 (0.125)
Insomnia - Early, Change at Hour 60	-0.87 (0.130)	-0.96 (0.133)
Insomnia - Early, Change at Hour 72	-0.54 (0.119)	-0.93 (0.122)
Insomnia - Early, Change at Day 7	-0.69 (0.130)	-0.95 (0.133)
Insomnia - Early, Change at Day 14	-0.78 (0.142)	-0.98 (0.145)
Insomnia - Early, Change at Day 21	-0.98 (0.156)	-0.95 (0.157)
Insomnia - Early, Change at Day 30	-1.05 (0.126)	-0.96 (0.130)
Insomnia - Middle, Change at Hour 2	-0.18 (0.089)	-0.08 (0.089)
Insomnia - Middle, Change at Hour 4	-0.20 (0.092)	-0.22 (0.092)
Insomnia - Middle, Change at Hour 8	-0.28 (0.092)	-0.22 (0.092)
Insomnia - Middle, Change at Hour 12	-0.30 (0.094)	-0.15 (0.094)
Insomnia - Middle, Change at Hour 24	-0.52 (0.103)	-0.84 (0.105)
Insomnia - Middle, Change at Hour 36	-0.64 (0.103)	-0.91 (0.105)
Insomnia - Middle, Change at Hour 48	-0.58 (0.106)	-0.88 (0.109)
Insomnia - Middle, Change at Hour 60	-0.67 (0.099)	-0.96 (0.101)
Insomnia - Middle, Change at Hour 72	-0.77 (0.101)	-1.00 (0.103)
Insomnia - Middle, Change at Day 7	-0.67 (0.112)	-0.89 (0.114)
Insomnia - Middle, Change at Day 14	-0.62 (0.135)	-0.85 (0.137)
Insomnia - Middle, Change at Day 21	-0.81 (0.139)	-0.79 (0.138)
Insomnia - Middle, Change at Day 30	-0.84 (0.120)	-0.91 (0.123)
Insomnia - Late, Change at Hour 2	-0.14 (0.091)	-0.03 (0.092)
Insomnia - Late, Change at Hour 4	-0.20 (0.095)	-0.13 (0.096)
Insomnia - Late, Change at Hour 8	-0.20 (0.090)	-0.23 (0.090)
Insomnia - Late, Change at Hour 12	-0.21 (0.091)	-0.23 (0.092)
Insomnia - Late, Change at Hour 24	-0.54 (0.100)	-0.59 (0.101)
Insomnia - Late, Change at Hour 36	-0.46 (0.102)	-0.45 (0.105)
Insomnia - Late, Change at Hour 48	-0.56 (0.097)	-0.61 (0.100)
Insomnia - Late, Change at Hour 60	-0.60 (0.098)	-0.63 (0.100)
Insomnia - Late, Change at Hour 72	-0.50 (0.104)	-0.76 (0.107)
Insomnia - Late, Change at Day 7	-0.46 (0.100)	-0.64 (0.102)
Insomnia - Late, Change at Day 14	-0.27 (0.128)	-0.66 (0.130)
Insomnia - Late, Change at Day 21	-0.51 (0.125)	-0.64 (0.126)
Insomnia - Late, Change at Day 30	-0.67 (0.099)	-0.72 (0.101)
Work and Activities, Change at Hour 2	-0.26 (0.109)	-0.41 (0.109)
Work and Activities, Change at Hour 4	-0.73 (0.130)	-0.72 (0.131)
Work and Activities, Change at Hour 8	-0.77 (0.139)	-1.02 (0.141)
Work and Activities, Change at Hour 12	-1.07 (0.151)	-1.18 (0.152)
Work and Activities, Change at Hour 24	-1.34 (0.149)	-1.33 (0.151)
Work and Activities, Change at Hour 36	-1.54 (0.146)	-1.65 (0.149)
Work and Activities, Change at Hour 48	-1.45 (0.138)	-1.71 (0.141)
Work and Activities, Change at Hour 60	-1.60 (0.134)	-2.04 (0.136)
Work and Activities, Change at Hour 72	-1.68 (0.143)	-2.06 (0.146)
Work and Activities, Change at Day 7	-1.66 (0.157)	-1.94 (0.160)
Work and Activities, Change at Day 14	-1.40 (0.161)	-1.84 (0.165)
Work and Activities, Change at Day 21	-1.75 (0.174)	-1.70 (0.178)
Work and Activities, Change at Day 30	-2.04 (0.142)	-2.00 (0.145)
Retardation, Change at Hour 2	-0.03 (0.088)	0.06 (0.089)
Retardation, Change at Hour 4	-0.20 (0.085)	0.00 (0.086)
Retardation, Change at Hour 8	-0.25 (0.085)	-0.13 (0.086)
Retardation, Change at Hour 12	-0.27 (0.082)	-0.29 (0.083)
Retardation, Change at Hour 24	-0.18 (0.090)	-0.17 (0.092)
Retardation, Change at Hour 36	-0.35 (0.082)	-0.38 (0.084)
Retardation, Change at Hour 48	-0.35 (0.079)	-0.24 (0.081)
Retardation, Change at Hour 60	-0.46 (0.066)	-0.55 (0.068)
Retardation, Change at Hour 72	-0.48 (0.073)	-0.44 (0.075)
Retardation, Change at Day 7	-0.33 (0.073)	-0.55 (0.074)
Retardation, Change at Day 14	-0.47 (0.061)	-0.58 (0.060)
Retardation, Change at Day 21	-0.51 (0.070)	-0.57 (0.068)
Retardation, Change at Day 30	-0.54 (0.056)	-0.55 (0.058)
Agitation, Change at Hour 2	-0.27 (0.078)	-0.47 (0.078)
Agitation, Change at Hour 4	-0.42 (0.082)	-0.65 (0.082)
Agitation, Change at Hour 8	-0.40 (0.081)	-0.71 (0.081)
Agitation, Change at Hour 12	-0.32 (0.093)	-0.62 (0.094)
Agitation, Change at Hour 24	-0.52 (0.081)	-0.74 (0.083)
Agitation, Change at Hour 36	-0.40 (0.092)	-0.66 (0.094)
Agitation, Change at Hour 48	-0.44 (0.087)	-0.78 (0.089)
Agitation, Change at Hour 60	-0.42 (0.097)	-0.64 (0.099)
Agitation, Change at Hour 72	-0.37 (0.092)	-0.74 (0.094)
Agitation, Change at Day 7	-0.39 (0.096)	-0.65 (0.097)
Agitation, Change at Day 14	-0.58 (0.107)	-0.67 (0.108)
Agitation, Change at Day 21	-0.56 (0.112)	-0.65 (0.114)
Agitation, Change at Day 30	-0.60 (0.075)	-0.73 (0.077)
Anxiety Psychic, Change at Hour 2	-0.45 (0.126)	-0.67 (0.126)
Anxiety Psychic, Change at Hour 4	-0.81 (0.138)	-0.93 (0.138)
Anxiety Psychic, Change at Hour 8	-0.89 (0.141)	-1.05 (0.142)
Anxiety Psychic, Change at Hour 12	-0.89 (0.143)	-1.01 (0.144)
Anxiety Psychic, Change at Hour 24	-1.00 (0.140)	-1.13 (0.141)
Anxiety Psychic, Change at Hour 36	-1.06 (0.141)	-1.20 (0.143)
Anxiety Psychic, Change at Hour 48	-0.92 (0.142)	-1.24 (0.144)
Anxiety Psychic, Change at Hour 60	-0.98 (0.131)	-1.51 (0.133)
Anxiety Psychic, Change at Hour 72	-1.08 (0.135)	-1.36 (0.137)
Anxiety Psychic, Change at Day 7	-0.70 (0.133)	-1.21 (0.134)
Anxiety Psychic, Change at Day 14	-0.76 (0.178)	-0.82 (0.184)
Anxiety Psychic, Change at Day 21	-0.94 (0.156)	-0.83 (0.158)
Anxiety Psychic, Change at Day 30	-1.25 (0.138)	-1.10 (0.141)
Anxiety Somatic, Change at Hour 2	-0.54 (0.100)	-0.61 (0.101)
Anxiety Somatic, Change at Hour 4	-0.71 (0.098)	-0.81 (0.099)
Anxiety Somatic, Change at Hour 8	-0.62 (0.102)	-0.69 (0.103)
Anxiety Somatic, Change at Hour 12	-0.60 (0.099)	-0.87 (0.100)
Anxiety Somatic, Change at Hour 24	-0.73 (0.103)	-0.77 (0.105)
Anxiety Somatic, Change at Hour 36	-0.75 (0.098)	-0.89 (0.100)
Anxiety Somatic, Change at Hour 48	-0.79 (0.100)	-0.96 (0.103)
Anxiety Somatic, Change at Hour 60	-0.88 (0.101)	-0.95 (0.104)
Anxiety Somatic, Change at Hour 72	-0.84 (0.088)	-1.08 (0.090)
Anxiety Somatic, Change at Day 7	-0.66 (0.112)	-0.92 (0.114)
Anxiety Somatic, Change at Day 14	-0.85 (0.139)	-0.63 (0.139)
Anxiety Somatic, Change at Day 21	-0.90 (0.119)	-1.01 (0.118)
Anxiety Somatic, Change at Day 30	-0.88 (0.110)	-0.97 (0.113)
Somatic Symptoms GI, Change at Hour 2	-0.22 (0.091)	-0.15 (0.092)
Somatic Symptoms GI, Change at Hour 4	-0.33 (0.096)	-0.39 (0.096)
Somatic Symptoms GI, Change at Hour 8	-0.56 (0.087)	-0.37 (0.087)
Somatic Symptoms GI, Change at Hour 12	-0.56 (0.090)	-0.45 (0.091)
Somatic Symptoms GI, Change at Hour 24	-0.48 (0.083)	-0.54 (0.084)
Somatic Symptoms GI, Change at Hour 36	-0.60 (0.084)	-0.51 (0.086)
Somatic Symptoms GI, Change at Hour 48	-0.56 (0.086)	-0.59 (0.088)
Somatic Symptoms GI, Change at Hour 60	-0.73 (0.091)	-0.71 (0.093)
Somatic Symptoms GI, Change at Hour 72	-0.77 (0.081)	-0.75 (0.082)
Somatic Symptoms GI, Change at Day 7	-0.47 (0.093)	-0.67 (0.095)
Somatic Symptoms GI, Change at Day 14	-0.64 (0.093)	-0.79 (0.094)
Somatic Symptoms GI, Change at Day 21	-0.61 (0.107)	-0.83 (0.108)
Somatic Symptoms GI, Change at Day 30	-0.77 (0.085)	-0.73 (0.087)
Somatic Symptoms General, Change at Hour 2	-0.18 (0.081)	-0.15 (0.079)
Somatic Symptoms General, Change at Hour 4	-0.29 (0.095)	-0.35 (0.094)
Somatic Symptoms General, Change at Hour 8	-0.38 (0.094)	-0.45 (0.093)
Somatic Symptoms General, Change at Hour 12	-0.50 (0.094)	-0.75 (0.093)
Somatic Symptoms General, Change at Hour 24	-0.65 (0.104)	-0.73 (0.104)
Somatic Symptoms General, Change at Hour 36	-0.55 (0.097)	-0.69 (0.098)
Somatic Symptoms General, Change at Hour 48	-0.61 (0.101)	-0.69 (0.102)
Somatic Symptoms General, Change at Hour 60	-0.79 (0.105)	-0.91 (0.105)
Somatic Symptoms General, Change at Hour 72	-0.80 (0.112)	-1.05 (0.113)
Somatic Symptoms General, Change at Day 7	-0.57 (0.102)	-0.93 (0.103)
Somatic Symptoms General, Change at Day 14	-0.66 (0.118)	-0.94 (0.118)
Somatic Symptoms General, Change at Day 21	-0.82 (0.124)	-0.67 (0.123)
Somatic Symptoms General, Change at Day 30	-0.77 (0.104)	-0.86 (0.106)
Genital Symptoms, Change at Hour 2	-0.05 (0.052)	0.07 (0.053)
Genital Symptoms, Change at Hour 4	-0.09 (0.065)	-0.01 (0.066)
Genital Symptoms, Change at Hour 8	-0.07 (0.070)	-0.03 (0.070)
Genital Symptoms, Change at Hour 12	-0.05 (0.083)	-0.09 (0.085)
Genital Symptoms, Change at Hour 24	-0.11 (0.089)	-0.13 (0.091)
Genital Symptoms, Change at Hour 36	-0.18 (0.091)	-0.31 (0.094)
Genital Symptoms, Change at Hour 48	-0.18 (0.092)	-0.39 (0.095)
Genital Symptoms, Change at Hour 60	-0.23 (0.084)	-0.37 (0.086)
Genital Symptoms, Change at Hour 72	-0.22 (0.102)	-0.59 (0.105)
Genital Symptoms, Change at Day 7	-0.52 (0.112)	-0.57 (0.115)
Genital Symptoms, Change at Day 14	-0.56 (0.149)	-0.66 (0.152)
Genital Symptoms, Change at Day 21	-0.67 (0.147)	-0.76 (0.149)
Genital Symptoms, Change at Day 30	-0.84 (0.131)	-0.62 (0.135)
Hypochondriasis, Change at Hour 2	-0.14 (0.077)	-0.30 (0.077)
Hypochondriasis, Change at Hour 4	-0.20 (0.071)	-0.28 (0.071)
Hypochondriasis, Change at Hour 8	-0.22 (0.073)	-0.26 (0.073)
Hypochondriasis, Change at Hour 12	-0.18 (0.076)	-0.34 (0.076)
Hypochondriasis, Change at Hour 24	-0.37 (0.069)	-0.32 (0.069)
Hypochondriasis, Change at Hour 36	-0.25 (0.079)	-0.30 (0.080)
Hypochondriasis, Change at Hour 48	-0.35 (0.075)	-0.30 (0.076)
Hypochondriasis, Change at Hour 60	-0.29 (0.075)	-0.34 (0.075)
Hypochondriasis, Change at Hour 72	-0.31 (0.077)	-0.36 (0.078)
Hypochondriasis, Change at Day 7	-0.25 (0.088)	-0.27 (0.089)
Hypochondriasis, Change at Day 14	-0.14 (0.102)	-0.33 (0.104)
Hypochondriasis, Change at Day 21	-0.30 (0.093)	-0.35 (0.094)
Hypochondriasis, Change at Day 30	-0.31 (0.069)	-0.40 (0.070)
Loss of Weight, Change at Hour 2	-0.11 (0.055)	-0.06 (0.055)
Loss of Weight, Change at Hour 4	-0.17 (0.063)	-0.02 (0.063)
Loss of Weight, Change at Hour 8	-0.19 (0.053)	-0.08 (0.053)
Loss of Weight, Change at Hour 12	-0.21 (0.067)	-0.02 (0.067)
Loss of Weight, Change at Hour 24	-0.25 (0.067)	-0.04 (0.067)
Loss of Weight, Change at Hour 36	-0.23 (0.066)	-0.15 (0.067)
Loss of Weight, Change at Hour 48	-0.23 (0.074)	-0.11 (0.076)
Loss of Weight, Change at Hour 60	-0.19 (0.065)	-0.19 (0.065)
Loss of Weight, Change at Hour 72	-0.15 (0.076)	-0.23 (0.078)
Loss of Weight, Change at Day 7	-0.38 (0.091)	-0.18 (0.093)
Loss of Weight, Change at Day 14	-0.44 (0.125)	-0.39 (0.127)
Loss of Weight, Change at Day 21	-0.38 (0.130)	-0.50 (0.132)
Loss of Weight, Change at Day 30	-0.46 (0.111)	-0.42 (0.115)
Insight, Change at Hour 2	0.01 (0.034)	-0.03 (0.034)
Insight, Change at Hour 4	0.01 (0.034)	-0.05 (0.034)
Insight, Change at Hour 8	0.05 (0.034)	-0.03 (0.034)
Insight, Change at Hour 12	-0.01 (0.034)	-0.03 (0.034)
Insight, Change at Hour 24	0.01 (0.034)	-0.05 (0.034)
Insight, Change at Hour 36	-0.01 (0.034)	-0.01 (0.034)
Insight, Change at Hour 48	-0.01 (0.034)	0.01 (0.034)
Insight, Change at Hour 60	-0.04 (0.034)	0.01 (0.034)
Insight, Change at Hour 72	-0.01 (0.034)	0.01 (0.034)
Insight, Change at Day 7	-0.02 (0.034)	-0.07 (0.034)
Insight, Change at Day 14	-0.02 (0.038)	-0.02 (0.038)
Insight, Change at Day 21	-0.02 (0.038)	-0.02 (0.038)
Insight, Change at Day 30	-0.02 (0.034)	-0.01 (0.034)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Depressed Mood, Hour 2: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5132
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.41 to 0.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.154
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Depressed Mood, Hour 4: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1672
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.61 to 0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.181
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Depressed Mood, Hour 8:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0963
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.30
	Confidence Interval	(2-Sided) 95%; -0.65 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.178
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Depressed Mood, Hour 12:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4803
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.49 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.183
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Depressed Mood, Hour 24:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0844
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.33
	Confidence Interval	(2-Sided) 95%; -0.71 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.191
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Depressed Mood, Hour 36: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1325
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -0.68 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.193
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Depressed Mood, Hour 48:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0332
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.41
	Confidence Interval	(2-Sided) 95%; -0.79 to -0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.192
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Depressed Mood, Hour 60:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1273
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -0.67 to 0.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.189
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Depressed Mood, Hour 72:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1059
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.30
	Confidence Interval	(2-Sided) 95%; -0.66 to 0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.182
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Depressed Mood, Day 7: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0683
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.40
	Confidence Interval	(2-Sided) 95%; -0.82 to 0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.215
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Depressed Mood, Day 14: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4458
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 95%; -0.64 to 0.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.232
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Depressed Mood, Day 21: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2905
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.24
	Confidence Interval	(2-Sided) 95%; -0.21 to 0.70
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.228
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Depressed Mood, Day 30: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3096
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 95%; -0.18 to 0.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.182
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Feeling of Guilt, Hour 2: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1925
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -0.55 to 0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.165
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Feeling of Guilt, Hour 4:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0101
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.44
	Confidence Interval	(2-Sided) 95%; -0.77 to -0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.168
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Feeling of Guilt, Hour 8:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1546
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.56 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.163
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Feeling of Guilt, Hour 12:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0901
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -0.62 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.168
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Feeling of Guilt, Hour 24:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0717
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -0.62 to 0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.162
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Feeling of Guilt, Hour 36:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0468
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.34
	Confidence Interval	(2-Sided) 95%; -0.68 to 0.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.169
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Feeling of Guilt, Hour 48:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2222
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.56 to 0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.173
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Feeling of Guilt, Hour 60:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0682
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -0.60 to 0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.156
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Feeling of Guilt, Hour 72:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0147
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.40
	Confidence Interval	(2-Sided) 95%; -0.72 to -0.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.160
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Feeling of Guilt, Day 7:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0837
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.32
	Confidence Interval	(2-Sided) 95%; -0.68 to 0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.182
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Feeling of Guilt, Day 14: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5828
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.46 to 0.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.179
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Feeling of Guilt, Day 21: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5674
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.43 to 0.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.168
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Feeling of Guilt, Day 30: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4613
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; -0.18 to 0.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.145
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Suicide, Hour 2:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3240
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.24 to 0.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.082
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Suicide, Hour 4:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3023
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.24 to 0.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.082
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Suicide, Hour 8:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4127
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -0.23 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.082
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Suicide, Hour 12: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2819
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.25 to 0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.082
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Suicide, Hour 24: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3884
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -0.23 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.082
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Suicide, Hour 36:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2750
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.25 to 0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.082
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Suicide, Hour 48:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1811
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95%; -0.27 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.082
	Estimation Comments

Statistical Analysis 34

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Suicide, Hour 60:MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3854
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -0.23 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.082
	Estimation Comments

Statistical Analysis 35

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Suicide, Hour 72: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3822
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -0.23 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.082
	Estimation Comments

Statistical Analysis 36

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Suicide, Day 7: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9255
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.17 to 0.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.082
	Estimation Comments

Statistical Analysis 37

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Suicide, Day 14: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6714
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.14 to 0.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.091
	Estimation Comments

Statistical Analysis 38

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Suicide, Day 21: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9838
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; -0.18 to 0.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.091
	Estimation Comments

Statistical Analysis 39

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Suicide, Day 30: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8884
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.17 to 0.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.083
	Estimation Comments

Statistical Analysis 40

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Early, Hour 2: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6996
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.23 to 0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.097
	Estimation Comments

Statistical Analysis 41

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Early, Hour 4: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4426
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 95%; -0.15 to 0.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.121
	Estimation Comments

Statistical Analysis 42

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Early, Hour 8: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8743
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.20 to 0.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.110
	Estimation Comments

Statistical Analysis 43

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Early, Hour 12: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3498
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; -0.12 to 0.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.118
	Estimation Comments

Statistical Analysis 44

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Early, Hour 24: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0839
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95%; -0.56 to 0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.151
	Estimation Comments

Statistical Analysis 45

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Early, Hour 36: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2595
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 95%; -0.49 to 0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.157
	Estimation Comments

Statistical Analysis 46

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Early, Hour 48: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0560
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.32
	Confidence Interval	(2-Sided) 95%; -0.66 to 0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.168
	Estimation Comments

Statistical Analysis 47

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Early, Hour 60: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6187
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.45 to 0.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.180
	Estimation Comments

Statistical Analysis 48

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Early, Hour 72 MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0187
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.39
	Confidence Interval	(2-Sided) 95%; -0.72 to -0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.163
	Estimation Comments

Statistical Analysis 49

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Early, Day 7: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1531
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95%; -0.62 to 0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.180
	Estimation Comments

Statistical Analysis 50

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Early, Day 14: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3341
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.58 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.197
	Estimation Comments

Statistical Analysis 51

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Early, Day 21: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8969
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -0.40 to 0.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.216
	Estimation Comments

Statistical Analysis 52

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Early, Day 30: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5862
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 95%; -0.25 to 0.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.174
	Estimation Comments

Statistical Analysis 53

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Middle, Hour 2: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3776
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.117
	Estimation Comments

Statistical Analysis 54

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Middle, Hour 4: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9029
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.26 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.121
	Estimation Comments

Statistical Analysis 55

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Middle, Hour 8: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6173
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.18 to 0.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.121
	Estimation Comments

Statistical Analysis 56

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Middle, Hour 12: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2433
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 95%; -0.10 to 0.39
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.124
	Estimation Comments

Statistical Analysis 57

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Middle, Hour 24 MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0234
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.32
	Confidence Interval	(2-Sided) 95%; -0.59 to -0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.139
	Estimation Comments

Statistical Analysis 58

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Middle, Hour 36: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0540
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -0.55 to 0.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.139
	Estimation Comments

Statistical Analysis 59

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Middle, Hour 48: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0406
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.30
	Confidence Interval	(2-Sided) 95%; -0.58 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.144
	Estimation Comments

Statistical Analysis 60

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Middle, Hour 60: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0295
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -0.56 to -0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.132
	Estimation Comments

Statistical Analysis 61

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Middle, Hour 72: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0925
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.50 to 0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.135
	Estimation Comments

Statistical Analysis 62

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Middle, Day 7: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1631
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.52 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.152
	Estimation Comments

Statistical Analysis 63

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Middle, Day 14: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2213
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.60 to 0.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.185
	Estimation Comments

Statistical Analysis 64

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Middle, Day 21: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9175
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.36 to 0.39
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.189
	Estimation Comments

Statistical Analysis 65

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Middle, Day 30: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6763
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -0.40 to 0.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.165
	Estimation Comments

Statistical Analysis 66

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Late, Hour 2: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3805
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.121
	Estimation Comments

Statistical Analysis 67

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Late, Hour 4: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6073
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 95%; -0.19 to 0.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.127
	Estimation Comments

Statistical Analysis 68

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Late, Hour 8: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7848
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.27 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.119
	Estimation Comments

Statistical Analysis 69

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Late, Hour 12: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9038
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.25 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.121
	Estimation Comments

Statistical Analysis 70

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Late, Hour 24: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6869
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.134
	Confidence Interval	(2-Sided) 95%; -0.32 to 0.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.134
	Estimation Comments

Statistical Analysis 71

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Late, Hour 36: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9272
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.26 to 0.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.139
	Estimation Comments

Statistical Analysis 72

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Late, Hour 48: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6931
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.31 to 0.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.131
	Estimation Comments

Statistical Analysis 73

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Late, Hour 60: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8262
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.29 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.132
	Estimation Comments

Statistical Analysis 74

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Late, Hour 72: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0749
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.54 to 0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.141
	Estimation Comments

Statistical Analysis 75

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Late, Day 7: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1923
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 95%; -0.45 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.135
	Estimation Comments

Statistical Analysis 76

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Late, Day 14: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0326
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95%; -0.73 to -0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.176
	Estimation Comments

Statistical Analysis 77

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Late, Day 21: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4440
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.47 to 0.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.171
	Estimation Comments

Statistical Analysis 78

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insomnia-Late, Day 30: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7057
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.32 to 0.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.134
	Estimation Comments

Statistical Analysis 79

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Work and Activities, Hour 2: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2865
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.42 to 0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.137
	Estimation Comments

Statistical Analysis 80

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Work and Activities, Hour 4: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9475
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.33 to 0.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.170
	Estimation Comments

Statistical Analysis 81

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Work and Activities, Hour 8: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1880
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.61 to 0.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.185
	Estimation Comments

Statistical Analysis 82

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Work and Activities, Hour 12: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5950
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95%; -0.51 to 0.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.203
	Estimation Comments

Statistical Analysis 83

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Work and Activities, Hour 24 : MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9636
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.39 to 0.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.200
	Estimation Comments

Statistical Analysis 84

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Work and Activities, Hour 36: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5836
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95%; -0.50 to 0.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.196
	Estimation Comments

Statistical Analysis 85

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Work and Activities, Hour 48 : MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1568
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95%; -0.63 to 0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.184
	Estimation Comments

Statistical Analysis 86

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Work and Activities, Hour 60: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0155
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.44
	Confidence Interval	(2-Sided) 5%; -0.79 to -0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.177
	Estimation Comments

Statistical Analysis 87

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Work and Activities, Hour 72: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0504
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95%; -0.76 to 0.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.192
	Estimation Comments

Statistical Analysis 88

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Work and Activities, Day 7: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1865
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 95%; -0.70 to 0.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.212
	Estimation Comments

Statistical Analysis 89

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Work and Activities, Day 14: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0518
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.43
	Confidence Interval	(2-Sided) 95%; -0.87 to 0.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.220
	Estimation Comments

Statistical Analysis 90

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Work and Activities, Day 21: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8330
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -0.42 to 0.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.239
	Estimation Comments

Statistical Analysis 91

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Work and Activities, Day 30: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8440
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.34 to 0.42
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.191
	Estimation Comments

Statistical Analysis 92

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Retardation, Hour 2: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4602
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 95%; -0.15 to 0.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.121
	Estimation Comments

Statistical Analysis 93

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Retardation, Hour 4: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0891
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.20
	Confidence Interval	(2-Sided) 95%; -0.03 to 0.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.117
	Estimation Comments

Statistical Analysis 94

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Retardation, Hour 8: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3088
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.117
	Estimation Comments

Statistical Analysis 95

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Retardation, Hour 12: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8560
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.24 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.112
	Estimation Comments

Statistical Analysis 96

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Retardation, Hour 24: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9702
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; -0.24 to 0.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.125
	Estimation Comments

Statistical Analysis 97

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Retardation, Hour 36: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8001
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.25 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.114
	Estimation Comments

Statistical Analysis 98

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Retardation, Hour 48: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3223
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.109
	Estimation Comments

Statistical Analysis 99

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Retardation, Hour 60: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3385
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.26 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.089
	Estimation Comments

Statistical Analysis 100

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Retardation, Hour 72: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7003
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.16 to 0.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.100
	Estimation Comments

Statistical Analysis 101

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Retardation, Day 7: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0311
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -0.41 to -0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.099
	Estimation Comments

Statistical Analysis 102

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Retardation, Day 14: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1976
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.26 to 0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.079
	Estimation Comments

Statistical Analysis 103

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Retardation, Day 21: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5489
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 95%; -0.24 to 0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.092
	Estimation Comments

Statistical Analysis 104

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Retardation, Day 30: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7992
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.17 to 0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.075
	Estimation Comments

Statistical Analysis 105

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Agitation, Hour 2: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0573
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95%; -0.40 to 0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.103
	Estimation Comments

Statistical Analysis 106

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Agitation, Hour 4: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0431
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -0.44 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.110
	Estimation Comments

Statistical Analysis 107

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Agitation, Hour 8: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0060
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.30
	Confidence Interval	(2-Sided) 95%; -0.52 to -0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.108
	Estimation Comments

Statistical Analysis 108

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Agitation, Hour 12: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0215
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.30
	Confidence Interval	(2-Sided) 95%; -0.55 to -0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.127
	Estimation Comments

Statistical Analysis 109

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Agitation, Hour 24: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0422
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -0.44 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.109
	Estimation Comments

Statistical Analysis 110

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Agitation, Hour 36: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0433
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95%; -0.51 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.126
	Estimation Comments

Statistical Analysis 111

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Agitation, Hour 48: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0051
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.34
	Confidence Interval	(2-Sided) 95%; -0.57 to -0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.118
	Estimation Comments

Statistical Analysis 112

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Agitation, Hour 60: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0973
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -0.48 to 0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.133
	Estimation Comments

Statistical Analysis 113

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Agitation, Hour 72: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0036
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95%; -0.63 to -0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.126
	Estimation Comments

Statistical Analysis 114

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Agitation, Day 7: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0498
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95%; -0.52 to 0.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.131
	Estimation Comments

Statistical Analysis 115

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Agitation, Day 14: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5111
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.39 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.147
	Estimation Comments

Statistical Analysis 116

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Agitation, Day 21: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5839
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.39 to 0.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.155
	Estimation Comments

Statistical Analysis 117

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Agitation, Day 30: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1905
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.33 to 0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.100
	Estimation Comments

Statistical Analysis 118

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Psychic, Hour 2: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1767
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -0.54 to 0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.162
	Estimation Comments

Statistical Analysis 119

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Psychic, Hour 4: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5182
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.47 to 0.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.180
	Estimation Comments

Statistical Analysis 120

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Psychic, Hour 8: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3930
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.53 to 0.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.185
	Estimation Comments

Statistical Analysis 121

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Psychic, Hour 12: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5212
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.50 to 0.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.189
	Estimation Comments

Statistical Analysis 122

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Psychic, Hour 24: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4741
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.50 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.184
	Estimation Comments

Statistical Analysis 123

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Psychic, Hour 36: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4482
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.51 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.186
	Estimation Comments

Statistical Analysis 124

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Psychic, Hour 48: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0963
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.31
	Confidence Interval	(2-Sided) 95%; -0.69 to 0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.187
	Estimation Comments

Statistical Analysis 125

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Psychic, Hour 60: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0030
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.52
	Confidence Interval	(2-Sided) 95%; -0.86 to -0.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.171
	Estimation Comments

Statistical Analysis 126

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Psychic, Hour 72: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1116
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 95%; -0.63 to 0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.177
	Estimation Comments

Statistical Analysis 127

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Psychic, Day 7: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0040
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.51
	Confidence Interval	(2-Sided) 95%; -0.86 to -0.17
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.173
	Estimation Comments

Statistical Analysis 128

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Psychic, Day 14 : MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8253
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.54 to 0.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.244
	Estimation Comments

Statistical Analysis 129

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Psychic, Day 21 : MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5795
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 95%; -0.30 to 0.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.209
	Estimation Comments

Statistical Analysis 130

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Psychic, Day 30: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4032
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 95%; -0.21 to 0.51
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.182
	Estimation Comments

Statistical Analysis 131

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Somatic, Hour 2: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6117
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -0.33 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.133
	Estimation Comments

Statistical Analysis 132

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Somatic, Hour 4: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4716
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.35 to 0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.130
	Estimation Comments

Statistical Analysis 133

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Somatic, Hour 8: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6041
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -0.34 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.136
	Estimation Comments

Statistical Analysis 134

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Somatic, Hour 12: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0424
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -0.53 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.132
	Estimation Comments

Statistical Analysis 135

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Somatic, Hour 24: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7622
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.32 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.138
	Estimation Comments

Statistical Analysis 136

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Somatic, Hour 36: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2689
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.40 to 0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.130
	Estimation Comments

Statistical Analysis 137

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Somatic, Hour 48 : MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2110
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.44 to 0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.134
	Estimation Comments

Statistical Analysis 138

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Somatic, Hour 60: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5873
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -0.34 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.135
	Estimation Comments

Statistical Analysis 139

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Somatic, Hour 72: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0450
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.46 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.114
	Estimation Comments

Statistical Analysis 140

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Somatic, Day 7: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0847
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95%; -0.57 to 0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.152
	Estimation Comments

Statistical Analysis 141

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Somatic, Day 14: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2522
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.22
	Confidence Interval	(2-Sided) 95%; -0.16 to 0.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.189
	Estimation Comments

Statistical Analysis 142

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Somatic, day 21: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5026
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95%; -0.43 to 0.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.160
	Estimation Comments

Statistical Analysis 143

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Anxiety Somatic, Day 30: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5911
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.38 to 0.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.149
	Estimation Comments

Statistical Analysis 144

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms Gastrointestinal, Hour 2: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5800
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 95%; -0.18 to 0.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.122
	Estimation Comments

Statistical Analysis 145

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms Gastrointestinal, Hour 4: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6754
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.31 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.129
	Estimation Comments

Statistical Analysis 146

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms Gastrointestinal, Hour 8: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1006
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 95%; -0.04 to 0.42
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.116
	Estimation Comments

Statistical Analysis 147

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms Gastrointestinal, Hour 12: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3588
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.120
	Estimation Comments

Statistical Analysis 148

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms Gastrointestinal, Hour 24: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5807
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 95%; -0.28 to 0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.109
	Estimation Comments

Statistical Analysis 149

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms Gastrointestinal, Hour 36: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4241
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.112
	Estimation Comments

Statistical Analysis 150

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms Gastrointestinal, Hour 48: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7984
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.26 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.115
	Estimation Comments

Statistical Analysis 151

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms Gastrointestinal, Hour 60: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8732
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.22 to 0.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.122
	Estimation Comments

Statistical Analysis 152

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms Gastrointestinal, Hour 72: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8621
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.19 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.107
	Estimation Comments

Statistical Analysis 153

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms Gastrointestinal, Day 7: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1087
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95%; -0.45 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.126
	Estimation Comments

Statistical Analysis 154

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms Gastrointestinal, Day 14: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2153
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.41 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.125
	Estimation Comments

Statistical Analysis 155

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms Gastrointestinal, Day 21: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1422
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -0.51 to 0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.145
	Estimation Comments

Statistical Analysis 156

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms Gastrointestinal, Day 30: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7211
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.19 to 0.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.114
	Estimation Comments

Statistical Analysis 157

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms General, Hour 2: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8224
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.18 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.103
	Estimation Comments

Statistical Analysis 158

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms General, Hour 4: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6362
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 95%; -0.31 to 0.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.126
	Estimation Comments

Statistical Analysis 159

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms General, Hour 8: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6094
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 95%; -0.31 to 0.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.123
	Estimation Comments

Statistical Analysis 160

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms General, Hour 12: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0457
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.49 to 0.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.123
	Estimation Comments

Statistical Analysis 161

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms General, Hour 24: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5691
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.36 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.140
	Estimation Comments

Statistical Analysis 162

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	Somatic Symptoms General, Hour 36: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2942
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.40 to 0.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.130
	Estimation Comments

Statistical Analysis 163

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms General, Hour 48: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5389
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.35 to 0.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.136
	Estimation Comments

Statistical Analysis 164

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms General, Hour 60: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4061
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.40 to 0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.141
	Estimation Comments

Statistical Analysis 165

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms General, Hour 72: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0990
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.56 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.153
	Estimation Comments

Statistical Analysis 166

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms General, Day 7: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0108
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.36
	Confidence Interval	(2-Sided) 95%; -0.63 to -0.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.138
	Estimation Comments

Statistical Analysis 167

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms General, Day 14: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0889
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 95%; -0.59 to 0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.160
	Estimation Comments

Statistical Analysis 168

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms General, Day 21: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3721
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 95%; -0.18 to 0.49
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.169
	Estimation Comments

Statistical Analysis 169

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Somatic Symptoms General, Day 30: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5513
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.36 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.141
	Estimation Comments

Statistical Analysis 170

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Genital Symptoms, Hour 2: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0748
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 95%; -0.01 to 0.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.067
	Estimation Comments

Statistical Analysis 171

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Genital Symptoms, Hour 4: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3545
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.087
	Estimation Comments

Statistical Analysis 172

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Genital Symptoms, Hour 8: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6531
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.14 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.094
	Estimation Comments

Statistical Analysis 173

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Genital Symptoms, Hour 12: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7520
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.26 to 0.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.115
	Estimation Comments

Statistical Analysis 174

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Genital Symptoms, Hour 24: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8861
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.26 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.123
	Estimation Comments

Statistical Analysis 175

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Genital Symptoms, Hour 36: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3280
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.38 to 0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.127
	Estimation Comments

Statistical Analysis 176

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Genital Symptoms, Hour 48: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1123
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.46 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.128
	Estimation Comments

Statistical Analysis 177

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Genital Symptoms, Hour 60: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2541
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.36 to 0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.116
	Estimation Comments

Statistical Analysis 178

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Genital Symptoms, Hour 72: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0110
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.37
	Confidence Interval	(2-Sided) 95%; -0.66 to -0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.143
	Estimation Comments

Statistical Analysis 179

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Genital Symptoms, Day 7: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7720
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.36 to 0.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.158
	Estimation Comments

Statistical Analysis 180

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Genital Symptoms, Day 14: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6311
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.52 to 0.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.210
	Estimation Comments

Statistical Analysis 181

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Genital Symptoms, Day 21: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6877
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.50 to 0.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.207
	Estimation Comments

Statistical Analysis 182

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Genital Symptoms, Day 30: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2465
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.22
	Confidence Interval	(2-Sided) 95%; -0.15 to 0.58
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.186
	Estimation Comments

Statistical Analysis 183

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Hypochondriasis, Hour 2: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1279
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.36 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.101
	Estimation Comments

Statistical Analysis 184

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Hypochondriasis, Hour 4: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3946
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.26 to 0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.093
	Estimation Comments

Statistical Analysis 185

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Hypochondriasis, Hour 8: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6694
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.23 to 0.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.095
	Estimation Comments

Statistical Analysis 186

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Hypochondriasis, Hour 12: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1113
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.36 to 0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.100
	Estimation Comments

Statistical Analysis 187

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Hypochondriasis, Hour 24: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5811
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.089
	Estimation Comments

Statistical Analysis 188

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Hypochondriasis, Hour 36: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6794
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.25 to 0.17
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.106
	Estimation Comments

Statistical Analysis 189

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Hypochondriasis, Hour 48: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6031
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -0.14 to 0.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.099
	Estimation Comments

Statistical Analysis 190

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Hypochondriasis, Hour 60: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6673
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.24 to 0.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.099
	Estimation Comments

Statistical Analysis 191

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Hypochondriasis, Hour 72: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6472
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.25 to 0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.102
	Estimation Comments

Statistical Analysis 192

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Hypochondriasis, Day 7: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8654
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.26 to 0.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.119
	Estimation Comments

Statistical Analysis 193

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Hypochondriasis, Day 14: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2101
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 95%; -0.48 to 0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.140
	Estimation Comments

Statistical Analysis 194

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Hypochondriasis, Day 21: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7128
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.30 to 0.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.126
	Estimation Comments

Statistical Analysis 195

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Hypochondriasis, Day 30: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3297
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.27 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.090
	Estimation Comments

Statistical Analysis 196

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Loss of weight, Hour 2: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4493
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -0.08 to 0.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.069
	Estimation Comments

Statistical Analysis 197

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Loss of weight, Hour 4: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0717
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 95%; -0.01 to 0.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.081
	Estimation Comments

Statistical Analysis 198

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Loss of Weight, Hour 8: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1054
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.066
	Estimation Comments

Statistical Analysis 199

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Loss of Weight, Hour 12: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0408
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.18
	Confidence Interval	(2-Sided) 95%; 0.01 to 0.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.088
	Estimation Comments

Statistical Analysis 200

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Loss of Weight, Hour 24: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0233
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.20
	Confidence Interval	(2-Sided) 95%; 0.03 to 0.38
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.088
	Estimation Comments

Statistical Analysis 201

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Loss of Weight, Hour 36: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3610
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.088
	Estimation Comments

Statistical Analysis 202

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Loss of Weight, Hour 48: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2358
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 95%; -0.08 to 0.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.100
	Estimation Comments

Statistical Analysis 203

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Loss of Weight, Hour 60: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9492
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.16 to 0.17
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.085
	Estimation Comments

Statistical Analysis 204

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Loss of Weight, Hour 72: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4352
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.28 to 0.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.102
	Estimation Comments

Statistical Analysis 205

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Loss of Weight, Day 7: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1176
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.20
	Confidence Interval	(2-Sided) 95%; -0.05 to 0.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.125
	Estimation Comments

Statistical Analysis 206

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Loss of Weight, Day 14: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7812
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -0.30 to 0.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.174
	Estimation Comments

Statistical Analysis 207

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Loss of Weight, Day 21: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5085
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.48 to 0.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.182
	Estimation Comments

Statistical Analysis 208

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Loss of Weight, Day 30: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8274
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -0.28 to 0.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.156
	Estimation Comments

Statistical Analysis 209

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insight, Hour 2: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3675
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.045
	Estimation Comments

Statistical Analysis 210

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insight, Hour 4: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1818
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 95%; -0.15 to 0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.045
	Estimation Comments

Statistical Analysis 211

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insight, Hour 8: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0826
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.17 to 0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.045
	Estimation Comments

Statistical Analysis 212

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insight, Hour 12: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6436
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.045
	Estimation Comments

Statistical Analysis 213

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insight, Hour 24: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1827
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 95%; -0.15 to 0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.045
	Estimation Comments

Statistical Analysis 214

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insight, Hour 36: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9859
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.045
	Estimation Comments

Statistical Analysis 215

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insight, Hour 48: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6672
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.045
	Estimation Comments

Statistical Analysis 216

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insight, Hour 60: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2031
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.03 to 0.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.046
	Estimation Comments

Statistical Analysis 217

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insight, Hour 72: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6664
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.045
	Estimation Comments

Statistical Analysis 218

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insight, Day 7: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3417
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.045
	Estimation Comments

Statistical Analysis 219

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insight, Day 14: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6622
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.12 to 0.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.051
	Estimation Comments

Statistical Analysis 220

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insight, Day 21: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9087
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.051
	Estimation Comments

Statistical Analysis 221

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Insight, Day 30: MMRM was used for analysis. The change from baseline in HAM-D individual item score at each visit was the dependent variable. Treatment, baseline HAM-D individual item score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms were explanatory variables included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8263
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.08 to 0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.046
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline at Key Time Points in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score
Description	The MADRS is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in participants with mood disorders. It was designed as an adjunct to the HAM-D, to be more sensitive than the Hamilton Scale to the changes brought on by antidepressants and other forms of treatment. Each item yielded a score of 0 to 6. The MADRS total score was calculated as the sum of the 10 individual item scores, which ranged from 0 to 60. Higher MADRS scores indicates more severe depression. A negative change from baseline indicates less severe depression. A positive change from baseline indicates more severe depression.
Time Frame	Baseline, Hour 60, Days 7 and 30

Outcome Measure Data

Analysis Population Description

All randomized participants who started study drug infusion, had a valid baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Placebo	SAGE-547 90 μg/kg/h
Arm/Group Description	Participants received an infusion rate equivalent to the 90 μg/kg/h group.	Participants received a 4-hour dose titration period of 30 μg/kg/h (0 to 4 hours), then 60 μg/kg/h (4 to 24 hours), then 90 μg/kg/h (24 to 52 hours), followed by a taper to 60 μg/kg/h (52 to 56 hours), and 30 μg/kg/h (56 to 60 hours).
Measure Participants	53	51
Hour 60	-15.66 (1.329)	-20.52 (1.333)
Day 7	-15.35 (1.658)	-18.91 (1.676)
Day 30	-20.52 (1.489)	-20.48 (1.504)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Hour 60: MMRM was used for analysis. The change from baseline in MADRS total score at each visit was the dependent variable. Treatment, baseline MADRS total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0033
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-4.86
	Confidence Interval	(2-Sided) 95%; -8.06 to -1.66
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.612
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Day 7: MMRM was used for analysis. The change from baseline in MADRS total score at each visit was the dependent variable. Treatment, baseline MADRS total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1017
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-3.56
	Confidence Interval	(2-Sided) 95%; -7.84 to 0.72
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.154
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Day 30: MMRM was used for analysis. The change from baseline in MADRS total score at each visit was the dependent variable. Treatment, baseline MADRS total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9845
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -3.72 to 3.79
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.884
	Estimation Comments

9. Secondary Outcome

Title	Percentage of Participants With Clinical Global Impression - Improvement (CGI-I) Response
Description	The CGI-I response was defined as having a score of 1 (very much improved) or 2 (much improved). CGI-I item employs a 7-point Likert scale to measure the overall improvement in the participant's condition post-treatment. The investigator rated the participant's total improvement whether or not it was due entirely to drug treatment. Response choices include: 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. The CGI-I was only rated at post-treatment assessments. By definition, all CGI-I assessments were evaluated against baseline conditions.
Time Frame	Hour 60, Days 7 and 30

Outcome Measure Data

Analysis Population Description

All randomized participants who started study drug infusion, had a valid baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Placebo	SAGE-547 90 μg/kg/h
Arm/Group Description	Participants received an infusion rate equivalent to the 90 μg/kg/h group.	Participants received a 4-hour dose titration period of 30 μg/kg/h (0 to 4 hours), then 60 μg/kg/h (4 to 24 hours), then 90 μg/kg/h (24 to 52 hours), followed by a taper to 60 μg/kg/h (52 to 56 hours), and 30 μg/kg/h (56 to 60 hours).
Measure Participants	53	51
Hour 60	55.8 105.3%	79.6 156.1%
Day 7	54.7 103.2%	70.0 137.3%
Day 30	78.8 148.7%	81.3 159.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Hour 60: GEE method was used for analysis. CGI-I response at each visit was the dependent variable. Treatment, baseline CGI-S score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	GEE method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.0
	Confidence Interval	(2-Sided) 95%; 2.0 to 12.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Day 7: GEE method was used for analysis. CGI-I response at each visit was the dependent variable. Treatment, baseline CGI-S score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0478
	Comments
	Method	GEE method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.9
	Confidence Interval	(2-Sided) 95%; 1.0 to 8.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Day 30: GEE method was used for analysis. CGI-I response at each visit was the dependent variable. Treatment, baseline CGI-S score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4399
	Comments
	Method	GEE method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; 0.5 to 4.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline in the Generalized Anxiety Disorder 7-Item Scale (GAD-7) Total Score
Description	The GAD-7 is a participant-rated, generalized anxiety symptom severity scale. Scoring for GAD-7 generalized anxiety is calculated by assigning scores of 0 = "not at all sure," 1 = "several days," 2 = "over half the days," and 3 = "nearly every day" to the response categories. The GAD-7 total score for the seven items ranges from 0 to 21, where a score of 0 to 4 = minimal anxiety, 5 to 9 = mild anxiety, 10 to 14 = moderate anxiety, and 15 to 21 = severe anxiety. The GAD-7 total score was calculated as the sum of the seven individual item scores. A negative change from baseline indicates less anxiety. A positive change from baseline indicates more anxiety.
Time Frame	Baseline, Hour 60, Days 7, 14, 21 and 30

Outcome Measure Data

Analysis Population Description

All randomized participants who started study drug infusion, had a valid baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Placebo	SAGE-547 90 μg/kg/h
Arm/Group Description	Participants received an infusion rate equivalent to the 90 μg/kg/h group.	Participants received a 4-hour dose titration period of 30 μg/kg/h (0 to 4 hours), then 60 μg/kg/h (4 to 24 hours), then 90 μg/kg/h (24 to 52 hours), followed by a taper to 60 μg/kg/h (52 to 56 hours), and 30 μg/kg/h (56 to 60 hours).
Measure Participants	53	51
Hour 60	-6.41 (0.814)	-7.58 (0.850)
Day 7	-7.67 (0.858)	-8.43 (0.879)
Day 14	-7.90 (0.937)	-9.76 (0.961)
Day 21	-8.92 (1.053)	-10.88 (1.081)
Day 30	-9.89 (0.884)	-10.20 (0.913)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Hour 60: MMRM was used for the analysis. The change from baseline in GAD-7 total score at each visit was the dependent variable. Treatment, baseline GAD-7 total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2636
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.17
	Confidence Interval	(2-Sided) 95%; -3.24 to 0.90
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.041
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Day 7: MMRM was used for the analysis. The change from baseline in GAD-7 total score at each visit was the dependent variable. Treatment, baseline GAD-7 total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4897
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.76
	Confidence Interval	(2-Sided) 95%; -2.96 to 1.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.103
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Day 14: MMRM was used for the analysis. The change from baseline in GAD-7 total score at each visit was the dependent variable. Treatment, baseline GAD-7 total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1341
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.86
	Confidence Interval	(2-Sided) 95%; -4.30 to 0.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.227
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Day 21: MMRM was used for the analysis. The change from baseline in GAD-7 total score at each visit was the dependent variable. Treatment, baseline GAD-7 total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1691
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.95
	Confidence Interval	(2-Sided) 95%; -4.76 to 0.85
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.408
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, SAGE-547 90 μg/kg/h
	Comments	Change at Day 30: MMRM was used for the analysis. The change from baseline in GAD-7 total score at each visit was the dependent variable. Treatment, baseline GAD-7 total score, pooled center, baseline antidepressant use, visit time point, and visit time point-by-treatment interaction terms as explanatory variables were included in the model. All explanatory variables including pooled center were treated as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7852
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.31
	Confidence Interval	(2-Sided) 95%; -2.60 to 1.97
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.149
	Estimation Comments

11. Secondary Outcome

Title	Percentage of Participants With Treatment Emergent Adverse Event (TEAE)
Description	An Adverse Event (AE) is 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 (eg, 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 is defined as an AE with onset on or after the start of study drug infusion, or any worsening of a pre-existing medical condition/AE with onset on or after the start of study drug infusion.
Time Frame	Up to approximately 37 days

Outcome Measure Data

Analysis Population Description

The safety set included all randomized participants who started the study drug infusion.

Arm/Group Title	Placebo	SAGE-547 90 μg/kg/h
Arm/Group Description	Participants received an infusion rate equivalent to the 90 μg/kg/h group.	Participants received a 4-hour dose titration period of 30 μg/kg/h (0 to 4 hours), then 60 μg/kg/h (4 to 24 hours), then 90 μg/kg/h (24 to 52 hours), followed by a taper to 60 μg/kg/h (52 to 56 hours), and 30 μg/kg/h (56 to 60 hours).
Measure Participants	53	51
Number [percentage of participants]	45.3 85.5%	49.0 96.1%

12. Secondary Outcome

Title	Time to Change in Antidepressant Medication
Description	The time to first start or increase in the dose and time to first stop or decrease in the dose of any antidepressant medication.
Time Frame	Up to approximately 37 days

Outcome Measure Data

Analysis Population Description

All randomized participants who started study drug infusion, had a valid baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Placebo	SAGE-547 90 μg/kg/h
Arm/Group Description	Participants received an infusion rate equivalent to the 90 μg/kg/h group.	Participants received a 4-hour dose titration period of 30 μg/kg/h (0 to 4 hours), then 60 μg/kg/h (4 to 24 hours), then 90 μg/kg/h (24 to 52 hours), followed by a taper to 60 μg/kg/h (52 to 56 hours), and 30 μg/kg/h (56 to 60 hours).
Measure Participants	53	51
Time to first start/increase in dose	8	10
Time to first stop/decrease in dose	18

Adverse Events

Time Frame	Up to approximately 37 days
Adverse Event Reporting Description	The Safety Set included all randomized participants who started the study drug infusion.
Arm/Group Title	Placebo		SAGE-547 90 μg/kg/h
Arm/Group Description	Participants received an infusion rate equivalent to the 90 μg/kg/h group.		Participants received a 4-hour dose titration period of 30 μg/kg/h (0 to 4 hours), then 60 μg/kg/h (4 to 24 hours), then 90 μg/kg/h (24 to 52 hours), followed by a taper to 60 μg/kg/h (52 to 56 hours), and 30 μg/kg/h (56 to 60 hours).
All Cause Mortality
	Placebo		SAGE-547 90 μg/kg/h
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/53 (0%)		0/51 (0%)
Serious Adverse Events
	Placebo		SAGE-547 90 μg/kg/h
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/53 (0%)		1/51 (2%)
Nervous system disorders
Altered state of consciousness	0/53 (0%)		1/51 (2%)
Syncope	0/53 (0%)		1/51 (2%)
Other (Not Including Serious) Adverse Events
	Placebo		SAGE-547 90 μg/kg/h
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/53 (24.5%)		21/51 (41.2%)
Gastrointestinal disorders
Nausea	2/53 (3.8%)		5/51 (9.8%)
General disorders
Fatigue	2/53 (3.8%)		3/51 (5.9%)
Infusion site pain	2/53 (3.8%)		5/51 (9.8%)
Nervous system disorders
Dizziness	4/53 (7.5%)		5/51 (9.8%)
Headache	6/53 (11.3%)		9/51 (17.6%)
Somnolence	2/53 (3.8%)		4/51 (7.8%)

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).