Trial Outcomes & Findings for A Study to Evaluate SAGE-217 in Adult Participants With Major Depressive Disorder (MDD) (NCT NCT03864614)

Last Updated: 2024-08-27

Results Overview

An adverse event (AE) was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal (investigational) product. For Part A, a TEAE was defined as an AE with onset after the first dose of SAGE-217.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1515 participants

Primary outcome timeframe

Up to 52 Weeks

Results posted on

2024-08-27

Participant Flow

Participants were enrolled at 38 study sites in Part A and 52 study sites in Part B in the United States.

Participants with Major Depressive Disorder (MDD) were enrolled in this study. This study was conducted in 2 parts, Part A enrolled de novo MDD participants and Part B enrolled MDD participants from the parent study 217- MDD-305 (NCT04476030). Data for Part B was collected and reported in a single arm for each participant who signed informed consent to enroll into this study to be treated with SAGE-217 if and when eligible to be treated.

Participant milestones

Participant milestones
Measure	Part A: Sage-217 High-dose Cohort Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the investigational product (IP), the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period	Part A: Sage-217 Low-dose Cohort Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period	Part B: Sage-217 Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Overall Study STARTED	513	645	80	277
Overall Study Dosed With SAGE-217 Within This Study	513	645	80	118
Overall Study COMPLETED	213	236	76	69
Overall Study NOT COMPLETED	300	409	4	208

Reasons for withdrawal

Reasons for withdrawal
Measure	Part A: Sage-217 High-dose Cohort Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the investigational product (IP), the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period	Part A: Sage-217 Low-dose Cohort Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period	Part B: Sage-217 Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Overall Study Participant Did Not Meet 50% Reduction in HAMD-17	116	173	0	0
Overall Study Withdrawal by Subject	72	100	1	21
Overall Study Lost to Follow-up	45	54	0	9
Overall Study Adverse Event	42	30	1	9
Overall Study Protocol Deviation	6	26	0	1
Overall Study Physician Decision	7	10	1	5
Overall Study Non-compliance With Investigational Drug	4	4	0	0
Overall Study Sponsor Decision	1	2	0	0
Overall Study Pregnancy	0	1	0	0
Overall Study Other	7	9	1	4
Overall Study Enrolled but did not receive SAGE-217	0	0	0	159

Baseline Characteristics

A Study to Evaluate SAGE-217 in Adult Participants With Major Depressive Disorder (MDD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part A: Sage-217 High-dose Cohort n=513 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the investigational product (IP), the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=645 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=80 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: Sage-217 n=190 Participants Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Total n=1428 Participants Total of all reporting groups
Age, Continuous	43.7 years STANDARD_DEVIATION 15.01 • n=5 Participants	44.7 years STANDARD_DEVIATION 14.31 • n=7 Participants	47.5 years STANDARD_DEVIATION 12.71 • n=5 Participants	38.9 years STANDARD_DEVIATION 12.39 • n=4 Participants	43.7 years STANDARD_DEVIATION 14.38 • n=21 Participants
Sex: Female, Male Female	331 Participants n=5 Participants	423 Participants n=7 Participants	66 Participants n=5 Participants	127 Participants n=4 Participants	947 Participants n=21 Participants
Sex: Female, Male Male	182 Participants n=5 Participants	222 Participants n=7 Participants	14 Participants n=5 Participants	63 Participants n=4 Participants	481 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	111 Participants n=5 Participants	139 Participants n=7 Participants	37 Participants n=5 Participants	40 Participants n=4 Participants	327 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	402 Participants n=5 Participants	506 Participants n=7 Participants	43 Participants n=5 Participants	150 Participants n=4 Participants	1101 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	6 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	7 Participants n=21 Participants
Race (NIH/OMB) Asian	18 Participants n=5 Participants	22 Participants n=7 Participants	1 Participants n=5 Participants	5 Participants n=4 Participants	46 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants
Race (NIH/OMB) Black or African American	45 Participants n=5 Participants	108 Participants n=7 Participants	7 Participants n=5 Participants	31 Participants n=4 Participants	191 Participants n=21 Participants
Race (NIH/OMB) White	432 Participants n=5 Participants	499 Participants n=7 Participants	72 Participants n=5 Participants	153 Participants n=4 Participants	1156 Participants n=21 Participants
Race (NIH/OMB) More than one race	7 Participants n=5 Participants	11 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	18 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants	3 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	8 Participants n=21 Participants
Region of Enrollment United States	513 participants n=5 Participants	645 participants n=7 Participants	80 participants n=5 Participants	190 participants n=4 Participants	1428 participants n=21 Participants

PRIMARY outcome

Timeframe: Up to 52 Weeks

Population: Safety Set included all participants who were administered SAGE-217.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=513 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=645 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=80 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs)	374 Participants	437 Participants	57 Participants	—	—

PRIMARY outcome

Timeframe: Up to 46 Weeks

Population: Study-specific Safety Set included all participants who signed the ICF for 217-MDD-303B and had at least 1 dosing of SAGE-217 within 217-MDD-303B. Data for Part B was collected and reported in a single arm for each participant who started treatment as specified.

An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal (investigational) product. For Part B, a TEAE was defined as an AE with onset on or after the first dose of SAGE-217 in MDD-303B for the participants who received placebo + ADT in parent study, or an AE with onset on or after the ICF signoff in MDD-303B for the participants who received SAGE-217 + ADT in parent study.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=118 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Part B: Number of Participants With TEAEs	87 Participants	—	—	—	—

PRIMARY outcome

Timeframe: Baseline up to 52 Weeks (Study Period 1-5)

Population: Safety Set included all participants who were administered SAGE-217. For Baseline: Number analyzed is participants of safety set who received SAGE-217 in corresponding study period; For Post-baseline: Number analyzed is participants with data available for analysis at a specific timepoint. A study period is a treatment cycle (treatment period+14-day follow-up) plus the observational period (until next treatment cycle or end of study, whichever is earlier) immediately following it.

C-SSRS scale consisted of a baseline evaluation that assessed lifetime experience as well as past 24-month experience of participants for SI and SB and a postbaseline evaluation that focused on suicidality since last study visit. C-SSRS included "yes" or "no"' responses for assessment of SI and SB as well as numeric ratings for severity of ideation, if present. The C-SSRS SI items included: 1. wish to be dead, 2. non-specific active suicidal thoughts, 3. active SI with any methods, 4. active SI with some intent, and 5. active SI with a specific plan (5 being the most severe). C-SSRS SB items included 1. preparatory acts or behavior, 2. aborted attempt, 3. interrupted attempt, 4. actual attempt (non-fatal), and 5. completed suicide (5 being worst). Participants with at least one SI question answered Yes or at least one SB question answered Yes post-baseline for the specific period is counted under SI or SB respectively.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=513 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=645 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=80 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 1: SB: Post-baseline	3 Participants	1 Participants	0 Participants	—	—
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 1: SI: Baseline	262 Participants	264 Participants	29 Participants	—	—
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 2: SI: Baseline	52 Participants	57 Participants	16 Participants	—	—
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 2: SI: Post-baseline	44 Participants	51 Participants	10 Participants	—	—
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 2: SB: Baseline	1 Participants	0 Participants	0 Participants	—	—
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 2: SB: Post-baseline	0 Participants	0 Participants	0 Participants	—	—
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 3: SI: Baseline	16 Participants	23 Participants	12 Participants	—	—
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 3: SI: Post-baseline	17 Participants	22 Participants	11 Participants	—	—
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 3: SB: Baseline	0 Participants	0 Participants	0 Participants	—	—
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 3: SB: Post-baseline	0 Participants	0 Participants	0 Participants	—	—
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 4: SI: Baseline	11 Participants	8 Participants	10 Participants	—	—
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 4: SI: Post-baseline	10 Participants	9 Participants	9 Participants	—	—
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 4: SB: Baseline	0 Participants	0 Participants	0 Participants	—	—
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 4: SB: Post-baseline	1 Participants	0 Participants	0 Participants	—	—
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 5: SI: Baseline	3 Participants	1 Participants	1 Participants	—	—
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 5: SI: Post-baseline	6 Participants	3 Participants	2 Participants	—	—
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 5: SB: Baseline	0 Participants	0 Participants	0 Participants	—	—
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 5: SB: Post-baseline	0 Participants	0 Participants	0 Participants	—	—
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 1: SI: Post-baseline	128 Participants	141 Participants	14 Participants	—	—
Part A: Number of Participants With Suicidal Ideation (SI) or Suicidal Behavior (SB) as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Study Period 1: SB: Baseline	6 Participants	8 Participants	0 Participants	—	—

PRIMARY outcome

Timeframe: Baseline up to 46 Weeks (Study Period 1-5)

Population: Period-Specific Safety Set included all participants who signed ICF for 217-MDD-303B and were dosed in respective Study Period. A Study Period is a treatment cycle followed by the immediate observation period until the first dose of the subsequent treatment cycle. Data for Part B was collected and reported in a single arm for each participant who started treatment as specified.

C-SSRS scale consisted of a baseline evaluation that assessed lifetime experience as well as past 24-month experience of participants for SI and SB and a postbaseline (PB) evaluation that focused on suicidality since last study visit. C-SSRS included "yes" or "no"' responses for assessment of SI and SB as well as numeric ratings for severity of ideation, if present. The C-SSRS SI items included: 1. wish to be dead, 2. non-specific active suicidal thoughts, 3. active SI with any methods, 4. active SI with some intent, and 5. active SI with a specific plan (5 being the most severe). C-SSRS SB items included 1. preparatory acts or behavior, 2. aborted attempt, 3. interrupted attempt, 4. actual attempt (non-fatal), and 5. completed suicide (5 being worst). Participants with at least one SI question answered Yes or at least one SB question answered Yes post-baseline for the specific period is counted under SI or SB respectively.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=118 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 1: SI: Baseline	17 Participants	—	—	—	—
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 1: SI: Post-baseline	16 Participants	—	—	—	—
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 1: SB: Baseline	0 Participants	—	—	—	—
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 1: SB: Post-baseline	1 Participants	—	—	—	—
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 2: SI: Baseline	19 Participants	—	—	—	—
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 2: SI: Post-baseline	24 Participants	—	—	—	—
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 2: SB: Baseline	0 Participants	—	—	—	—
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 2: SB: Post-baseline	0 Participants	—	—	—	—
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 3: SI: Baseline	9 Participants	—	—	—	—
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 3: SI: Post-baseline	9 Participants	—	—	—	—
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 3: SB: Baseline	0 Participants	—	—	—	—
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 3: SB: Post-baseline	0 Participants	—	—	—	—
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 4: SI: Baseline	5 Participants	—	—	—	—
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 4: SI: Post-baseline	6 Participants	—	—	—	—
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 4: SB: Baseline	0 Participants	—	—	—	—
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 4: SB: Post-baseline	0 Participants	—	—	—	—
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 5: SI: Baseline	1 Participants	—	—	—	—
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 5: SI: Post-baseline	1 Participants	—	—	—	—
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 5: SB: Baseline	0 Participants	—	—	—	—
Part B: Number of Participants With Suicidal Ideation (SI) and Suicidal Behavior (SB) as Assessed by the C-SSRS Study Period 5: SB: Post-baseline	0 Participants	—	—	—	—

SECONDARY outcome

Timeframe: Up to 52 Weeks

Population: For Part A: FAS included all participants in the Safety Set who had HAMD-17 (change from baseline \>=50%) response at Treatment Cycle 1 Day 15 and the discontinuation from study date, if it existed, was after the end of Treatment Cycle 1. For Part B: Safety Set included all participants who received a dose of SAGE-217 either in the parent study 217-MDD-305 or within this protocol 217-MDD-303B.

For Part A, the first day of the first repeat treatment is Treatment Cycle 2 Day 1. For Part B, participants who had "placebo + ADT" in the parent study (217-MDD-305), the first repeat treatment of SAGE-217 was the second treatment within MDD-303B. Participants who had SAGE-217 + ADT in the parent study (217-MDD-305), the first repeat treatment of SAGE-217 was the first treatment within MDD-303B. For Part A, as prespecified, data for this outcome measure was collected for Sage-217 High-dose Cohort and Sage-217 30 mg Cohort (Low Dose + Dose Switch). For Part B, data for this outcome measure is presented as per the designated arms in the parent study (217-MDD-305). Analysis used Kaplan-Meier estimates where the participants with no repeat treatment were censored.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=338 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=489 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=57 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT n=133 Participants Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Parts A and B: Time to First Repeat Treatment With SAGE-217	281 days Interval 191.0 to There was no observed failure time (i.e. time to repeat treatment) for which the upper bound of the confidence interval for the Kaplan-Meier estimate is less than 0.5, hence the upper limit of confidence interval remains not estimable.	135 days Interval 121.0 to 166.0	79 days Interval 64.0 to There was no observed failure time (i.e. time to repeat treatment) for which the upper bound of the confidence interval for the Kaplan-Meier estimate is less than 0.5, hence the upper limit of confidence interval remains not estimable.	233 days Interval 121.0 to There was no observed failure time (i.e. time to repeat treatment) for which the upper bound of the confidence interval for the Kaplan-Meier estimate is less than 0.5, hence the upper limit of confidence interval remains not estimable.	—

SECONDARY outcome

Timeframe: Up to 52 Weeks

Population: For Part A: FAS included all participants in the Safety Set who had HAMD-17 response at Treatment Cycle 1 Day 15 and the discontinuation from study date, if it existed, was after the end of Treatment Cycle 1. For Part B: FAS included all participants in the study-specific safety set (dosed at least once within this protocol) who had at least 1 HAMD-17 total score available after the first dose of SAGE-217 within 217-MDD-303B.

Participants who continued in the study beyond 56 days from the last study drug dose (in parent study for Part B) and had a HAMD-17 total score ≥20 between the end of first treatment cycle and start of next treatment cycle qualified for repeat treatment for SAGE-217. The 17-item HAM-D was used for measuring severity of depression. It comprised individual ratings of 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 were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score can range from 0 to 52, and higher scores indicated a greater degree of depression. For Part B, data for this outcome measure is presented as per the designated arms in the parent study (217-MDD-305).

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=338 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=409 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=80 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT n=57 Participants Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT n=61 Participants Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Parts A and B: Number of Participants Who Achieved the Requirements for Repeat Treatment for SAGE-217	174 Participants	224 Participants	80 Participants	28 Participants	61 Participants

SECONDARY outcome

Timeframe: Up to 52 Weeks

Population: For Part A: FAS included all participants in safety set who had HAMD-17 response at Treatment Cycle 1 Day 15 and discontinuation from study date, if it existed, was after end of Treatment Cycle 1. For Part B: FAS included all participants in study-specific safety set (dosed at least once within this protocol) who had at least 1 HAMD-17 total score available after first dose of SAGE-217 within 217-MDD-303B.

The response of initial treatment and/or repeat treatment was assessed by HAMD-17. The 17-item HAM-D scale was used for measuring severity of depression. The HAM-D comprised individual ratings of following symptoms scored in range of 0 to 2: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. Following symptoms were scored in range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. total score range=0 to 52, and higher scores indicated greater degree of depression. Participants who had a HAM-D total score \>=20 within the protocol were eligible for at least 1 repeat treatment in study. For Part B, data for this outcome measure is presented as per the designated arms in parent study (217-MDD-305). Participants who did not have any re-treatment were included with number of re-treatments equal to 0.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=338 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=409 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=80 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT n=57 Participants Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT n=61 Participants Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Parts A and B: Number of Repeat Treatment Cycles of SAGE-217 for Each Participant	0.8 repeat treatment cycles Standard Deviation 1.11	0.9 repeat treatment cycles Standard Deviation 1.13	2.8 repeat treatment cycles Standard Deviation 0.97	1.6 repeat treatment cycles Standard Deviation 0.80	1.9 repeat treatment cycles Standard Deviation 0.97

SECONDARY outcome

Timeframe: Baseline, Day 15 in Study Period 1

Population: The Safety Set was defined as all participants who received SAGE-217. Overall number analyzed is the number of participants with data available for analysis at a specified timepoint.

The 17-item HAM-D scale was used for measuring severity of depression. The 17-item HAM-D comprises individual ratings related to the following symptoms: depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, insomnia (early, middle, late), work and activities, retardation (slowness of thought and speech; impaired ability to concentrate; decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms (gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and insight. Each item is scored in a range of 0 to 2 or 0 to 4. The total score ranges from 0 to 52 with higher scores indicating a greater degree of depression. A negative change from baseline indicates improvement. A study period is a treatment cycle (treatment period+14-day follow-up) plus the observational period (until next treatment cycle or end of study, whichever is earlier) immediately following it.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=465 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=607 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=80 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Part A: Change From Baseline (CFB) in the HAMD-17 Total Score at Day 15 in Study Period 1	-15.3 score on a scale Standard Deviation 6.58	-14.6 score on a scale Standard Deviation 7.09	-20.1 score on a scale Standard Deviation 4.61	—	—

SECONDARY outcome

Timeframe: Baseline, Day 15 of treatment cycles 2, 3, 4, and 5

Population: FAS included all participants in the Safety Set who had HAMD-17 response at Treatment Cycle 1 Day 15 and a discontinuation from study date, if it existed, was after the end of Treatment Cycle 1. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at a specific timepoint.

The 17-item HAM-D scale was used for measuring severity of depression. The 17-item HAM-D comprises individual ratings related to the following symptoms: depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, insomnia (early, middle, late), work and activities, retardation (slowness of thought and speech; impaired ability to concentrate; decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms (gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and insight. Each item is scored in a range of 0 to 2 or 0 to 4. The total score ranges from 0 to 52 with higher scores indicating a greater degree of depression. A negative change from baseline indicates improvement. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=150 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=188 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=78 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Part A: Change From Baseline (CFB) in the HAMD-17 Total Score at Day 15 of Each Treatment Cycle Treatment cycle 2: CFB at Day 15	-13.3 score on a scale Standard Deviation 6.36	-12.3 score on a scale Standard Deviation 6.49	-15.4 score on a scale Standard Deviation 7.21	—	—
Part A: Change From Baseline (CFB) in the HAMD-17 Total Score at Day 15 of Each Treatment Cycle Treatment cycle 3: CFB at Day 15	-12.2 score on a scale Standard Deviation 8.06	-12.5 score on a scale Standard Deviation 6.26	-15.1 score on a scale Standard Deviation 6.24	—	—
Part A: Change From Baseline (CFB) in the HAMD-17 Total Score at Day 15 of Each Treatment Cycle Treatment cycle 4: CFB at Day 15	-11.1 score on a scale Standard Deviation 6.42	-11.7 score on a scale Standard Deviation 7.52	-15.8 score on a scale Standard Deviation 7.12	—	—
Part A: Change From Baseline (CFB) in the HAMD-17 Total Score at Day 15 of Each Treatment Cycle Treatment cycle 5: CFB at Day 15	-9.0 score on a scale Standard Deviation 7.17	-11.6 score on a scale Standard Deviation 6.65	-17.5 score on a scale Standard Deviation 8.47	—	—

SECONDARY outcome

Timeframe: Baseline, Day 15 of Study Period 1, 2, 3, 4, and 5

Population: FAS included all participants who signed the ICF for 217-MDD-303B and had at least 1 dosing of SAGE-217 within 217-MDD-303B and had at least 1 HAMD-17 total score available after the first dose of SAGE-217 within 217-MDD-303B. Overall number of participants analyzed is participants in FAS who were dosed in the specific period. Data for this outcome measure was collected and analyzed as per study period.

The 17-item HAM-D scale was used to measure the severity of depression. The 17-item HAM-D comprises individual ratings related to the following symptoms: depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, insomnia (early, middle, late), work and activities, retardation (slowness of thought and speech; impaired ability to concentrate; decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms (gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and insight. Each item is scored in a range of 0 to 2 or 0 to 4. The total score ranges from 0 to 52 with higher scores indicating a greater degree of depression. A negative change from baseline indicates improvement. Study period is defined as treatment cycle (28 days) followed by immediate observation period (maximum 46 weeks), until the first dose of the subsequent treatment cycle.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=52 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=85 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=42 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT n=20 Participants Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT n=5 Participants Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Part B: Change From Baseline in the HAMD-17 Total Score at Day 15 of Each Treatment (Initial and/or Repeat Treatment) Cycle	-10.1 score on a scale Standard Deviation 6.43	-10.7 score on a scale Standard Deviation 6.49	-9.6 score on a scale Standard Deviation 7.53	-9.7 score on a scale Standard Deviation 7.60	-10.8 score on a scale Standard Deviation 9.26

SECONDARY outcome

Timeframe: Day 15 of treatment cycle 1

Population: The Safety Set was defined as all participants who received SAGE-217. Overall number analyzed is the number of participants with data available for analysis at a specified timepoint.

HAM-D response was defined as a ≥50% reduction in HAM-D score from baseline, at the end of each 14-day treatment period. The 17-item HAM-D scale was used for measuring severity of depression. The HAM-D comprised 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 were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score can range from 0 to 52, and higher scores indicated a greater degree of depression. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. Percentage are rounded off.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=513 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=645 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=80 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Part A: Percentage of Participants Who Achieved HAM-D Response During Treatment Cycle 1	67.3 percentage of participants	65.9 percentage of participants	100 percentage of participants	—	—

SECONDARY outcome

Timeframe: Day 15 of Study Period 2, 3, 4, and 5

Population: FAS included all participants in the Safety Set who had HAMD-17 response at Treatment Cycle 1 Day 15 and the discontinuation from study date, if it existed, was after the end of Treatment Cycle 1. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at given timepoint.

HAM-D response was defined as a ≥50% reduction in HAM-D score from baseline, at the end of each 14-day treatment period. The 17-item HAM-D scale was used for measuring severity of depression. The HAM-D comprised 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 were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score can range from 0 to 52, and higher scores indicated a greater degree of depression. A study period is a treatment cycle (treatment period+14-day follow-up) plus the observational period (until next treatment cycle or end of study, whichever is earlier) immediately following it. Percentage are rounded off.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=150 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=188 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=78 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Part A: Percentage of Participants Who Achieved HAM-D Response During Each Study Period Study Period 3: Day 15	58.0 percentage of participants	59.3 percentage of participants	68.6 percentage of participants	—	—
Part A: Percentage of Participants Who Achieved HAM-D Response During Each Study Period Study Period 4: Day 15	38.2 percentage of participants	55.0 percentage of participants	75.5 percentage of participants	—	—
Part A: Percentage of Participants Who Achieved HAM-D Response During Each Study Period Study Period 2: Day 15	65.3 percentage of participants	62.8 percentage of participants	67.9 percentage of participants	—	—
Part A: Percentage of Participants Who Achieved HAM-D Response During Each Study Period Study Period 5: Day 15	25.0 percentage of participants	58.8 percentage of participants	81.8 percentage of participants	—	—

SECONDARY outcome

Timeframe: Day 15 of Study Period 1, 2, 3, 4, and 5

HAM-D response was defined as a ≥50% reduction in HAM-D score from baseline, at the end of each 14-day treatment period. The 17-item HAM-D scale was used for measuring severity of depression. The HAM-D comprised 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 were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score can range from 0 to 52, and higher scores indicated a greater degree of depression. A study period is defined as treatment cycle (28 days) followed by immediate observation period (maximum 46 weeks), until the first dose of the subsequent treatment cycle. Percentage are rounded off.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=52 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=85 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=42 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT n=20 Participants Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT n=5 Participants Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Part B: Percentage of Participants Who Achieved HAM-D Response	46.2 percentage of participants	47.1 percentage of participants	38.1 percentage of participants	30.0 percentage of participants	60.0 percentage of participants

SECONDARY outcome

Timeframe: Day 15 of treatment cycle 1

Population: The Safety Set was defined as all participants who received SAGE-217. Overall number analyzed is the number of participants with data available for analysis at a specified timepoint.

Remission was defined as having a HAM-D total score of ≤7. The 17-item HAM-D scale was used for measuring severity of depression. The HAM-D comprised 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 were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score can range from 0 to 52, and higher scores indicated a greater degree of depression. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. Percentage are rounded off.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=465 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=607 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=80 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Part A: Percentage of Participants Who Achieved HAM-D Remission During Treatment Cycle 1	40.9 percentage of participants	40.2 percentage of participants	40.0 percentage of participants	—	—

SECONDARY outcome

Timeframe: Day 15 of Study Periods 2, 3, 4, and 5

Remission was defined as having a HAM-D total score of ≤7. The 17-item HAM-D scale was used for measuring severity of depression. The HAM-D comprised 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 were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score can range from 0 to 52, and higher scores indicated a greater degree of depression. A study period is a treatment cycle (treatment period+14-day follow-up) plus the observational period (until next treatment cycle or end of study, whichever is earlier) immediately following it. Percentage are rounded off.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=150 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=188 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=78 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Part A: Percentage of Participants Who Achieved HAM-D Remission During Each Study Period Study Period 2: Day 15	38.7 percentage of participants	31.9 percentage of participants	37.2 percentage of participants	—	—
Part A: Percentage of Participants Who Achieved HAM-D Remission During Each Study Period Study Period 3: Day 15	34.8 percentage of participants	29.6 percentage of participants	32.9 percentage of participants	—	—
Part A: Percentage of Participants Who Achieved HAM-D Remission During Each Study Period Study Period 4: Day 15	23.5 percentage of participants	32.5 percentage of participants	43.4 percentage of participants	—	—
Part A: Percentage of Participants Who Achieved HAM-D Remission During Each Study Period Study Period 5: Day 15	16.7 percentage of participants	29.4 percentage of participants	63.6 percentage of participants	—	—

SECONDARY outcome

Timeframe: Day 15 of Study Period 1, 2, 3, 4, and 5

Remission was defined as having a HAM-D total score of ≤7. The 17-item HAM-D scale was used for measuring severity of depression. The HAM-D comprised 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 were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score can range from 0 to 52, and higher scores indicated a greater degree of depression. A Study Period is defined as Treatment Cycle (28 days) followed by the immediate observational period (maximum 46 weeks), until the first dose of the subsequent treatment cycle. Percentage are rounded off.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=52 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=85 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=42 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT n=20 Participants Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT n=5 Participants Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Part B: Percentage of Participants Who Achieved HAM-D Remission	19.2 percentage of participants	29.4 percentage of participants	26.2 percentage of participants	20.0 percentage of participants	40.0 percentage of participants

SECONDARY outcome

Timeframe: Day 15 of treatment cycle 1

Population: The Safety Set was defined as all participants who received SAGE-217. Overall number analyzed is the number of participants with data available for analysis at a specified timepoint.

The CGI scale consists of 3 items. Only the first 2 items are being used in this study. The CGI-I employed a 7-point Likert scale to measure the overall improvement in the participant's condition posttreatment. The Investigator rated the participant's total improvement compared to baseline, whether or not it was due entirely to drug treatment. Response choices included: 0=not assessed, 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse. The CGI-I is only rated at posttreatment assessments. CGI-I response was defined as having a CGI-I score of "very much improved" or "much improved." Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. Percentage are rounded off.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=464 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=608 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=80 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Part A: Percentage of Participants Who Achieved Clinical Global Impression - Improvement (CGI-I) Response During Treatment Cycle 1	78.9 percentage of participants	75.0 percentage of participants	96.3 percentage of participants	—	—

SECONDARY outcome

Timeframe: Day 15 of Study Periods 2, 3, 4, and 5

The CGI scale consists of 3 items. Only the first 2 items are being used in this study. The CGI-I employed a 7-point Likert scale to measure the overall improvement in the participant's condition posttreatment. The Investigator rated the participant's total improvement compared to baseline, whether or not it was due entirely to drug treatment. Response choices included: 0=not assessed, 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse. The CGI-I is only rated at posttreatment assessments. CGI-I response was defined as having a CGI-I score of "very much improved" or "much improved." A study period is a treatment cycle (treatment period+14-day follow-up) plus the observational period (until next treatment cycle or end of study, whichever is earlier) immediately following it. Percentage are rounded off.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=150 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=188 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=78 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Part A: Percentage of Participants Who Achieved CGI-I Response During Each Study Period Study Period 2: Day 15	76.7 percentage of participants	75.0 percentage of participants	79.5 percentage of participants	—	—
Part A: Percentage of Participants Who Achieved CGI-I Response During Each Study Period Study Period 3: Day 15	65.2 percentage of participants	73.2 percentage of participants	80.9 percentage of participants	—	—
Part A: Percentage of Participants Who Achieved CGI-I Response During Each Study Period Study Period 4: Day 15	52.9 percentage of participants	60.0 percentage of participants	84.9 percentage of participants	—	—
Part A: Percentage of Participants Who Achieved CGI-I Response During Each Study Period Study Period 5: Day 15	33.3 percentage of participants	68.8 percentage of participants	90.9 percentage of participants	—	—

SECONDARY outcome

Timeframe: Day 15 of Study Period 1, 2, 3, 4, and 5

The CGI scale consists of 3 items. Only the first 2 items are being used in this study. The CGI-I employed a 7-point Likert scale to measure the overall improvement in the participant's condition posttreatment. The Investigator rated the participant's total improvement compared to baseline, whether or not it was due entirely to drug treatment. Response choices included: 0=not assessed, 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse. The CGI-I is only rated at posttreatment assessments. CGI-I response was defined as having a CGI-I score of "very much improved" or "much improved." A Study Period is defined as Treatment Cycle (28 days) followed by the immediate observational period (maximum 46 weeks), until the first dose of the subsequent treatment cycle. Percentage are rounded off.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=52 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=85 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=42 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT n=20 Participants Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT n=5 Participants Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Part B: Percentage of Participants Who Achieved CGI-I Response	53.8 percentage of participants	63.5 percentage of participants	64.3 percentage of participants	55.0 percentage of participants	60.0 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Day 15 of treatment cycle 1

Population: The Safety Set was defined as all participants who received SAGE-217. Overall number analyzed is the number of participants with data available for analysis at a specified timepoint.

The CGI-S uses a 7-point Likert scale to rate the severity of the participant's mental illness at the time of assessment, relative to the clinician's past experience with participants who had the same diagnosis. Considering total clinical experience, a participant was assessed on severity of mental illness at the time of rating as 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; and 7=extremely ill. A higher score indicated extreme illness. A negative change from baseline indicated improvement. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=464 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=608 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=80 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Part A: Change From Baseline in Clinical Global Impression - Severity (CGI-S) Score During Treatment Cycle 1	-2.3 score on a scale Standard Deviation 1.22	-2.1 score on a scale Standard Deviation 1.25	-2.4 score on a scale Standard Deviation 1.01	—	—

SECONDARY outcome

Timeframe: Baseline, Day 15 of treatment cycles 2, 3, 4, and 5

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=150 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=188 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=78 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Part A: Change From Baseline in CGI-S Score During Each Treatment Cycle Treatment Cycle 2: CFB at Day 15	-2.0 score on a scale Standard Deviation 1.15	-1.9 score on a scale Standard Deviation 1.23	-2.2 score on a scale Standard Deviation 1.43	—	—
Part A: Change From Baseline in CGI-S Score During Each Treatment Cycle Treatment Cycle 3: CFB at Day 15	-1.8 score on a scale Standard Deviation 1.32	-1.8 score on a scale Standard Deviation 1.21	-2.1 score on a scale Standard Deviation 1.35	—	—
Part A: Change From Baseline in CGI-S Score During Each Treatment Cycle Treatment Cycle 4: CFB at Day 15	-1.8 score on a scale Standard Deviation 1.16	-1.7 score on a scale Standard Deviation 1.33	-2.4 score on a scale Standard Deviation 1.64	—	—
Part A: Change From Baseline in CGI-S Score During Each Treatment Cycle Treatment Cycle 5: CFB at Day 15	-1.2 score on a scale Standard Deviation 1.27	-1.9 score on a scale Standard Deviation 1.09	-2.7 score on a scale Standard Deviation 1.83	—	—

SECONDARY outcome

Timeframe: Baseline Day 15 of Study Period 1, 2, 3, 4, and 5

The CGI-S uses a 7-point Likert scale to rate the severity of the participant's mental illness at the time of assessment, relative to the clinician's past experience with participants who had the same diagnosis. Considering total clinical experience, a participant was assessed on severity of mental illness at the time of rating as 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; and 7=extremely ill. A higher score indicated extreme illness. A negative change from baseline indicated improvement. A Study Period is defined as Treatment Cycle (28 days) followed by the immediate observational period (maximum 46 weeks), until the first dose of the subsequent treatment cycle.

Outcome measures

Outcome measures
Measure	Part A: Sage-217 High-dose Cohort n=52 Participants Participants received SAGE-217, 50 milligrams (mg), orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in Hamilton Rating Scale for Depression \[HAMD\]-17 total score by Day 15) entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item Patient Health Questionnaire (PHQ-9); participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Low-dose Cohort n=85 Participants Participants received SAGE-217, 30 mg, orally, once daily from Day 1 through 14 followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part A: Sage-217 Dose-switch Cohort n=42 Participants Participants received SAGE-217, 30 mg, orally, once daily in treatment Cycle 1 Day 1 through Day 14 followed by 14-day follow-up period and switched to 50 mg orally, once daily in a subsequent treatment cycle. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle. After the treatment period participants who had a response (a ≥50% reduction from baseline in HAMD-17 total score by Day 15) or remission entered a 48-week observational period. During the 48-week observational period, HAMD-17 responders returned to the site every 8 weeks for clinical assessments. Participants were assessed remotely every 14 days via the participant reported 9-item PHQ-9; participants with PHQ-9 score ≥10 returned to the site to be assessed by the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of the IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period.	Part B: SAGE-217 + ADT n=20 Participants Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.	Part B: SAGE-217 + ADT n=5 Participants Participants in the parent study (217-MDD-305) received SAGE-217 capsules, orally, once daily along with an assigned ADT. Participants who were eligible to enter the current study from parent study 217-MDD-305 entered the 46-week observational period. Participants were followed with remote assessment of the participant-reported PHQ-9 every 2 weeks; if the PHQ-9 score was ≥10, the participant returned to the site approximately 1 week later and was assessed for the clinician administered HAMD-17. If the HAMD-17 total score was ≥20 and 56 days had elapsed since the last dose of IP, the participant began a 14-day SAGE-217 treatment period, which was followed by a 14-day follow-up period. Participants received SAGE-217 50 mg or 40 mg at the discretion of the investigator, orally, once daily for 14 days followed by 14-day follow-up period. Each 14-day treatment period plus corresponding 14-day follow-up period was considered a treatment cycle.
Part B: Change From Baseline in CGI-S Score	-1.5 score on a scale Standard Deviation 1.18	-1.8 score on a scale Standard Deviation 1.15	-1.7 score on a scale Standard Deviation 1.26	-1.4 score on a scale Standard Deviation 1.39	-1.4 score on a scale Standard Deviation 1.52

Adverse Events

Part A: Sage-217 High-dose Cohort

Serious events: 18 serious events

Other events: 371 other events

Deaths: 0 deaths

Part A: Sage-217 Low-dose Cohort

Serious events: 19 serious events

Other events: 435 other events

Deaths: 1 deaths

Part A: Sage-217 Dose-switch Cohort

Serious events: 1 serious events

Other events: 57 other events

Deaths: 0 deaths

Part B: Sage-217 All Participants

Serious events: 4 serious events

Other events: 87 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Monitor

Sage Therapeutics

Phone: (617) 299-8380

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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).
Publication restrictions are in place

Restriction type: OTHER